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Dr. David Z. Rose is an Associate Professor in the Department of Neurology at USF Health, the Neurology Medical Director, a Neuro-Icu Member, and part of the Critical Care Steering Committee. In this video Dr. Rose discusses the AREST trial known as Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation.

Link to Abstract-
https://clinicaltrials.gov/ct2/show/NCT02283294

Abstract-
The goal of this study is to see if starting Apixaban earlier than standard of treatment reduces the risk of second stroke in adults with atrial fibrillation.

This is an open label, randomized, active control, parallel-group pilot trial to see if starting APIXABAN at days 0-3 (TIA), days 3-5 (small stroke), and days 7-9 (medium stroke) reduces fatal and/or recurrent stroke/TIA in 120 people who have had a recent (within 48 hours of symptoms) TIA or small to medium ischemic stroke. The subjects will be randomly assigned to one of two treatment arms in a 1:1 ratio (apixaban or warfarin). From screening to monthly follow-up visits, subjects will be observed for a total of 180 days.

The following are the primary outcome measures:

Number of people who had a fatal stroke, recurrent ischaemic stroke, or TIA as a composite endpoint [180-day time frame]

Measures of Secondary Outcomes:

The number of people who had an intracranial hemorrhage as determined by MRI/CT [duration: 180 days]

Dr. Grapsa works at the Guys and St Thomas NHS Trust as a consultant cardiologist. Dr. Grapsa is an associate professor at King's College in London and is part of the UK's premier structural valve disease group. She also serves as the editor-in-chief of JACC Case Reports, the chair of the European Society of Cardiology's Women Task Force in Imaging, and the secretary of the ESC's Valvular Heart Disease Council.

In this podcast Dr. Grapsa discusses Staphylococcus Aureus Infective Endocarditis.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccas.2021.10.002

Abstract-
A 19-year-old female patient presented with Staphylococcus aureus infective endocarditis, with suspected subdural brain hemorrhage, disseminated intravascular coagulopathy, and septic renal as well as spleen infarcts. The patient had extensive vegetations on the mitral and tricuspid valves and underwent urgent mitral and tricuspid repair. This paper discusses the clinical case and current evidence regarding the management and treatment of Staphylococcus aureus endocarditis.
Take-Home Messages
• Echocardiography should be administered expeditiously as the optimal modality for the initial work-up of suspected IE and in the management of most patients with IE. TEE improves sensitivity and TTE improves specificity in detecting complications of IE, so both tests are necessary. TEE is superior for detecting small vegetations.
• CTA is highly sensitive for identifying complications of IE (eg, abscess or aneurysm) and complex IE (eg, PVE), in patients with suboptimal echo imaging and surgical planning in IE.
• 18F-FDG PET-CT: Although not sufficiently sensitive for diagnosing NVE, molecular imaging (mainly with 18F-FDG PET-CT) is an important advance in PVE and CIED-IE as well as in detecting systemic infective foci/septic emboli that often lead to changes in patient management. Use of 18F-FDG PET-CT influences outcomes and is recommended in European IE guidelines but not in the AHA statement.
• WBC scintigraphy is a specific whole-body test to locate infection in prosthetic valve and CIED IE but, currently, there is no clear recommendation in guidelines. It is quite useful in early PVE (where PET-CT, when done <3 months postsurgery, may pick up nonspecific sterile inflammation) and can best identify metastatic foci of infection.
• Surgery: Repair is the surgical method of choice when applicable. Main targets of surgery are the complete removal of infective tissue and reconstruction of affected tissue. In complex IE cases, bioprosthetic valves may be superior to metallic in terms of anticoagulation and have less bleeding risk.
• Antibiotic prophylaxis: There is harmony in the French, AHA, and ESC guidelines to limit prophylaxis to patients with the highest risk of a poor outcome with IE, including prosthetic heart valves, valve repair that includes annuloplasty rings or clips, left ventricular assist devices, complex congenital heart defect either repaired or unrepaired, and orthotopic transplanted hearts with valvulopathy. The United Kingdom’s NICE took the approach of recommending ABx prophylaxis for no group on a routine basis.
Introduction
JACC Patient Pathways is a new initiative from the JACC family to reflect the multidisciplinary collaboration that contributes to optimal patient care and decision-making. The Pathways will highlight the evidence-based discussions that are necessary to solve a clinical problem through an actual patient’s journey.

As clinicians are faced with challenging clinical cases, it is important to understand how current knowledge based on clinical guidelines and the published data can inform decisions. JACC Patient Pathways is a multiparametric approach to this patient journey that provides an interactive illustration, a paper that integrates the clinical case with current evidence, and a video discussion between expert clinicians.

This paper, which the authors are requesting to be copublished with JACC and JACC: Case Reports, begins with the clinical case and continues with mini reviews on the basic considerations of the case. The scope of the paper is not to provide an extensive review of the topic, but rather to act as guidance for clinicians who may encounter similar cases.

Case Presentation
A 19-year-old female patient presented to the emergency department with 5 days of vomiting, fever, intermittent abdominal pain, myalgia, and weakness. She arrived in the United Kingdom from Brazil 6 weeks ago during the coronavirus disease-2019 (COVID-19) pandemic. On presentation, the patient was in extremis: she was hypoxic, acidotic, and hypotensive with a blood pressure of 86/49 mm Hg, a heart rate of 140-150 beats/min, and a respiratory rate of 22 breaths/min. Electrocardiography (ECG) demonstrated sinus tachycardia (Figure 1). She was subsequently referred for extracorporeal membrane oxygenation (ECMO). Her chest x-ray (Figure 2) demonstrated opacified lungs. It was determined that she required a full-body computed tomography (CT) scan on her way to the intensive care unit. The patient was septic and had acute renal injury. She also tested negative for COVID-19, HIV, and hepatitis. Blood cultures proved to be positive for Staphylococcus aureus (Figure 3).

Shortly after undergoing CT scanning, she received a transthoracic echocardiogram (TTE) (Videos 1, 2, 3, 4, 5, and 6), which demonstrated extensive vegetations on the mitral valve and right ventricular wall and good biventricular systolic functioning. She was therefore diagnosed with Staphylococcus aureus endocarditis of the mitral valve and right heart chambers.

After a multidisciplinary meeting with the surgeons, critical care clinicians, hematology, infectious disease, and cardiology, it was determined that the patient required urgent surgery within 24 hours of admission. She underwent mitral and tricuspid valve repair (Figure 6) and experienced mild residual mitral regurgitation immediately postoperatively (Videos 7, 8, 9, 10, 11, and 12). The ECGs were performed during the same day, with TTE taking place in the morning followed by the intraoperative transesophageal echocardiogram (TEE) in the afternoon.

Dr. Grapsa works at the Guys and St Thomas NHS Trust as a consultant cardiologist. Dr. Grapsa is an associate professor at King's College in London and is part of the UK's premier structural valve disease group. She also serves as the editor-in-chief of JACC Case Reports, the chair of the European Society of Cardiology's Women Task Force in Imaging, and the secretary of the ESC's Valvular Heart Disease Council.

In this video Dr. Grapsa discusses Staphylococcus Aureus Infective Endocarditis.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccas.2021.10.002

Abstract-
A 19-year-old female patient presented with Staphylococcus aureus infective endocarditis, with suspected subdural brain hemorrhage, disseminated intravascular coagulopathy, and septic renal as well as spleen infarcts. The patient had extensive vegetations on the mitral and tricuspid valves and underwent urgent mitral and tricuspid repair. This paper discusses the clinical case and current evidence regarding the management and treatment of Staphylococcus aureus endocarditis.
Take-Home Messages
• Echocardiography should be administered expeditiously as the optimal modality for the initial work-up of suspected IE and in the management of most patients with IE. TEE improves sensitivity and TTE improves specificity in detecting complications of IE, so both tests are necessary. TEE is superior for detecting small vegetations.
• CTA is highly sensitive for identifying complications of IE (eg, abscess or aneurysm) and complex IE (eg, PVE), in patients with suboptimal echo imaging and surgical planning in IE.
• 18F-FDG PET-CT: Although not sufficiently sensitive for diagnosing NVE, molecular imaging (mainly with 18F-FDG PET-CT) is an important advance in PVE and CIED-IE as well as in detecting systemic infective foci/septic emboli that often lead to changes in patient management. Use of 18F-FDG PET-CT influences outcomes and is recommended in European IE guidelines but not in the AHA statement.
• WBC scintigraphy is a specific whole-body test to locate infection in prosthetic valve and CIED IE but, currently, there is no clear recommendation in guidelines. It is quite useful in early PVE (where PET-CT, when done <3 months postsurgery, may pick up nonspecific sterile inflammation) and can best identify metastatic foci of infection.
• Surgery: Repair is the surgical method of choice when applicable. Main targets of surgery are the complete removal of infective tissue and reconstruction of affected tissue. In complex IE cases, bioprosthetic valves may be superior to metallic in terms of anticoagulation and have less bleeding risk.
• Antibiotic prophylaxis: There is harmony in the French, AHA, and ESC guidelines to limit prophylaxis to patients with the highest risk of a poor outcome with IE, including prosthetic heart valves, valve repair that includes annuloplasty rings or clips, left ventricular assist devices, complex congenital heart defect either repaired or unrepaired, and orthotopic transplanted hearts with valvulopathy. The United Kingdom’s NICE took the approach of recommending ABx prophylaxis for no group on a routine basis.
Introduction
JACC Patient Pathways is a new initiative from the JACC family to reflect the multidisciplinary collaboration that contributes to optimal patient care and decision-making. The Pathways will highlight the evidence-based discussions that are necessary to solve a clinical problem through an actual patient’s journey.

As clinicians are faced with challenging clinical cases, it is important to understand how current knowledge based on clinical guidelines and the published data can inform decisions. JACC Patient Pathways is a multiparametric approach to this patient journey that provides an interactive illustration, a paper that integrates the clinical case with current evidence, and a video discussion between expert clinicians.

This paper, which the authors are requesting to be copublished with JACC and JACC: Case Reports, begins with the clinical case and continues with mini reviews on the basic considerations of the case. The scope of the paper is not to provide an extensive review of the topic, but rather to act as guidance for clinicians who may encounter similar cases.

Case Presentation
A 19-year-old female patient presented to the emergency department with 5 days of vomiting, fever, intermittent abdominal pain, myalgia, and weakness. She arrived in the United Kingdom from Brazil 6 weeks ago during the coronavirus disease-2019 (COVID-19) pandemic. On presentation, the patient was in extremis: she was hypoxic, acidotic, and hypotensive with a blood pressure of 86/49 mm Hg, a heart rate of 140-150 beats/min, and a respiratory rate of 22 breaths/min. Electrocardiography (ECG) demonstrated sinus tachycardia (Figure 1). She was subsequently referred for extracorporeal membrane oxygenation (ECMO). Her chest x-ray (Figure 2) demonstrated opacified lungs. It was determined that she required a full-body computed tomography (CT) scan on her way to the intensive care unit. The patient was septic and had acute renal injury. She also tested negative for COVID-19, HIV, and hepatitis. Blood cultures proved to be positive for Staphylococcus aureus (Figure 3).

Shortly after undergoing CT scanning, she received a transthoracic echocardiogram (TTE) (Videos 1, 2, 3, 4, 5, and 6), which demonstrated extensive vegetations on the mitral valve and right ventricular wall and good biventricular systolic functioning. She was therefore diagnosed with Staphylococcus aureus endocarditis of the mitral valve and right heart chambers.

After a multidisciplinary meeting with the surgeons, critical care clinicians, hematology, infectious disease, and cardiology, it was determined that the patient required urgent surgery within 24 hours of admission. She underwent mitral and tricuspid valve repair (Figure 6) and experienced mild residual mitral regurgitation immediately postoperatively (Videos 7, 8, 9, 10, 11, and 12). The ECGs were performed during the same day, with TTE taking place in the morning followed by the intraoperative transesophageal echocardiogram (TEE) in the afternoon.

