Mathilde Vermeer, MS, Ph.D. Student at UMCG Cardiology Research Institute speaks about Publication: Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.
Link to Article:
https://www.jci.org/articles/view/140615
Link to Abstract:
https://www.science.org/doi/10.1126/scitranslmed.abd1817
Abstract:
By skipping the first start codon, the start codon c.1A>G mutation in KLHL24, which encodes the ubiquitin ligase KLHL24, leads in the deletion of 28 N-terminal amino acids (KLHL24-N28). KLHL24-N28 causes gain of function in skin, producing epidermolysis bullosa simplex by overly targeting intermediate filament keratin-14 for proteasomal breakdown (EBS). Dilated cardiomyopathy (DCM) is found in the majority of EBS patients, although the pathogenic process in the heart remains unclear. We predicted that KLHL24-N28 causes excessive desmin degradation, resulting in DCM, because desmin is the cardiac analog of keratin-14. Dynamically loaded engineering heart tissues (dyn-EHTs) were created from cardiomyocytes produced from human induced pluripotent stem cells (hiPSCs) from two patients and three nonfamilial controls. Desmin protein levels were shown to be tenfold lower in patient-derived dyn-EHTs, which corresponded to decreased desmin levels seen in patients' explanted hearts. Tissue dilatation, reduced mitochondrial function, lower force values, and higher cardiomyocyte stress followed this. KLHL24-mediated desmin degradation was verified in HEK293 transfection tests. Desmin protein levels were restored in patient-derived dyn-EHTs via KLHL24 RNA interference or direct desmin overexpression, restoring shape and function. To summarize, the presence of KLHL24-N28 in cardiomyocytes causes excessive desmin degradation, which affects tissue shape and function and may be avoided by restoring desmin protein levels.
Overview:
Inherited cardiomyopathies are common illnesses with a wide range of causes. New causal genes are found on a regular basis. We think we were the first to discover a connection between the KLHL24:c.1A>G mutation (Met1Val), which causes epidermolysis bullosa simplex (EBS) in the skin and dilated cardiomyopathy (DCM) in the heart (1). Around 33 individuals with identical gain-of-function mutations leading to DCM have been documented since our first finding (2, 3). Despite these reports, the causal consequences of KLHL24 gain-of-function mutations in cardiomyopathy have yet to be determined.
The KLHL24:c.1A>G mutation is one of five known methionine start codon mutations in ubiquitin ligase KLHL24 (c.1A>G, c.1A>T, c.2T>C, c.3G>A, and c.3G>T), which results in the loss of 28 N-terminal amino acids (KLHL24-N28) by bypassing the first start codon. KLHL24 acts as a ubiquitin ligase in the epidermis, creating a protein complex with CUL3 and RBX1 to facilitate keratin 14 degradation. Through KLHL24 auto-ubiquitination, this process is kept in check. The mutant protein KLHL24-N28, on the other hand, is unable to perform auto-ubiquitination and hence is more stable. Excessive ubiquitination and, as a result, breakdown of keratin 14 occurs, resulting in skin fragility.
Keratins (KRT) are intermediate filaments (IFs) proteins that are required for the cytoskeletal network of keratinocytes in the skin. When cells are stretched, IFs provide cells with flexibility to minor deformations while also strengthening them (8). EBS and hereditary cardiomyopathies have been linked to mutations in genes encoding various IFs, which play important regulatory functions in stretch-bearing tissues including the skin and the heart (9, 10). In cardiomyocytes and skeletal muscle cells, Desmin (DES) is a crucial IF (11). Desmin filaments connect myofibrils and expand the z-discs, producing a supporting latticework that runs from the sarcolemma to the nuclear envelope. They help to orient, stabilize, and transmit signals between the nucleus, cell membrane, mitochondria, and myofibrils. Mitochondrial dysfunction is one of the first and most visible abnormalities when the IF network in the heart is disrupted. Desmin network failure also causes nuclear delamination and intercalated disc abnormalities, which eventually contribute to heart function loss. Desminopathies have been linked to a number of DES mutations as well as mutations in other genes that impact the desmin network.
We predicted that KLHL24-N28 causes excessive desmin degradation in the heart, resulting in DCM, because desmin belongs to the same highly conserved intermediate filament protein family as keratins (15). We employed human induced pluripotent stem cells (hiPSCs) to differentiate patient-specific KLHL24WT/c.1A>G cardiomyocytes to test this notion. A dynamically loaded engineered heart tissue (dyn-EHT) model was used to investigate the role of KLHL24 in cardiac tissue compliance (i.e., stretching the desmin network) (16). To replicate the stress (preload and afterload) experienced by the heart, a polydimethylsiloxane (PDMS) strip is connected to engineered heart tissues (EHT). Finite element modeling may be used to calculate tissue contractile force by bending the strip (FEM). This system can also be dynamically grown, allowing researchers to see the morphological and functional changes that occur during ventricular dilation, which was crucial in identifying a clinically relevant phenotype in desmoplakin-mutated hiPSC-CMs (16). We show that a gain-of-function mutation in KLHL24, which results in KLHL24-N28 and causes excessive desmin degradation in cardiomyocytes, negatively affecting the shape and function of dyn-EHTs, may be avoided by KLHL24 RNA interference or direct desmin overexpression.
Outcomes:
EBS in families with dilated cardiomyopathy. Two patients of Dutch descent, both carriers of the KLHL24:c gene, were included in this research. Figure 1A, II:3, and III:2 show