In this Podcast, Professor Leontien Kremer, MD of the Princess Máxima Center, along with PHd candidates Dr.Esmee C. de Baat of the Princess Máxima Center, Dr. Jan M. Leeink of the Amsterdam University Medical Centers, and Dr. Remy Merkx of the Radboud University Medical Center discuss Cardiac Disease in Childhood Cancer Survivors and Risk Prediction, Prevention, and Surveillance.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2020.08.006

Abstract-
Cardiac disease is a key issue among the expanding population of pediatric cancer survivors. Cardiotoxicity caused by anthracyclines and chest irradiation is still a topic of discussion in today's medical world. Evidence on traditional cardiovascular risk factors in childhood cancer survivors is growing, and mitoxantrone has emerged as an important treatment-related risk factor. The goal of developing international monitoring recommendations is to detect and manage heart illnesses early and prevent symptomatic disease. Risk prediction algorithms are gaining popularity as a way to personalize prevention and surveillance. This State-of-the-Art Review compiles findings from a comprehensive PubMed search on cardiac problems following children cancer treatment. The prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac disorders in pediatric cancer survivors are discussed here.
Highlights

• Anthracyclines, mitoxantrone, and the dose of chest-directed radiation are the key risk factors for heart illness in childhood cancer survivors.

• Using primary prevention techniques, the risk of anthracycline-induced cardiomyopathy may be reduced.

• Traditional cardiovascular risk factors are more prevalent in pediatric cancer survivors; screening and early care are critical to reducing risk.

• Multivariable risk prediction models could aid in the personalization of preventative and surveillance plans.

Introduction

Children's cancer survival rates have grown dramatically in recent decades, with 5-year survival rates now above 80%. (1). Long-term health repercussions in the expanding population of childhood cancer survivors (CCS) remain, nevertheless, a major source of concern (2). Cardiac disease caused by anthracyclines, mitoxantrone, and/or chest-directed radiotherapy (chest RT) can manifest as myocardial dysfunction and heart failure, but it can also manifest as valvular disease, coronary artery disease, arrhythmias, and pericardial disease, depending on the specific cardiotoxic agent (3).


We focus on long-term cardiac problems after children cancer therapy in this State-of-the-Art Review. In this population, we cover the prevalence, risk factors, prevention, prediction, and surveillance of heart illness (Central Illustration). We conducted a systematic search of PubMed for articles describing cardiac side effects in children receiving cardiotoxic cancer therapies. We restricted our search to full-text English-language papers published during the last ten years. We chose publications having a research cohort in which more than half of the participants had been treated for pediatric cancer before the age of 21. We looked for studies with a minimum of 500 CCS for studies describing the prevalence or cumulative incidence of heart failure, and a minimum of 100 CCS for the other outcomes. Previous Cochrane searches (4–6) turned up studies on primary preventive measures. 74 studies were selected to be described in this review based on these criteria (Figure 1). Supplementary Table 1 contains the whole search strategy.

In this video, Professor Leontien Kremer, MD of the Princess Máxima Center, along with PHd candidates Dr.Esmee C. de Baat of the Princess Máxima Center, Dr. Jan M. Leeink of the Amsterdam University Medical Centers, and Dr. Remy Merkx of the Radboud University Medical Center discuss Cardiac Disease in Childhood Cancer Survivors and Risk Prediction, Prevention, and Surveillance.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2020.08.006

Abstract-
Cardiac disease is a key issue among the expanding population of pediatric cancer survivors. Cardiotoxicity caused by anthracyclines and chest irradiation is still a topic of discussion in today's medical world. Evidence on traditional cardiovascular risk factors in childhood cancer survivors is growing, and mitoxantrone has emerged as an important treatment-related risk factor. The goal of developing international monitoring recommendations is to detect and manage heart illnesses early and prevent symptomatic disease. Risk prediction algorithms are gaining popularity as a way to personalize prevention and surveillance. This State-of-the-Art Review compiles findings from a comprehensive PubMed search on cardiac problems following children cancer treatment. The prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac disorders in pediatric cancer survivors are discussed here.
Highlights

• Anthracyclines, mitoxantrone, and the dose of chest-directed radiation are the key risk factors for heart illness in childhood cancer survivors.

• Using primary prevention techniques, the risk of anthracycline-induced cardiomyopathy may be reduced.

• Traditional cardiovascular risk factors are more prevalent in pediatric cancer survivors; screening and early care are critical to reducing risk.

• Multivariable risk prediction models could aid in the personalization of preventative and surveillance plans.

Introduction

Children's cancer survival rates have grown dramatically in recent decades, with 5-year survival rates now above 80%. (1). Long-term health repercussions in the expanding population of childhood cancer survivors (CCS) remain, nevertheless, a major source of concern (2). Cardiac disease caused by anthracyclines, mitoxantrone, and/or chest-directed radiotherapy (chest RT) can manifest as myocardial dysfunction and heart failure, but it can also manifest as valvular disease, coronary artery disease, arrhythmias, and pericardial disease, depending on the specific cardiotoxic agent (3).


We focus on long-term cardiac problems after children cancer therapy in this State-of-the-Art Review. In this population, we cover the prevalence, risk factors, prevention, prediction, and surveillance of heart illness (Central Illustration). We conducted a systematic search of PubMed for articles describing cardiac side effects in children receiving cardiotoxic cancer therapies. We restricted our search to full-text English-language papers published during the last ten years. We chose publications having a research cohort in which more than half of the participants had been treated for pediatric cancer before the age of 21. We looked for studies with a minimum of 500 CCS for studies describing the prevalence or cumulative incidence of heart failure, and a minimum of 100 CCS for the other outcomes. Previous Cochrane searches (4–6) turned up studies on primary preventive measures. 74 studies were selected to be described in this review based on these criteria (Figure 1). Supplementary Table 1 contains the whole search strategy.

Dr. Pavel Osmanick works at the University Hospital Kralovske Vinohrady, Third Faculty of Medicine, along with Charles University, in Prague, Czech Republic. In this video Dr. Osmanick discusses The Efficacy and Safety of Hybrid Ablations for Atrial Fibrillation.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacep.2021.04.013

Abstract
Objectives
This study sought to comprehensively determine the procedural safety and midterm efficacy of hybrid ablations.
Background
Hybrid ablation of atrial fibrillation (AF) (thoracoscopic ablation followed by catheter ablation) has been used for patients with nonparoxysmal AF; however, accurate data regarding efficacy and safety are still limited.
Methods
Patients with nonparoxysmal AF underwent thoracoscopic, off-pump ablation using the COBRA Fusion radiofrequency system (Estech) followed by a catheter ablation 3 months afterward. The safety of the procedure was assessed using sequential brain magnetic resonance and neuropsychological examinations at baseline (1 day before), postoperatively (2-4 days for brain magnetic resonance imaging or 1 month for neuropsychological examination), and at 9 months after the surgical procedure. Implantable loop recorders were used to detect arrhythmia recurrence. Arrhythmia-free survival (the primary efficacy endpoint) was defined as no episodes of AF or atrial tachycardia while off antiarrhythmic drugs, redo ablations or cardioversions.
Results
Fifty-nine patients (age: 62.5 ± 10.5 years) were enrolled, 37 (62.7%) were men, and the mean follow-up was 30.3 ± 10.8 months. Thoracoscopic ablation was successfully performed in 55 (93.2%) patients. On baseline magnetic resonance imaging, chronic ischemic brain lesions were present in 60.0% of patients. New ischemic lesions on postoperative magnetic resonance imaging were present in 44.4%. Major postoperative cognitive dysfunction was present in 27.0% and 17.6% at 1 and 9 months postoperatively, respectively. The probability of arrhythmia-free survival was 54.0% (95% CI: 41.3-66.8) at 1 year and 43.8% (95% CI: 30.7–57.0) at 2 years.
Conclusions
The thoracoscopic ablation is associated with a high risk of silent cerebral ischemia. The midterm efficacy of hybrid ablations is moderate.

Dr. Pavel Osmanick works at the University Hospital Kralovske Vinohrady, Third Faculty of Medicine, along with Charles University, in Prague, Czech Republic. In this video Dr. Osmanick discusses The Efficacy and Safety of Hybrid Ablations for Atrial Fibrillation.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacep.2021.04.013

Abstract
Objectives
This study sought to comprehensively determine the procedural safety and midterm efficacy of hybrid ablations.
Background
Hybrid ablation of atrial fibrillation (AF) (thoracoscopic ablation followed by catheter ablation) has been used for patients with nonparoxysmal AF; however, accurate data regarding efficacy and safety are still limited.
Methods
Patients with nonparoxysmal AF underwent thoracoscopic, off-pump ablation using the COBRA Fusion radiofrequency system (Estech) followed by a catheter ablation 3 months afterward. The safety of the procedure was assessed using sequential brain magnetic resonance and neuropsychological examinations at baseline (1 day before), postoperatively (2-4 days for brain magnetic resonance imaging or 1 month for neuropsychological examination), and at 9 months after the surgical procedure. Implantable loop recorders were used to detect arrhythmia recurrence. Arrhythmia-free survival (the primary efficacy endpoint) was defined as no episodes of AF or atrial tachycardia while off antiarrhythmic drugs, redo ablations or cardioversions.
Results
Fifty-nine patients (age: 62.5 ± 10.5 years) were enrolled, 37 (62.7%) were men, and the mean follow-up was 30.3 ± 10.8 months. Thoracoscopic ablation was successfully performed in 55 (93.2%) patients. On baseline magnetic resonance imaging, chronic ischemic brain lesions were present in 60.0% of patients. New ischemic lesions on postoperative magnetic resonance imaging were present in 44.4%. Major postoperative cognitive dysfunction was present in 27.0% and 17.6% at 1 and 9 months postoperatively, respectively. The probability of arrhythmia-free survival was 54.0% (95% CI: 41.3-66.8) at 1 year and 43.8% (95% CI: 30.7–57.0) at 2 years.
Conclusions
The thoracoscopic ablation is associated with a high risk of silent cerebral ischemia. The midterm efficacy of hybrid ablations is moderate.

Dr. Christine Albert, MD works in the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles, California. In This video Dr. Albert discusses Diabetes and the Risk of Sudden Death in Coronary Artery Disease Patients Without Severe Systolic Dysfunction.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacep.2021.05.014

Abstract
In patients with coronary artery disease (CAD) who do not qualify for implantable cardioverter-defibrillators, this study sought to determine the absolute and relative associations of diabetes mellitus (DM) and hemoglobin A1c (HbA1c) with sudden and/or arrhythmic death (SAD) versus other modes of death.

Background

Patients with CAD and diabetes are at an increased risk of SAD; however, given competing causes of death, it is unclear whether these patients would benefit from implantable cardioverter-defibrillators and/or whether HbA1c could help with SAD risk stratification.

Methods

Competing risk analyses were used to compare the absolute and relative risks of SAD versus non-SAD by DM status and HbA1c level in the PRE-DETERMINE study of 5,764 patients with CAD with left ventricular ejection fraction (LVEF) of >30% to 35 percent and to identify risk factors for SAD among 1,782 patients with DM.

Results

DM and HbA1c were significantly associated with SAD and non-SAD over a median follow-up of 6.8 years (P 0.05 for all comparisons); however, the cumulative incidence of non-SAD (19.2 percent; 95 percent CI: 17.3 percent -21.2 percent) in DM patients was nearly 4 times higher than SAD (4.8 percent; 95 percent CI: 3.8 percent -5.9 percent). Absolute risk followed a similar pattern across HbA1c groups. HbA1c was not connected with SAD in studies limited to diabetic patients, although decreased LVEF, atrial fibrillation, and ECG measures were all linked to a higher risk of SAD.

Conclusions

Patients with CAD and LVEF of >30% to 35% who had DM and/or increased HbA1c have a considerably higher absolute risk of dying from non-SAD than from SAD. Clinical risk factors, not HbA1c, were linked to the incidence of SAD in diabetic individuals. (NCT01114269; PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study)

Dr. Christine Albert, MD works in the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles, California. In This video Dr. Albert discusses Diabetes and the Risk of Sudden Death in Coronary Artery Disease Patients Without Severe Systolic Dysfunction.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacep.2021.05.014

Abstract
In patients with coronary artery disease (CAD) who do not qualify for implantable cardioverter-defibrillators, this study sought to determine the absolute and relative associations of diabetes mellitus (DM) and hemoglobin A1c (HbA1c) with sudden and/or arrhythmic death (SAD) versus other modes of death.

Background

Patients with CAD and diabetes are at an increased risk of SAD; however, given competing causes of death, it is unclear whether these patients would benefit from implantable cardioverter-defibrillators and/or whether HbA1c could help with SAD risk stratification.

Methods

Competing risk analyses were used to compare the absolute and relative risks of SAD versus non-SAD by DM status and HbA1c level in the PRE-DETERMINE study of 5,764 patients with CAD with left ventricular ejection fraction (LVEF) of >30% to 35 percent and to identify risk factors for SAD among 1,782 patients with DM.

Results

DM and HbA1c were significantly associated with SAD and non-SAD over a median follow-up of 6.8 years (P 0.05 for all comparisons); however, the cumulative incidence of non-SAD (19.2 percent; 95 percent CI: 17.3 percent -21.2 percent) in DM patients was nearly 4 times higher than SAD (4.8 percent; 95 percent CI: 3.8 percent -5.9 percent). Absolute risk followed a similar pattern across HbA1c groups. HbA1c was not connected with SAD in studies limited to diabetic patients, although decreased LVEF, atrial fibrillation, and ECG measures were all linked to a higher risk of SAD.

Conclusions

Patients with CAD and LVEF of >30% to 35% who had DM and/or increased HbA1c have a considerably higher absolute risk of dying from non-SAD than from SAD. Clinical risk factors, not HbA1c, were linked to the incidence of SAD in diabetic individuals. (NCT01114269; PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study)

Dr. Simon Parlow is part of the CAPITAL Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. In this video Dr. Parlow discusses an Unusual Case of Obstructive Shock.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccas.2021.10.017

Abstract-
Abstract
A 54-year-old guy was admitted to the hospital with severe obstructive shock. A right atrial tumor was discovered to be the source of severe right ventricular inflow blockage and inadequate cardiac output. To alleviate the obstruction, the patient was treated with an emergency balloon catheter intervention, which resulted in hemodynamic stabilization. A positive result for diffuse large B-cell lymphoma was later found on the pathology report. (Intermediate level of difficulty.)
Presentation History

A 54-year-old male with dyspnea, limb edema, stomach bloating, and exhaustion reported to a peripheral hospital with a 2-week history of symptoms. The patient had increased hypotension and drowsiness over the next 1 to 2 hours, necessitating intubation and the start of vasopressor therapy. He was then transported to our quaternary care cardiac intensive care unit at the University of Ottawa Heart Institute in Ottawa, Ontario, Canada, for additional evaluation and management.



Learning Outcomes

•

To be able to come up with a differential diagnosis for a patient who has obstructive shock.



•

To gain a better understanding of the function of hemodynamics in the treatment of obstructive shock caused by an intracardiac mass



He was severely hemodynamically unstable when he arrived. To keep his blood pressure at 75/58 mm Hg, he needed three vasopressors. He was bradycardic, with a sinus rhythm heart rate of 47 beats per minute. He was drugged and ventilated during his physical examination. With thready peripheral pulses and chilly extremities, he was mottled. His neck and face were reddish and swelled, and his veins were distended. On precordial auscultation, his heart sounds were hardly audible, with no murmurs or additional heart sounds detected. His lungs were both clean on auscultation. He had a somewhat enlarged abdomen but was not peritonitic. He'd had a Foley catheter put, but he hadn't peed in several hours. Despite ventilation with 100% inhaled proportion of inspired oxygen, he was hypoxemic, with an arterial Po2 of 75 mm Hg. With an arterial pH of 6.85 and a blood bicarbonate level of 4 mmol/L, his serum lactate level was 21.2 mmol/L.



Previous Medical Experience

During a visit to a peripheral emergency department two weeks before to his presentation, he was diagnosed with pericarditis and prescribed colchicine and ibuprofen. His previous medical history was basically unremarkable, save for cigarette smoking, and he had never taken any home remedies. He had no allergies or a history of illicit drug usage.



Differential Diagnosis is a term used to describe the process of distinguishing between two

The clinical examination and biochemical results of the patient are consistent with deep shock, as evidenced by hypotension and obvious signs of end-organ hypoperfusion (decreased level of consciousness, anuria, and elevated lactate). Several clinical symptoms can be seen at the bedside to assist in determining the subtype of shock. Symptoms of poor cardiac output, such as chilly extremities and thready pulses, as well as signs of high left ventricular (LV) or right ventricular (RV) filling pressures, such as pulmonary edema, peripheral edema, and jugular venous distention, are common in both cardiogenic and obstructive shock (1). Other types of shock, such as hypovolemic and distributive shock, as well as septic shock, are ruled out by the combination of these clinical symptoms. Furthermore, no clear symptoms of infection were present. The differential diagnosis based on our patient's clinical exam includes obstructive shock due to cardiac tamponade, large pulmonary embolism or an obstructive mass, or cardiogenic shock due to significant LV or RV dysfunction.



Investigations

We started with an immediate point-of-care ultrasound to figure out what was causing the patient's shock. We found a big tumor in the right atrium with expansion across the tricuspid valve (TV). The right ventricle was underfilled and RV inflow was limited, resulting in decreased LV preload and cardiac output. The inferior vena cava (IVC) was a plethora of veins that were noncollapsible. The patient was transferred to the catheterization laboratory on an emergency basis for additional care after receiving a fast bolus of intravenous crystalloid fluid.



By navigating past the obstructive mass and into the pulmonary artery, we were able to get pressure tracings in each chamber and do a right-sided heart catheterization for hemodynamic assessment. The superior vena cava (SVC) pressure was found to be significantly higher than the right atrial (RA) pressure, with a gradient of 11 mm Hg. In addition, the RV diastolic pressure was 33 mm Hg higher than the RA pressure. The hemodynamic data taken during right-sided heart catheterization are shown in Table 1, and the diagnostic angiography and percutaneous intervention are shown in Figures 1A to 1D, as well as Videos 1, 2, and 3.

Dr. Simon Parlow is part of the CAPITAL Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. In this video Dr. Parlow discusses an Unusual Case of Obstructive Shock.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccas.2021.10.017

Abstract-
Abstract
A 54-year-old guy was admitted to the hospital with severe obstructive shock. A right atrial tumor was discovered to be the source of severe right ventricular inflow blockage and inadequate cardiac output. To alleviate the obstruction, the patient was treated with an emergency balloon catheter intervention, which resulted in hemodynamic stabilization. A positive result for diffuse large B-cell lymphoma was later found on the pathology report. (Intermediate level of difficulty.)
Presentation History

A 54-year-old male with dyspnea, limb edema, stomach bloating, and exhaustion reported to a peripheral hospital with a 2-week history of symptoms. The patient had increased hypotension and drowsiness over the next 1 to 2 hours, necessitating intubation and the start of vasopressor therapy. He was then transported to our quaternary care cardiac intensive care unit at the University of Ottawa Heart Institute in Ottawa, Ontario, Canada, for additional evaluation and management.



Learning Outcomes

•

To be able to come up with a differential diagnosis for a patient who has obstructive shock.



•

To gain a better understanding of the function of hemodynamics in the treatment of obstructive shock caused by an intracardiac mass



He was severely hemodynamically unstable when he arrived. To keep his blood pressure at 75/58 mm Hg, he needed three vasopressors. He was bradycardic, with a sinus rhythm heart rate of 47 beats per minute. He was drugged and ventilated during his physical examination. With thready peripheral pulses and chilly extremities, he was mottled. His neck and face were reddish and swelled, and his veins were distended. On precordial auscultation, his heart sounds were hardly audible, with no murmurs or additional heart sounds detected. His lungs were both clean on auscultation. He had a somewhat enlarged abdomen but was not peritonitic. He'd had a Foley catheter put, but he hadn't peed in several hours. Despite ventilation with 100% inhaled proportion of inspired oxygen, he was hypoxemic, with an arterial Po2 of 75 mm Hg. With an arterial pH of 6.85 and a blood bicarbonate level of 4 mmol/L, his serum lactate level was 21.2 mmol/L.



Previous Medical Experience

During a visit to a peripheral emergency department two weeks before to his presentation, he was diagnosed with pericarditis and prescribed colchicine and ibuprofen. His previous medical history was basically unremarkable, save for cigarette smoking, and he had never taken any home remedies. He had no allergies or a history of illicit drug usage.



Differential Diagnosis is a term used to describe the process of distinguishing between two

The clinical examination and biochemical results of the patient are consistent with deep shock, as evidenced by hypotension and obvious signs of end-organ hypoperfusion (decreased level of consciousness, anuria, and elevated lactate). Several clinical symptoms can be seen at the bedside to assist in determining the subtype of shock. Symptoms of poor cardiac output, such as chilly extremities and thready pulses, as well as signs of high left ventricular (LV) or right ventricular (RV) filling pressures, such as pulmonary edema, peripheral edema, and jugular venous distention, are common in both cardiogenic and obstructive shock (1). Other types of shock, such as hypovolemic and distributive shock, as well as septic shock, are ruled out by the combination of these clinical symptoms. Furthermore, no clear symptoms of infection were present. The differential diagnosis based on our patient's clinical exam includes obstructive shock due to cardiac tamponade, large pulmonary embolism or an obstructive mass, or cardiogenic shock due to significant LV or RV dysfunction.



Investigations

We started with an immediate point-of-care ultrasound to figure out what was causing the patient's shock. We found a big tumor in the right atrium with expansion across the tricuspid valve (TV). The right ventricle was underfilled and RV inflow was limited, resulting in decreased LV preload and cardiac output. The inferior vena cava (IVC) was a plethora of veins that were noncollapsible. The patient was transferred to the catheterization laboratory on an emergency basis for additional care after receiving a fast bolus of intravenous crystalloid fluid.



By navigating past the obstructive mass and into the pulmonary artery, we were able to get pressure tracings in each chamber and do a right-sided heart catheterization for hemodynamic assessment. The superior vena cava (SVC) pressure was found to be significantly higher than the right atrial (RA) pressure, with a gradient of 11 mm Hg. In addition, the RV diastolic pressure was 33 mm Hg higher than the RA pressure. The hemodynamic data taken during right-sided heart catheterization are shown in Table 1, and the diagnostic angiography and percutaneous intervention are shown in Figures 1A to 1D, as well as Videos 1, 2, and 3.

Chris is a cardiologist who works in both clinical and academic settings. His research interests include cardiovascular medicine, cardiac rhythm disorders, and public health. He received a full scholarship to Pembroke School and graduated as Dux with the highest tertiary entry rating. He was awarded a Rhodes Scholarship after studying medicine at the University of Adelaide, where he was elected to the University Council. At the University of Oxford, he studied clinical trials, epidemiology, and population health for master's degrees before completing a PhD in cardiovascular medicine. In this video Dr. Wong discusses the Risk Thresholds for Total and Beverage-Specific Alcohol Consumption and Incident Atrial Fibrillation.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacep.2021.05.013

Abstract-
Objectives
This study sought to characterize associations of total and beverage-specific alcohol consumption with incident atrial fibrillation (AF).
Background
Although binge drinking and moderate to high consumption of alcohol are both established risk factors for AF, comparatively less is known about the effect of low alcohol consumption and whether associations differ by specific alcoholic beverages.
Methods
Using data from the UK Biobank, total and beverage-specific alcohol consumption was calculated as UK standard drinks (8 g alcohol) per week. Past drinkers and those with a history of AF were excluded. Incident AF events were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias.
Results
We studied 403,281 middle-aged individuals (52.4% female). Over a median follow-up time of 11.4 years (IQR: 10.7-12.3 years), a total of 21,312 incident AF events occurred. A J-shaped association of total alcohol consumption was observed, with lowest risk of AF with fewer than 7 drinks/week. Beverage-specific analyses demonstrated harmful associations of beer/cider consumption with any consumption. In contrast, consumption of red wine, white wine, and spirits up to 10, 8, and 3 drinks/week, respectively, was not associated with increased risk.
Conclusions
In this predominantly White population, low levels of alcohol consumption (<7 U.K. standard drinks [56 g alcohol]/week) were associated with lowest AF risk. Low consumption of red and white wine and very low consumption of spirits may not be associated with increased AF risk, whereas any consumption of beer/cider may be associated with harm. These findings may have important implications for the primary prevention of AF that should be explored in future studies.

Chris is a cardiologist who works in both clinical and academic settings. His research interests include cardiovascular medicine, cardiac rhythm disorders, and public health. He received a full scholarship to Pembroke School and graduated as Dux with the highest tertiary entry rating. He was awarded a Rhodes Scholarship after studying medicine at the University of Adelaide, where he was elected to the University Council. At the University of Oxford, he studied clinical trials, epidemiology, and population health for master's degrees before completing a PhD in cardiovascular medicine. In this video Dr. Wong discusses the Risk Thresholds for Total and Beverage-Specific Alcohol Consumption and Incident Atrial Fibrillation.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacep.2021.05.013

Abstract-
Objectives
This study sought to characterize associations of total and beverage-specific alcohol consumption with incident atrial fibrillation (AF).
Background
Although binge drinking and moderate to high consumption of alcohol are both established risk factors for AF, comparatively less is known about the effect of low alcohol consumption and whether associations differ by specific alcoholic beverages.
Methods
Using data from the UK Biobank, total and beverage-specific alcohol consumption was calculated as UK standard drinks (8 g alcohol) per week. Past drinkers and those with a history of AF were excluded. Incident AF events were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias.
Results
We studied 403,281 middle-aged individuals (52.4% female). Over a median follow-up time of 11.4 years (IQR: 10.7-12.3 years), a total of 21,312 incident AF events occurred. A J-shaped association of total alcohol consumption was observed, with lowest risk of AF with fewer than 7 drinks/week. Beverage-specific analyses demonstrated harmful associations of beer/cider consumption with any consumption. In contrast, consumption of red wine, white wine, and spirits up to 10, 8, and 3 drinks/week, respectively, was not associated with increased risk.
Conclusions
In this predominantly White population, low levels of alcohol consumption (<7 U.K. standard drinks [56 g alcohol]/week) were associated with lowest AF risk. Low consumption of red and white wine and very low consumption of spirits may not be associated with increased AF risk, whereas any consumption of beer/cider may be associated with harm. These findings may have important implications for the primary prevention of AF that should be explored in future studies.

Dr. Mouaz H. Al-Mallah is a cardiologist working at Houston Methodist Hospital in Houston, Texas. He graduated from the American University of Beirut Faculty of Medicine with a medical degree. In this video Dr. Al-Mallah discusses

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jcmg.2021.01.024

Abstract-
Objectives
The aim of this analysis is to examine the incremental prognostic value of coronary artery calcium (CAC) score and myocardial flow reserve (MFR) in patients with suspected coronary artery disease (CAD) undergoing positron emission tomography (PET) myocardial perfusion imaging (MPI).
Background
Advances in cardiac PET and computed tomography imaging enabled the simultaneous acquisition of anatomic and physiological data for patients suspected of CAD.
Methods
Consecutive patients who underwent PET MPI and CAC score calculation at King Abdulaziz Cardiac Center, Riyadh, Saudi Arabia, between May 2011 and May 2018 were included in the study. MPI and CAC images were obtained in the same setting. The primary endpoint of the study was a composite of cardiac death and nonfatal myocardial infarction. Cox proportional hazard regression was used to assess the incremental prognostic value of CAC and MFR by sequentially adding the variables to a model that included clinical and PET variables.
Results
A total of 4,008 patients (mean age 59.7 ± 11.6 years, 55% women) were included in the analysis. Risk factors were prevalent (77.6% hypertension, 58.1% diabetes). In total, 35.9% of the cohort had CAC of 0, 16.5% had CAC ≥400, and 43.9% had MFR <2. Over a median follow up of 1.9 years, 130 (3.2%) patients had cardiac death/nonfatal myocardial infarction. CAC and MFR score added incremental prognostic value over clinical and perfusion variables (base model: c-index 0.8137; Akaike information criterion [AIC]: 1,865.877; p = 0.0011; CAC model: c-index = 0.8330; AIC: 1,850.810; p = 0.045 vs. base model; MFR model: c-index = 0.8279; AIC: 1,859.235; p = 0.024). Combining CAC and MFR did not enhance risk prediction (c-index = 0.8435; AIC: 1,846.334; p = 0.074 vs. MFR model; p = 0.21 vs. CAC model.)
Conclusions
In this large cohort of patients referred for PET MPI, both CAC and MFR independently added incremental prognostic value over clinical and MPI variables. Although combining both may have synergetic prognostic effect, this relation was not shown in multivariable model of this analysis.

Dr. Mouaz H. Al-Mallah is a cardiologist working at Houston Methodist Hospital in Houston, Texas. He graduated from the American University of Beirut Faculty of Medicine with a medical degree. In this video Dr. Al-Mallah discusses

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jcmg.2021.01.024

Abstract-
Objectives
The aim of this analysis is to examine the incremental prognostic value of coronary artery calcium (CAC) score and myocardial flow reserve (MFR) in patients with suspected coronary artery disease (CAD) undergoing positron emission tomography (PET) myocardial perfusion imaging (MPI).
Background
Advances in cardiac PET and computed tomography imaging enabled the simultaneous acquisition of anatomic and physiological data for patients suspected of CAD.
Methods
Consecutive patients who underwent PET MPI and CAC score calculation at King Abdulaziz Cardiac Center, Riyadh, Saudi Arabia, between May 2011 and May 2018 were included in the study. MPI and CAC images were obtained in the same setting. The primary endpoint of the study was a composite of cardiac death and nonfatal myocardial infarction. Cox proportional hazard regression was used to assess the incremental prognostic value of CAC and MFR by sequentially adding the variables to a model that included clinical and PET variables.
Results
A total of 4,008 patients (mean age 59.7 ± 11.6 years, 55% women) were included in the analysis. Risk factors were prevalent (77.6% hypertension, 58.1% diabetes). In total, 35.9% of the cohort had CAC of 0, 16.5% had CAC ≥400, and 43.9% had MFR <2. Over a median follow up of 1.9 years, 130 (3.2%) patients had cardiac death/nonfatal myocardial infarction. CAC and MFR score added incremental prognostic value over clinical and perfusion variables (base model: c-index 0.8137; Akaike information criterion [AIC]: 1,865.877; p = 0.0011; CAC model: c-index = 0.8330; AIC: 1,850.810; p = 0.045 vs. base model; MFR model: c-index = 0.8279; AIC: 1,859.235; p = 0.024). Combining CAC and MFR did not enhance risk prediction (c-index = 0.8435; AIC: 1,846.334; p = 0.074 vs. MFR model; p = 0.21 vs. CAC model.)
Conclusions
In this large cohort of patients referred for PET MPI, both CAC and MFR independently added incremental prognostic value over clinical and MPI variables. Although combining both may have synergetic prognostic effect, this relation was not shown in multivariable model of this analysis.

Dr. Park, Duk-woo is a cardiologist who practices in Seoul, South Korea. He earned his MBBS from Kung Hee University and his MD in cardiology from Ulsan University. Later, he completed a cardiology super specialization at the University of Ulsan. In this video Dr. Park discusses Racial Differences in the Incidence and Impact of Prosthesis-Patient Mismatch After Transcatheter Aortic Valve Replacement.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jcin.2021.08.038

Abstract
The goal of this study was to assess the incidence and prognostic relevance of prosthesis-patient mismatch (PPM) following TAVR by racial groupings.
Because Asian persons have smaller annulus and valve diameters than Western ones, background PPM after TAVR may be of more concern.

Methods

From January 2015 through November 2019, the TP-TAVR (Transpacific TAVR Registry) was an international multicenter cohort study of patients with severe aortic stenosis who underwent TAVR in the United States and South Korea. At the indexed effective orifice area, PPM was classified as moderate (0.65-0.85 cm2/m2) or severe (0.655 cm2/m2). At one year, the primary outcome was a combination of mortality, stroke, or rehospitalization.

Results

The incidence of PPM was substantially lower in the Asian population (33.6 percent; moderate, 26.5 percent; severe, 7.1 percent) than in the non-Asian population among 1,101 eligible patients (533 Asian and 569 non-Asian) (54.5 percent ; moderate, 29.8 percent ; severe, 24.7 percent ). PPM and non-PPM patients had similar 1-year rates of the primary outcome (27.5 percent vs 28.1 percent; P = 0.69); this pattern was constant for Asian (25.4 percent vs 25.2 percent; P = 0.31) and non-Asian (28.7 percent vs 32.1 percent; P = 0.97) individuals. In the overall population (HR: 0.95; 95 percent CI: 0.74-1.21), Asian patients (HR: 1.07; 95 percent CI: 0.74-1.55), and non-Asian patients (HR: 1.07; 95 percent CI: 0.74-1.55), the risk for the primary outcome did not differ significantly between the PPM and non-PPM groups after multivariable adjustment (HR: 0.86; 95 percent CI: 0.63-1.19).

Conclusions

The incidence of PPM was considerably lower in Asian patients than in non-Asian individuals in this study of patients with severe aortic stenosis who underwent TAVR. Regardless of racial group, the 1-year risk for the major composite outcome was similar in the PPM and non-PPM groups. (NCT03826264; Transpacific TAVR Registry [TP-TAVR])

Dr. Park, Duk-woo is a cardiologist who practices in Seoul, South Korea. He earned his MBBS from Kung Hee University and his MD in cardiology from Ulsan University. Later, he completed a cardiology super specialization at the University of Ulsan. In this video Dr. Park discusses Racial Differences in the Incidence and Impact of Prosthesis-Patient Mismatch After Transcatheter Aortic Valve Replacement.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jcin.2021.08.038

Abstract
The goal of this study was to assess the incidence and prognostic relevance of prosthesis-patient mismatch (PPM) following TAVR by racial groupings.
Because Asian persons have smaller annulus and valve diameters than Western ones, background PPM after TAVR may be of more concern.

Methods

From January 2015 through November 2019, the TP-TAVR (Transpacific TAVR Registry) was an international multicenter cohort study of patients with severe aortic stenosis who underwent TAVR in the United States and South Korea. At the indexed effective orifice area, PPM was classified as moderate (0.65-0.85 cm2/m2) or severe (0.655 cm2/m2). At one year, the primary outcome was a combination of mortality, stroke, or rehospitalization.

Results

The incidence of PPM was substantially lower in the Asian population (33.6 percent; moderate, 26.5 percent; severe, 7.1 percent) than in the non-Asian population among 1,101 eligible patients (533 Asian and 569 non-Asian) (54.5 percent ; moderate, 29.8 percent ; severe, 24.7 percent ). PPM and non-PPM patients had similar 1-year rates of the primary outcome (27.5 percent vs 28.1 percent; P = 0.69); this pattern was constant for Asian (25.4 percent vs 25.2 percent; P = 0.31) and non-Asian (28.7 percent vs 32.1 percent; P = 0.97) individuals. In the overall population (HR: 0.95; 95 percent CI: 0.74-1.21), Asian patients (HR: 1.07; 95 percent CI: 0.74-1.55), and non-Asian patients (HR: 1.07; 95 percent CI: 0.74-1.55), the risk for the primary outcome did not differ significantly between the PPM and non-PPM groups after multivariable adjustment (HR: 0.86; 95 percent CI: 0.63-1.19).

Conclusions

The incidence of PPM was considerably lower in Asian patients than in non-Asian individuals in this study of patients with severe aortic stenosis who underwent TAVR. Regardless of racial group, the 1-year risk for the major composite outcome was similar in the PPM and non-PPM groups. (NCT03826264; Transpacific TAVR Registry [TP-TAVR])

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccas.2021.07.030

Abstract-
During structural heart procedures, invasive pressure-volume loop analysis enables for direct monitoring of changing intraventricular cardiac mechanics. The goal of this study was to show how right and left ventricular mechanics changed after transcatheter edge-to-edge tricuspid regurgitation correction. (Advanced level of difficulty.)

Presentation History

Despite receiving optimal medical therapy, an 84-year-old woman with known right ventricular (RV) heart failure due to severe tricuspid valve insufficiency presented to a peripheral hospital with decreased exercise tolerance and progressive reports of dyspnea (New York Heart Association functional class IV). She was normotensive with bimalleolar edema on physical examination. In the presence of atrial dilatation and severe tricuspid regurgitation with a massive central jet and no further significant valvular disease, transthoracic and transesophageal echocardiography revealed normal left ventricular (LV) and reduced RV function (adequate longitudinal contraction but severely reduced radial contraction) (Figure 1). For endovascular tricuspid valve repair, the patient was referred to our center (Thorax Center, Erasmus University Medical Center, Rotterdam, the Netherlands).

Previous Medical Experience

Hypertension, chronic obstructive pulmonary disease, transient ischemic attack, and atrial fibrillation were among the patient's medical conditions.



Differential Diagnosis is a term used to describe the process of distinguishing between two

This isn't true.



Investigations

Because of her age and frailty (The Society of Thoracic Surgeons score, 3.7 percent), the patient was turned down for surgical tricuspid valve replacement and was instead scheduled for transcatheter edge-to-edge tricuspid valve repair (TEETR) with comprehensive periprocedural hemodynamic monitoring.



Management

TEETR was conducted under general anesthesia with the patient under transesophageal echocardiographic supervision. A pulmonary artery catheter and a conductance catheter were used for periprocedural hemodynamic monitoring, providing pressure-volume loop (PVL) monitoring (CD Leycom). Before and after TEETR, a comprehensive invasive hemodynamic assessment was performed, including PVL measurement of the right and left ventricles. The conductance catheter remained at the apex of the left ventricle during TEETR. The volume calibration of the conductance catheter was done with thermodilution, and parallel conductance was determined with hypertonic saline. Following a conduction catheter exchange between the right and left ventricles, volume calibration and parallel conductance measurements were repeated. Under fluoroscopic guidance and visual inspection of segmental loops, the conduction catheter was positioned in the ventricular apex, ensuring that the segments were in the same place within the appropriate chamber during data gathering. End-systolic elastance (Ees) was calculated using single-beat maximal pressure (Pmax). The patient exhibited atrial fibrillation with little beat-to-beat abnormalities during the operation. Along the septal-anterior commissure, two clips (TriClip XT, Abbott) were used (Figure 1). Figure 2 summarizes LV and RV PVL plots with matching end-systolic pressure-volume and end-diastolic pressure-volume relationships, both before and after TEETR, with corresponding quantifications in Table 1.

Cardiac output increased from 2.9 liters per minute before TEETR to 3.4 liters per minute after TEETR. After TEETR, LV PVL migrated rightward, with LV end-diastolic volume increasing from 77.9 to 105.6 mL and LV stroke volume increasing from 53.4 to 67.9 mL. TEETR reduced RV end-diastolic volume from 101.9 to 84.3 mL. After TEETR, the right ventricle's tau, a constant indicating the exponential reduction in ventricular pressure during the early relaxation period of diastole, reduced from 187.7 to 70.7 ms. After TEETR, the RV's stroke work (SW) and pressure-volume area (PVA) decreased (with a higher SW/PVA ratio of 0.54 to 0.68), indicating enhanced mechanical efficiency. Furthermore, TEETR improved RV systolic and diastolic intraventricular dyssynchrony (32.6 percent to 10.0 percent and 28.8 percent to 12.4 percent , respectively). The RV ratio of end-systolic elastance (Ees) to effective arterial elastance (Ea) (Ees/Ea) (representing right ventricular-pulmonary artery coupling) increased from 0.43 to 0.98, resulting in a drop in RV regurgitant volume from 44 to 7 mL. After TEETR, the RV ejection percent reduced (60.4 percent to 47.0 percent ). Maximal RV dP/dt (rate of rise in ventricular pressure) was reduced by half after TEETR, whereas Emax (maximal elastance) remained unchanged (0.44 to 0.41 mm Hg/mL).



Discussion

The purpose of TEETR is to prevent tricuspid regurgitation in the right ventricle. Invasive PVL analysis can be used to document in situ the biventricular hemodynamic effects of structural heart operations, giving researchers a better understanding of cardiac mechanics. The SW/PVA ratio increased following TEETR, indicating a decrease in RV myocardial energy demand. Although the RV ejection fraction fell slightly (47%), intraventricular systolic and diastolic dyssynchrony improved. Furthermore, as a result of the enhanced pulmonary flow caused by TEETR, RV Ees/Ea rose. The load-independent Ees more than doubled, indicating a better cardiac contractile condition (1). Ea was a stable indicator of pulmonary vascular resistance and consequently RV afterload. The RV maximum dP/dt decreased following TEETR, however this is a heavily load-dependent measure. The RV volume at 15 mm Hg (V15mmHg) and mechanical intraventricular dyssynchrony, on the other hand, reduced, indicating better myocardial intrinsic contractility. These properties, together with a higher SW/PVA ratio, point to a significant increase in RV efficiency.



TEETR elevated LV preload and LV myocardial metabolic demand, as measured by LV end-diastolic volume, SW, and PVA. These events, on the other hand, were well tolerated and were linked to enhanced overall cardiac output, LV stroke volume, and steady LV intraventricular dyssynchrony and Ees/Ea (ie, LV-aortic coupling). In 18 patients up to 6 months following TEETR, PVL observations of increased LV filling (reflected by higher LV end-diastolic volume and stroke volume) and reduced RV loading were in agreement with cardiac magnetic resonance–based visualizations by Rommel et al (2). There are various limits to PVL analysis in this scenario. Thermodilution-based cardiac output measurement in the context of valvular insufficiency has inherent limitations that were not confirmed by a second (e.g., Fick) test. Furthermore, parallel conductance was evaluated using hypertonic saline; however, clip material influence with RV or LV conductance cannot be ruled out.



Follow-Up

TEETR resulted in a considerable reduction in tricuspid regurgitation from enormous to mild or moderate, according to a transthoracic echocardiogram performed before discharge (Figure 1).



Conclusions

In a patient with significant isolated tricuspid regurgitation, invasive PVL study revealed immediate beneficial cardiomechanical effects of TEETR. TEETR produced the following results: 1) improved intraventricular dyssynchrony; 2) enhanced LV loading and LV myocardial metabolic demand; and 3) increased RV unloading, increased pulmonary artery flow, and lowered RV myocardial metabolic demand.



Author Disclosures and Funding Support

PulseCath BV has paid personal fees to Dr. Barros Bastos. CD Leycom and Dr. Schreuder have a working and financial relationship, according to Dr. Schreuder. Dr. Daemen has received institutional grants and research support from AstraZeneca, Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Pie Medical, Siemens Health Care, and ReCor Medical, as well as consulting and speaker fees from Abiomed, ACIST Medical, Boston Scientific, ReCor Medical, PulseCath, Pie Medical, Siemens Health Care, and ReCor Medical. Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, PulseCath BV, Abiomed, Daiichi Sankyo, and Siemens have all given Dr. Van Mieghem research grants. Dr. van den Enden has disclosed that he has no ties to disclose that are relevant to the content of this paper.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccas.2021.07.030

Abstract-
During structural heart procedures, invasive pressure-volume loop analysis enables for direct monitoring of changing intraventricular cardiac mechanics. The goal of this study was to show how right and left ventricular mechanics changed after transcatheter edge-to-edge tricuspid regurgitation correction. (Advanced level of difficulty.)

Presentation History

Despite receiving optimal medical therapy, an 84-year-old woman with known right ventricular (RV) heart failure due to severe tricuspid valve insufficiency presented to a peripheral hospital with decreased exercise tolerance and progressive reports of dyspnea (New York Heart Association functional class IV). She was normotensive with bimalleolar edema on physical examination. In the presence of atrial dilatation and severe tricuspid regurgitation with a massive central jet and no further significant valvular disease, transthoracic and transesophageal echocardiography revealed normal left ventricular (LV) and reduced RV function (adequate longitudinal contraction but severely reduced radial contraction) (Figure 1). For endovascular tricuspid valve repair, the patient was referred to our center (Thorax Center, Erasmus University Medical Center, Rotterdam, the Netherlands).

Previous Medical Experience

Hypertension, chronic obstructive pulmonary disease, transient ischemic attack, and atrial fibrillation were among the patient's medical conditions.



Differential Diagnosis is a term used to describe the process of distinguishing between two

This isn't true.



Investigations

Because of her age and frailty (The Society of Thoracic Surgeons score, 3.7 percent), the patient was turned down for surgical tricuspid valve replacement and was instead scheduled for transcatheter edge-to-edge tricuspid valve repair (TEETR) with comprehensive periprocedural hemodynamic monitoring.



Management

TEETR was conducted under general anesthesia with the patient under transesophageal echocardiographic supervision. A pulmonary artery catheter and a conductance catheter were used for periprocedural hemodynamic monitoring, providing pressure-volume loop (PVL) monitoring (CD Leycom). Before and after TEETR, a comprehensive invasive hemodynamic assessment was performed, including PVL measurement of the right and left ventricles. The conductance catheter remained at the apex of the left ventricle during TEETR. The volume calibration of the conductance catheter was done with thermodilution, and parallel conductance was determined with hypertonic saline. Following a conduction catheter exchange between the right and left ventricles, volume calibration and parallel conductance measurements were repeated. Under fluoroscopic guidance and visual inspection of segmental loops, the conduction catheter was positioned in the ventricular apex, ensuring that the segments were in the same place within the appropriate chamber during data gathering. End-systolic elastance (Ees) was calculated using single-beat maximal pressure (Pmax). The patient exhibited atrial fibrillation with little beat-to-beat abnormalities during the operation. Along the septal-anterior commissure, two clips (TriClip XT, Abbott) were used (Figure 1). Figure 2 summarizes LV and RV PVL plots with matching end-systolic pressure-volume and end-diastolic pressure-volume relationships, both before and after TEETR, with corresponding quantifications in Table 1.

Cardiac output increased from 2.9 liters per minute before TEETR to 3.4 liters per minute after TEETR. After TEETR, LV PVL migrated rightward, with LV end-diastolic volume increasing from 77.9 to 105.6 mL and LV stroke volume increasing from 53.4 to 67.9 mL. TEETR reduced RV end-diastolic volume from 101.9 to 84.3 mL. After TEETR, the right ventricle's tau, a constant indicating the exponential reduction in ventricular pressure during the early relaxation period of diastole, reduced from 187.7 to 70.7 ms. After TEETR, the RV's stroke work (SW) and pressure-volume area (PVA) decreased (with a higher SW/PVA ratio of 0.54 to 0.68), indicating enhanced mechanical efficiency. Furthermore, TEETR improved RV systolic and diastolic intraventricular dyssynchrony (32.6 percent to 10.0 percent and 28.8 percent to 12.4 percent , respectively). The RV ratio of end-systolic elastance (Ees) to effective arterial elastance (Ea) (Ees/Ea) (representing right ventricular-pulmonary artery coupling) increased from 0.43 to 0.98, resulting in a drop in RV regurgitant volume from 44 to 7 mL. After TEETR, the RV ejection percent reduced (60.4 percent to 47.0 percent ). Maximal RV dP/dt (rate of rise in ventricular pressure) was reduced by half after TEETR, whereas Emax (maximal elastance) remained unchanged (0.44 to 0.41 mm Hg/mL).



Discussion

The purpose of TEETR is to prevent tricuspid regurgitation in the right ventricle. Invasive PVL analysis can be used to document in situ the biventricular hemodynamic effects of structural heart operations, giving researchers a better understanding of cardiac mechanics. The SW/PVA ratio increased following TEETR, indicating a decrease in RV myocardial energy demand. Although the RV ejection fraction fell slightly (47%), intraventricular systolic and diastolic dyssynchrony improved. Furthermore, as a result of the enhanced pulmonary flow caused by TEETR, RV Ees/Ea rose. The load-independent Ees more than doubled, indicating a better cardiac contractile condition (1). Ea was a stable indicator of pulmonary vascular resistance and consequently RV afterload. The RV maximum dP/dt decreased following TEETR, however this is a heavily load-dependent measure. The RV volume at 15 mm Hg (V15mmHg) and mechanical intraventricular dyssynchrony, on the other hand, reduced, indicating better myocardial intrinsic contractility. These properties, together with a higher SW/PVA ratio, point to a significant increase in RV efficiency.



TEETR elevated LV preload and LV myocardial metabolic demand, as measured by LV end-diastolic volume, SW, and PVA. These events, on the other hand, were well tolerated and were linked to enhanced overall cardiac output, LV stroke volume, and steady LV intraventricular dyssynchrony and Ees/Ea (ie, LV-aortic coupling). In 18 patients up to 6 months following TEETR, PVL observations of increased LV filling (reflected by higher LV end-diastolic volume and stroke volume) and reduced RV loading were in agreement with cardiac magnetic resonance–based visualizations by Rommel et al (2). There are various limits to PVL analysis in this scenario. Thermodilution-based cardiac output measurement in the context of valvular insufficiency has inherent limitations that were not confirmed by a second (e.g., Fick) test. Furthermore, parallel conductance was evaluated using hypertonic saline; however, clip material influence with RV or LV conductance cannot be ruled out.



Follow-Up

TEETR resulted in a considerable reduction in tricuspid regurgitation from enormous to mild or moderate, according to a transthoracic echocardiogram performed before discharge (Figure 1).



Conclusions

In a patient with significant isolated tricuspid regurgitation, invasive PVL study revealed immediate beneficial cardiomechanical effects of TEETR. TEETR produced the following results: 1) improved intraventricular dyssynchrony; 2) enhanced LV loading and LV myocardial metabolic demand; and 3) increased RV unloading, increased pulmonary artery flow, and lowered RV myocardial metabolic demand.



Author Disclosures and Funding Support

PulseCath BV has paid personal fees to Dr. Barros Bastos. CD Leycom and Dr. Schreuder have a working and financial relationship, according to Dr. Schreuder. Dr. Daemen has received institutional grants and research support from AstraZeneca, Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Pie Medical, Siemens Health Care, and ReCor Medical, as well as consulting and speaker fees from Abiomed, ACIST Medical, Boston Scientific, ReCor Medical, PulseCath, Pie Medical, Siemens Health Care, and ReCor Medical. Abbott Vascular, Boston Scientific, Edwards Lifesciences, Medtronic, PulseCath BV, Abiomed, Daiichi Sankyo, and Siemens have all given Dr. Van Mieghem research grants. Dr. van den Enden has disclosed that he has no ties to disclose that are relevant to the content of this paper.

Dr. Stephane Heymans studied public health at Harvard University in Cambridge. MA and now works at Maastricht University Medical Center in the Netherlands. In this video Dr. Heymans discusses the Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

Link to Abstract-
https://academic.oup.com/eurheartj/article/42/2/162/5959816

Abstract-

Dilated cardiomyopathy (DCM) is caused by a combination of hereditary and acquired factors. Until now, clinical decision-making in DCM has primarily been predicated on ejection fraction (EF) and NYHA categorization, with the DCM heterogeneity being overlooked. The goal of this work was to uncover pathophysiological differences between DCM subgroups by using phenotypic clustering to integrate aetiologies, comorbidities, and cardiac function along cardiac transcript levels.

Methods and outcomes-

We included 795 DCM patients from the Maastricht Cardiomyopathy Registry who were phenotyped in depth, which comprised extensive clinical data on aetiology and comorbodies, imaging, and endomyocardial biopsies. Based on unsupervised hierarchical clustering of principal components, four mutually exclusive and clinically different phenogroups (PG) were identified: [PG1] moderate systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. Pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, reduced EF) gene expression were found in cardiac samples (n = 91). Furthermore, even after accounting for well-known clinical indicators, event-free survival differed between the four phenogroups. Decision tree modeling identified four clinical parameters (autoimmune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be assigned to one of four phenogroups with corresponding outcomes (n = 789; Spain, n = 352, and Italy, n = 437), demonstrating the phenogrouping's applicability.

Conclusion-

The current investigation found four distinct DCM phenotypes, each with distinct clinical presentations, underlying molecular profiles, and outcomes, paving the door for a more individualized treatment approach.

Dr. David P. Kao is a cardiologist connected with UCHealth University of Colorado Hospital in Aurora, Colorado. He graduated from Johns Hopkins University School of Medicine with a medical degree. In this video Dr. Kao discusses extracting Vocal Biomarkers for Pulmonary Congestion With a Smartphone App.


Link to the abstract
https://www.jacc.org/doi/10.1016/j.jchf.2021.10.007

Abstract-
Introduction

In patients with acute decompensated heart failure (ADHF), pulmonary congestion is the most common reason for admission, and chronic pulmonary congestion predicts poor post-hospitalization outcomes (1). Tracking fluid retention over the course of HF could help to avoid ADHF hospitalization and enhance inpatient care quality. However, objectively assessing congestion in a cost-effective, regular, and accurate manner remains difficult.



Machine learning (ML) has sped up "nonclinical" adoption of automated and functional speech recognition systems, but it's still unclear whether these systems can be used to track physiologic factors like lung congestion for clinical application. A number of studies have made use of the smartphone, which is a ubiquitous and noninvasive instrument for collecting patient data, and studies have also revealed a link between fluid retention and vocal cord vibration (2,3). Amir et al. (4) investigate the idea of utilizing a smartphone app to detect pulmonary congestion using voice analysis. In this editorial, we examine the significance of this study for HF management, potential alternative techniques, and some cautionary notes on equity in the use of such technologies with vulnerable groups.

Vocal Biomarker Tracking and Alerting Challenges

Because the spectrum of congestion is lower dimensional, it may be easier for doctors to evaluate, understand, and intervene on in a focused manner than a global indicator of HF condition such as New York Heart Association functional class (3). According to Amir and et al (4), the HearO software requires a patient to read specified sentences into their smartphone. The app reports disparities between a patient's present speech features and those in a reference state, such as euvolemia, using a set of fixed analytic measurements. The authors reveal that the app's voice analysis findings differ significantly between hospital admission and discharge.

This strategy, however, has a number of significant drawbacks. For the app to be useful, patients must, for example, engage with it and read the relevant sentence. Many nonpharmacologic self-care advice for people with HF are inconsistent, suggesting that involvement with a system like the HearO app may be unsatisfactory.

Another significant drawback of the HearO app is that it may be difficult to achieve genuine euvolemia during hospitalization. ADHF can show in a variety of ways, and lung congestion may not be the best clinical reference point in many cases (1). Given these considerations, a more holistic monitoring approach, such as leveraging always-on virtual assistants like Alexa or Siri to personalize clinical warnings, may be more beneficial. However, developing and training efficient ML models would necessitate vast, rich data sets (5), and the use of passive, continuous listening, of course, poses further privacy problems. For example, there are still difficulties in limiting language and dialect prejudice, therefore the use of smartphone technology in the clinic necessitates careful planning during development.

Expanding the Clinical Applications of Vocal Biomarker Tracking

Individuals with ADHF frequently appear with identical symptoms in clinical practice. Speech alterations related with ADHF could be learned over time for a single patient, thereby improving alarm accuracy and advance notification timing. Instead than depending on speech metrics to identify congestion just at admission or discharge, as the HearO app does, speech measures might be made more granular and diverse. By measuring distinct symptom kinds, phrase length and actual word content, for example, could be used to enhance vocal cord vibration. However, whereas a single worrisome signal, such as vocal cord vibration, may be as easy as triggering a formal clinical assessment, an abundance of concerning signals may complicate already complicated clinical operations. If smartphone-based ADHF management, such as the HearO app, is to be scaled, it will be necessary to determine what steps to take based on the nature of the warning signal in order to allow for cheap, frequent, and accurate volume assessments on a specific schedule and on an ad hoc basis without compromising quality of care or contributing to provider burnout.

A Word of Caution on Technology in Medicine

Bias is a problem in artificial intelligence, which has just recently received a lot of attention (3,6). Algorithms rely on developers to make modeling and data decisions, which both enable for bias to be introduced and systemic prejudice to be reinforced. Fairness, operational tolerances, and unfavorable effects on vulnerable populations should all be carefully considered while developing software, especially in safety-critical contexts.

Voice biomarker detection can be hampered by a variety of biases, including representational, measurement, omitted variable, algorithmic, and social biases (6). Any patient-monitoring device should assure demographic parity, equalized odds, equal opportunity, treatment equality, and fairness, in addition to standard efficacy standards. Because speech recording quality could be stratified according to socioeconomic level, the HearO app emphasizes how limited access to modern smartphones (e.g., the latest iPhone or Android devices) may effect future quality of care. As additional sectors of medicine use these devices to collect data, the HF community should consider how discrepancies in data could harm our patients.

Conclusions

Dr. Amir et al. (4) have highlighted active speech analysis as a significant step forward in increasing the techniques available to assess patients with HF. Although still in its infancy, the use of widely available mobile technologies shows that it has the potential to be widely adopted, as opposed to extremely invasive tactics that require dedicated gear. Before clinical application, more research and validation is required, but success in a use case like HearO could open the way for even more convenient and generalizable solutions.

Author Disclosures and Funding Support

Dr. Kao has served as a consultant to Codex Health, Inc. Dr. Ravindra has indicated that he has no ties to disclose that are relevant to the content of this study.

Footnotes

The authors certify that they complied with the authors' institutions' human research committees and animal welfare rules, as well as Food and Drug Administration procedures, including patient permission where relevant. Visit the Author Center for further information.

Dr. David P. Kao is a cardiologist connected with UCHealth University of Colorado Hospital in Aurora, Colorado. He graduated from Johns Hopkins University School of Medicine with a medical degree. In this video Dr. Kao discusses extracting Vocal Biomarkers for Pulmonary Congestion With a Smartphone App.


Link to the abstract
https://www.jacc.org/doi/10.1016/j.jchf.2021.10.007

Abstract-
Introduction

In patients with acute decompensated heart failure (ADHF), pulmonary congestion is the most common reason for admission, and chronic pulmonary congestion predicts poor post-hospitalization outcomes (1). Tracking fluid retention over the course of HF could help to avoid ADHF hospitalization and enhance inpatient care quality. However, objectively assessing congestion in a cost-effective, regular, and accurate manner remains difficult.



Machine learning (ML) has sped up "nonclinical" adoption of automated and functional speech recognition systems, but it's still unclear whether these systems can be used to track physiologic factors like lung congestion for clinical application. A number of studies have made use of the smartphone, which is a ubiquitous and noninvasive instrument for collecting patient data, and studies have also revealed a link between fluid retention and vocal cord vibration (2,3). Amir et al. (4) investigate the idea of utilizing a smartphone app to detect pulmonary congestion using voice analysis. In this editorial, we examine the significance of this study for HF management, potential alternative techniques, and some cautionary notes on equity in the use of such technologies with vulnerable groups.

Vocal Biomarker Tracking and Alerting Challenges

Because the spectrum of congestion is lower dimensional, it may be easier for doctors to evaluate, understand, and intervene on in a focused manner than a global indicator of HF condition such as New York Heart Association functional class (3). According to Amir and et al (4), the HearO software requires a patient to read specified sentences into their smartphone. The app reports disparities between a patient's present speech features and those in a reference state, such as euvolemia, using a set of fixed analytic measurements. The authors reveal that the app's voice analysis findings differ significantly between hospital admission and discharge.

This strategy, however, has a number of significant drawbacks. For the app to be useful, patients must, for example, engage with it and read the relevant sentence. Many nonpharmacologic self-care advice for people with HF are inconsistent, suggesting that involvement with a system like the HearO app may be unsatisfactory.

Another significant drawback of the HearO app is that it may be difficult to achieve genuine euvolemia during hospitalization. ADHF can show in a variety of ways, and lung congestion may not be the best clinical reference point in many cases (1). Given these considerations, a more holistic monitoring approach, such as leveraging always-on virtual assistants like Alexa or Siri to personalize clinical warnings, may be more beneficial. However, developing and training efficient ML models would necessitate vast, rich data sets (5), and the use of passive, continuous listening, of course, poses further privacy problems. For example, there are still difficulties in limiting language and dialect prejudice, therefore the use of smartphone technology in the clinic necessitates careful planning during development.

Expanding the Clinical Applications of Vocal Biomarker Tracking

Individuals with ADHF frequently appear with identical symptoms in clinical practice. Speech alterations related with ADHF could be learned over time for a single patient, thereby improving alarm accuracy and advance notification timing. Instead than depending on speech metrics to identify congestion just at admission or discharge, as the HearO app does, speech measures might be made more granular and diverse. By measuring distinct symptom kinds, phrase length and actual word content, for example, could be used to enhance vocal cord vibration. However, whereas a single worrisome signal, such as vocal cord vibration, may be as easy as triggering a formal clinical assessment, an abundance of concerning signals may complicate already complicated clinical operations. If smartphone-based ADHF management, such as the HearO app, is to be scaled, it will be necessary to determine what steps to take based on the nature of the warning signal in order to allow for cheap, frequent, and accurate volume assessments on a specific schedule and on an ad hoc basis without compromising quality of care or contributing to provider burnout.

A Word of Caution on Technology in Medicine

Bias is a problem in artificial intelligence, which has just recently received a lot of attention (3,6). Algorithms rely on developers to make modeling and data decisions, which both enable for bias to be introduced and systemic prejudice to be reinforced. Fairness, operational tolerances, and unfavorable effects on vulnerable populations should all be carefully considered while developing software, especially in safety-critical contexts.

Voice biomarker detection can be hampered by a variety of biases, including representational, measurement, omitted variable, algorithmic, and social biases (6). Any patient-monitoring device should assure demographic parity, equalized odds, equal opportunity, treatment equality, and fairness, in addition to standard efficacy standards. Because speech recording quality could be stratified according to socioeconomic level, the HearO app emphasizes how limited access to modern smartphones (e.g., the latest iPhone or Android devices) may effect future quality of care. As additional sectors of medicine use these devices to collect data, the HF community should consider how discrepancies in data could harm our patients.

Conclusions

Dr. Amir et al. (4) have highlighted active speech analysis as a significant step forward in increasing the techniques available to assess patients with HF. Although still in its infancy, the use of widely available mobile technologies shows that it has the potential to be widely adopted, as opposed to extremely invasive tactics that require dedicated gear. Before clinical application, more research and validation is required, but success in a use case like HearO could open the way for even more convenient and generalizable solutions.

Author Disclosures and Funding Support

Dr. Kao has served as a consultant to Codex Health, Inc. Dr. Ravindra has indicated that he has no ties to disclose that are relevant to the content of this study.

Footnotes

The authors certify that they complied with the authors' institutions' human research committees and animal welfare rules, as well as Food and Drug Administration procedures, including patient permission where relevant. Visit the Author Center for further information.

Dr. Danielle E. Soranno is a pediatric nephrologist affiliated with Children's Hospital Colorado in Aurora, Colorado. She graduated from Case Western Reserve University School of Medicine with a medical degree. In this video Dr. Soranno discusses Acute Kidney Injury Results in Long-Term Diastolic Dysfunction That Is Prevented by Histone Deacetylase Inhibition.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacbts.2020.11.013

• This is the first long-term (1-year) study in mice to look at both the renal and systemic consequences of acute kidney damage. Transcutaneous glomerular filtration rate was used to track kidney function over time.

• Diastolic dysfunction was caused by AKI, which was followed by hypertension. The ejection fraction was kept. When compared to sham controls, myocardial ATP levels were lower one year following AKI.

• Mice treated with ITF2357, a histone deacetylase inhibitor, had normal diastolic function, blood pressure, and cardiac ATP after AKI.

• Metabolomics research suggests that ITF2357 therapy preserves energy metabolism pathways.

Summary

Acute kidney damage (AKI) is linked to long-term cardiovascular morbidity and mortality, according to growing epidemiological evidence. The authors provide a one-year investigation of cardiorenal outcomes in male mice after bilateral ischemia-reperfusion damage. These findings imply that AKI induces long-term cardiac metabolome dysfunction, which is linked to diastolic dysfunction and hypertension. Mice given ITF2357, a histone deacetylase inhibitor, had their heart function preserved and remained normotensive throughout the trial. ITF2357 was found to be ineffective in preventing renal fibrosis following AKI.

Introduction

Acute kidney damage (AKI) affects both children and adults who are hospitalized (1,2). Patients with AKI have worse outcomes than those who do not, including higher morbidity and death, longer hospital stays, and higher hospitalization expenses (3–7). AKI induces nonrenal organ dysfunction, and systemic illnesses, not AKI, are the major cause of death in AKI patients (8–10). The short-term systemic effects of AKI have been documented in mouse models, including an increase in serum interleukin (IL)-6, lung inflammation, heart dysfunction, liver injury, and metabolic disturbances (11–14). These studies have focused on nonrenal consequences in the near term, usually analyzing results after 24 to 72 hours (15,16). AKI's long-term systemic consequences have yet to be studied in mouse models.



Patients who survive their episodes of AKI have an increased chance of acquiring a variety of long-term consequences, including cardiovascular disease, hence research into the long-term systemic sequelae of AKI in murine models is necessary (17,18). Patients with AKI have an increased risk of heart failure, according to a large body of evidence (19–23). Cho et al. recently published a study that found a link between AKI and diastolic dysfunction in elderly patients with femoral neck fractures (24). There is a scarcity of research on the pathophysiology that links AKI to a long-term risk of heart failure.



Histone deacetylase inhibitors (HDACi) have an impact on epigenetic gene regulation and nongenomic physiological processes (25–27). We recently showed that ITF2357/givinostat, an HDACi now in phase 3 clinical trials in Duchenne muscular dystrophy patients, improves diastolic function in a rat model of hypertension and protects animals from aging-induced diastolic failure (28).



We used our mouse model of bilateral ischemia reperfusion AKI to conduct a 1-year study to examine the systemic effects of one episode of AKI on the lung, liver, and heart, as well as circulating cytokines, metabolites, and kidney recovery and function. We also looked at the effect(s) of HDACi medication on cardiorenal outcomes such blood pressure, cardiac function, and metabolism. We predicted that AKI would have long-term systemic consequences and that inhibiting HDAC would improve cardiorenal outcomes.



Methods

Animals

The National Institutes of Health Guide for the Care and Use of Laboratory Animals was followed during the experiments. The Animal Care and Use Committee of the University of Colorado in Denver, Colorado, authorized the protocol. Male C57BL/6 mice aged six to seven weeks (Jackson Laboratories, Bar Harbor, Maine) were fed a regular diet and given free access to water. On post-operative day 3, mice in the ITF2357 therapy group were given chow. ITF2357 chow (Dyets Inc., Bethlehem, Pennsylvania) was custom made with 555 mg/kg of ITF2357 in Teklad 2920X Rodent Diet (Envigo, Indianapolis, Indiana), resulting in a daily dose of 50 mg/kg. Jackson Laboratories aged 12-month study controls, which came two weeks before sacrifice.



Rate of glomerular filtration

The transcutaneous filtration rate (tGFR) was measured using a transdermal continuous renal function monitor (MediBeacon GMBH, Mannheim, Germany) and a fluorescein isothiocyanate (FITC) tail-vein injection, as directed by the manufacturer. Mice were given at least three days to recover from baseline readings before surgery.



Surgeries

On 8-week-old mice, surgical operations were conducted. Mice were given either a sham or an AKI treatment. Ketamine (VetOne, MWI, Boise, Idaho) and Xylazine were used to anesthetize mice for all procedures (VetOne, Bimed-MTC Animal Health Inc., Cambridge, Ontario, Canada). Throughout the treatment, mice were placed on a heating pad that was kept at 36° C to 40°C. Both renal pedicles were clamped for 25 minutes using a ventral technique (12), and the abdomen was closed in two layers. Mice were given 750 l of warmed saline/buprenorphine hydrochloride (0.3 mg/ml, PAR Pharmaceuticals, Chestnut Ridge, New York) subcutaneously after surgery, followed by 750 l of normal saline for 5 days.



Tissue

To determine inclusion status, 100 l of blood was obtained through retro-orbital bleed after 24 hours. Blood urea nitrogen (BUN) >70 mg/dl or serum creatinine (SCr) >0.7 mg/dl were the criteria for study inclusion in the AKI groups. The investigators were then blinded to the group assignment. Blood was taken through cardiac puncture, allowed to clot at room temperature, then centrifuged for 10 minutes at 4,000 g. The serum was taken and centrifuged for 1 minute at 4,000 g. Urine was collected and flash frozen at several study time points. At the time of sacrifice, the kidneys, liver, lung, heart, and muscle were collected; one-half was flash frozen, while the other half was formalin fixed and paraffin embedded. The heart was weighed, and the right and left ventricles were separated (LV). The upper portion of the right ventricle and the right ventricle were flash frozen. The caudal half of the LV was flash frozen after being placed in optimal cutting temperature (OCT) compound. At each study time point, the participants' weight was recorded. The tibia was dissected and measured, and the gastrocnemius muscle was cut, flash frozen, and weighed during sacrifice.



Kidney health

BioAssay Systems QuantiChrom Urea Assay Kit Cat: (DIUR-500) (BioAssay Systems, Hayward, California) and Pointe Scientific Creatinine (Enzymatic) Reagent Kit (Cat: C7548-480) were used to quantify BUN, serum, and urine creatinine (Pointe Scientific Inc, Canton, Michigan). The 12-month SCr was calculated utilizing the Comparative Pathology Core at UC and the Element DC Veterinary Chemistry Analyzer (Fujifilm, Serial # 73110474, Stamford, Connecticut [sponsored by Heska, Des Moines, Iowa]). The manufacturer's instructions were followed to assess neutrophil gelatinase-associated lipocalin (NGAL) using an enzyme-linked immunosorbent assay (ELISA) (R and D Systems, Minneapolis, Minnesota) (detection level: 8.8 pg/ml). Following the manufacturer's instructions, cytokines were quantified using a customized U-Plex Biomarker-1 (Cat # K15069L-S, Meso Scale Discovery, Rockville, Maryland). The Renin 1 Mouse ELISA Kit (Cat # EMREN1, Invitrogen, Carlsbad, California) was used to measure plasma renin, which was done according to the manufacturer's instructions.



Histology of the kidney

On the kidney, picrosirius red (PSR) was used, as well as normal histological staining methods with Sirius Red F3B. (Sigma-Aldrich, St. Louis, Missouri). An Olympus BX41 microscope (Olympus, Waltham, Massachusetts) with a linear polarizer was used to visualize ten cortical pictures at 100 magnification. The % area of polarization was calculated using imaging software (Image J). Immunohistochemistry for collagen type 3 was performed using a goat anti-type III collagen antibody (Cat # 1330-01, Southern Biotech, Birmingham, Alabama [1:100]), followed by rabbit antigoat horseradish peroxidase (Ref # P0449, Dako, Carpinteria, California [1:200]) and analyzed as previously described (29). PSR and collagen 3 levels were measured in both kidneys, and the average was used for analysis.



Western blot analysis

As previously described, kidneys were homogenized and analyzed with either -smooth muscle actin (SMA) primary antibody (ab32575, Abcam, Cambridge, United Kingdom, 1:5000) or KIM-1 primary antibody (Cat#: AF1817, R and D Systems, Minneapolis, Minnesota, 1:1000) using 1 RIPA buffer (Cell Signaling Technology, Danvers, Massachusetts) (29). Blots were normalized using the Revert Total Protein Stain (Cat # 926-11010, Licor, Lincoln, Nebraska) as a loading control and conducted as directed by the manufacturer.



Assay for hydroxyproline

Each sample's hydroxyproline content was determined in the left kidney, as previously described (29).



Blood pressure and echocardiography

Mean arterial blood pressure measurements were taken using a noninvasive computerized tail-cuff system (CODA High Throughput System, Kent Scientific Corp, Torrington, Connecticut), and transthoracic echocardiography and Doppler analyses were performed using Vevo2100 instruments (VisualSonics, Toronto, Ontario, Canada) (28).



Collagen portion of the LV

As previously mentioned, the percentage of collagen tissue in the LV was determined using 1-year cardiac tissue samples (28).



ATP (adenosine triphosphate) is a type of ATP

Pre-weighed LV tissue was treated according to manufacturer's instructions using commercially available reagents (Abcam, ab833355) and normalized to LV weight.



Metabolomics

As previously reported, frozen heart and plasma samples were processed (14). The mean values for each group were determined, and pairwise group comparisons were done using the Student's t-test. p values were adjusted for the false discovery rate (FDR) in single-molecule analysis using Benjamini-ad Hochberg's hoc approach (30). The threshold for statistical significance was fixed at p 0.05. Metabolites with nominal p values 0.05 were entered into the Pathway Analysis feature of MetaboAnalyst 3.0 for pathway enrichment analysis (31). Compound Name was used to identify metabolites and was changed to conform to MetaboAnalyst's nomenclature limits.



Lung myeloperoxidase detection

MPO (myeloperoxidase) in the lungs was tested as described previously (12).


Statistics

Analysis of variance (ANOVA) was used to compare groups, with Tukey post hoc adjustment for multiple comparisons and a significance level of 0.05. Unpaired Student's t-tests were used to compare two groups, assuming a Gaussian distribution with Welch's correction and a statistical significance of p0.05. The mean and standard error of the mean are used to present the data (SEM).



Results

There were n = 5 to 11 people in each cohort. On post-operative days 1, 3, 7, 14 and months 1, 3, 6, 9, and 12, mice were sacrificed after AKI or sham (Figure 1). SCr (Figure 2B) recovered early but did not normalize until the 9-month time point, whereas BUN (Figure 2A) remained elevated throughout the 1-year research. tGFR was used to monitor serial kidney function; 1 year after AKI, there was a declining but still significant decline in tGFR (Figure 2C). Supplementary Figure 1 shows individual tGFR values for each time point. Figure 2D shows an increase in urine NGAL in the AKI cohort up to 1 month, after which there was no significant change.

Dr. Danielle E. Soranno is a pediatric nephrologist affiliated with Children's Hospital Colorado in Aurora, Colorado. She graduated from Case Western Reserve University School of Medicine with a medical degree. In this video Dr. Soranno discusses Acute Kidney Injury Results in Long-Term Diastolic Dysfunction That Is Prevented by Histone Deacetylase Inhibition.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jacbts.2020.11.013

• This is the first long-term (1-year) study in mice to look at both the renal and systemic consequences of acute kidney damage. Transcutaneous glomerular filtration rate was used to track kidney function over time.

• Diastolic dysfunction was caused by AKI, which was followed by hypertension. The ejection fraction was kept. When compared to sham controls, myocardial ATP levels were lower one year following AKI.

• Mice treated with ITF2357, a histone deacetylase inhibitor, had normal diastolic function, blood pressure, and cardiac ATP after AKI.

• Metabolomics research suggests that ITF2357 therapy preserves energy metabolism pathways.

Summary

Acute kidney damage (AKI) is linked to long-term cardiovascular morbidity and mortality, according to growing epidemiological evidence. The authors provide a one-year investigation of cardiorenal outcomes in male mice after bilateral ischemia-reperfusion damage. These findings imply that AKI induces long-term cardiac metabolome dysfunction, which is linked to diastolic dysfunction and hypertension. Mice given ITF2357, a histone deacetylase inhibitor, had their heart function preserved and remained normotensive throughout the trial. ITF2357 was found to be ineffective in preventing renal fibrosis following AKI.

Introduction

Acute kidney damage (AKI) affects both children and adults who are hospitalized (1,2). Patients with AKI have worse outcomes than those who do not, including higher morbidity and death, longer hospital stays, and higher hospitalization expenses (3–7). AKI induces nonrenal organ dysfunction, and systemic illnesses, not AKI, are the major cause of death in AKI patients (8–10). The short-term systemic effects of AKI have been documented in mouse models, including an increase in serum interleukin (IL)-6, lung inflammation, heart dysfunction, liver injury, and metabolic disturbances (11–14). These studies have focused on nonrenal consequences in the near term, usually analyzing results after 24 to 72 hours (15,16). AKI's long-term systemic consequences have yet to be studied in mouse models.



Patients who survive their episodes of AKI have an increased chance of acquiring a variety of long-term consequences, including cardiovascular disease, hence research into the long-term systemic sequelae of AKI in murine models is necessary (17,18). Patients with AKI have an increased risk of heart failure, according to a large body of evidence (19–23). Cho et al. recently published a study that found a link between AKI and diastolic dysfunction in elderly patients with femoral neck fractures (24). There is a scarcity of research on the pathophysiology that links AKI to a long-term risk of heart failure.



Histone deacetylase inhibitors (HDACi) have an impact on epigenetic gene regulation and nongenomic physiological processes (25–27). We recently showed that ITF2357/givinostat, an HDACi now in phase 3 clinical trials in Duchenne muscular dystrophy patients, improves diastolic function in a rat model of hypertension and protects animals from aging-induced diastolic failure (28).



We used our mouse model of bilateral ischemia reperfusion AKI to conduct a 1-year study to examine the systemic effects of one episode of AKI on the lung, liver, and heart, as well as circulating cytokines, metabolites, and kidney recovery and function. We also looked at the effect(s) of HDACi medication on cardiorenal outcomes such blood pressure, cardiac function, and metabolism. We predicted that AKI would have long-term systemic consequences and that inhibiting HDAC would improve cardiorenal outcomes.



Methods

Animals

The National Institutes of Health Guide for the Care and Use of Laboratory Animals was followed during the experiments. The Animal Care and Use Committee of the University of Colorado in Denver, Colorado, authorized the protocol. Male C57BL/6 mice aged six to seven weeks (Jackson Laboratories, Bar Harbor, Maine) were fed a regular diet and given free access to water. On post-operative day 3, mice in the ITF2357 therapy group were given chow. ITF2357 chow (Dyets Inc., Bethlehem, Pennsylvania) was custom made with 555 mg/kg of ITF2357 in Teklad 2920X Rodent Diet (Envigo, Indianapolis, Indiana), resulting in a daily dose of 50 mg/kg. Jackson Laboratories aged 12-month study controls, which came two weeks before sacrifice.



Rate of glomerular filtration

The transcutaneous filtration rate (tGFR) was measured using a transdermal continuous renal function monitor (MediBeacon GMBH, Mannheim, Germany) and a fluorescein isothiocyanate (FITC) tail-vein injection, as directed by the manufacturer. Mice were given at least three days to recover from baseline readings before surgery.



Surgeries

On 8-week-old mice, surgical operations were conducted. Mice were given either a sham or an AKI treatment. Ketamine (VetOne, MWI, Boise, Idaho) and Xylazine were used to anesthetize mice for all procedures (VetOne, Bimed-MTC Animal Health Inc., Cambridge, Ontario, Canada). Throughout the treatment, mice were placed on a heating pad that was kept at 36° C to 40°C. Both renal pedicles were clamped for 25 minutes using a ventral technique (12), and the abdomen was closed in two layers. Mice were given 750 l of warmed saline/buprenorphine hydrochloride (0.3 mg/ml, PAR Pharmaceuticals, Chestnut Ridge, New York) subcutaneously after surgery, followed by 750 l of normal saline for 5 days.



Tissue

To determine inclusion status, 100 l of blood was obtained through retro-orbital bleed after 24 hours. Blood urea nitrogen (BUN) >70 mg/dl or serum creatinine (SCr) >0.7 mg/dl were the criteria for study inclusion in the AKI groups. The investigators were then blinded to the group assignment. Blood was taken through cardiac puncture, allowed to clot at room temperature, then centrifuged for 10 minutes at 4,000 g. The serum was taken and centrifuged for 1 minute at 4,000 g. Urine was collected and flash frozen at several study time points. At the time of sacrifice, the kidneys, liver, lung, heart, and muscle were collected; one-half was flash frozen, while the other half was formalin fixed and paraffin embedded. The heart was weighed, and the right and left ventricles were separated (LV). The upper portion of the right ventricle and the right ventricle were flash frozen. The caudal half of the LV was flash frozen after being placed in optimal cutting temperature (OCT) compound. At each study time point, the participants' weight was recorded. The tibia was dissected and measured, and the gastrocnemius muscle was cut, flash frozen, and weighed during sacrifice.



Kidney health

BioAssay Systems QuantiChrom Urea Assay Kit Cat: (DIUR-500) (BioAssay Systems, Hayward, California) and Pointe Scientific Creatinine (Enzymatic) Reagent Kit (Cat: C7548-480) were used to quantify BUN, serum, and urine creatinine (Pointe Scientific Inc, Canton, Michigan). The 12-month SCr was calculated utilizing the Comparative Pathology Core at UC and the Element DC Veterinary Chemistry Analyzer (Fujifilm, Serial # 73110474, Stamford, Connecticut [sponsored by Heska, Des Moines, Iowa]). The manufacturer's instructions were followed to assess neutrophil gelatinase-associated lipocalin (NGAL) using an enzyme-linked immunosorbent assay (ELISA) (R and D Systems, Minneapolis, Minnesota) (detection level: 8.8 pg/ml). Following the manufacturer's instructions, cytokines were quantified using a customized U-Plex Biomarker-1 (Cat # K15069L-S, Meso Scale Discovery, Rockville, Maryland). The Renin 1 Mouse ELISA Kit (Cat # EMREN1, Invitrogen, Carlsbad, California) was used to measure plasma renin, which was done according to the manufacturer's instructions.



Histology of the kidney

On the kidney, picrosirius red (PSR) was used, as well as normal histological staining methods with Sirius Red F3B. (Sigma-Aldrich, St. Louis, Missouri). An Olympus BX41 microscope (Olympus, Waltham, Massachusetts) with a linear polarizer was used to visualize ten cortical pictures at 100 magnification. The % area of polarization was calculated using imaging software (Image J). Immunohistochemistry for collagen type 3 was performed using a goat anti-type III collagen antibody (Cat # 1330-01, Southern Biotech, Birmingham, Alabama [1:100]), followed by rabbit antigoat horseradish peroxidase (Ref # P0449, Dako, Carpinteria, California [1:200]) and analyzed as previously described (29). PSR and collagen 3 levels were measured in both kidneys, and the average was used for analysis.



Western blot analysis

As previously described, kidneys were homogenized and analyzed with either -smooth muscle actin (SMA) primary antibody (ab32575, Abcam, Cambridge, United Kingdom, 1:5000) or KIM-1 primary antibody (Cat#: AF1817, R and D Systems, Minneapolis, Minnesota, 1:1000) using 1 RIPA buffer (Cell Signaling Technology, Danvers, Massachusetts) (29). Blots were normalized using the Revert Total Protein Stain (Cat # 926-11010, Licor, Lincoln, Nebraska) as a loading control and conducted as directed by the manufacturer.



Assay for hydroxyproline

Each sample's hydroxyproline content was determined in the left kidney, as previously described (29).



Blood pressure and echocardiography

Mean arterial blood pressure measurements were taken using a noninvasive computerized tail-cuff system (CODA High Throughput System, Kent Scientific Corp, Torrington, Connecticut), and transthoracic echocardiography and Doppler analyses were performed using Vevo2100 instruments (VisualSonics, Toronto, Ontario, Canada) (28).



Collagen portion of the LV

As previously mentioned, the percentage of collagen tissue in the LV was determined using 1-year cardiac tissue samples (28).



ATP (adenosine triphosphate) is a type of ATP

Pre-weighed LV tissue was treated according to manufacturer's instructions using commercially available reagents (Abcam, ab833355) and normalized to LV weight.



Metabolomics

As previously reported, frozen heart and plasma samples were processed (14). The mean values for each group were determined, and pairwise group comparisons were done using the Student's t-test. p values were adjusted for the false discovery rate (FDR) in single-molecule analysis using Benjamini-ad Hochberg's hoc approach (30). The threshold for statistical significance was fixed at p 0.05. Metabolites with nominal p values 0.05 were entered into the Pathway Analysis feature of MetaboAnalyst 3.0 for pathway enrichment analysis (31). Compound Name was used to identify metabolites and was changed to conform to MetaboAnalyst's nomenclature limits.



Lung myeloperoxidase detection

MPO (myeloperoxidase) in the lungs was tested as described previously (12).


Statistics

Analysis of variance (ANOVA) was used to compare groups, with Tukey post hoc adjustment for multiple comparisons and a significance level of 0.05. Unpaired Student's t-tests were used to compare two groups, assuming a Gaussian distribution with Welch's correction and a statistical significance of p0.05. The mean and standard error of the mean are used to present the data (SEM).



Results

There were n = 5 to 11 people in each cohort. On post-operative days 1, 3, 7, 14 and months 1, 3, 6, 9, and 12, mice were sacrificed after AKI or sham (Figure 1). SCr (Figure 2B) recovered early but did not normalize until the 9-month time point, whereas BUN (Figure 2A) remained elevated throughout the 1-year research. tGFR was used to monitor serial kidney function; 1 year after AKI, there was a declining but still significant decline in tGFR (Figure 2C). Supplementary Figure 1 shows individual tGFR values for each time point. Figure 2D shows an increase in urine NGAL in the AKI cohort up to 1 month, after which there was no significant change.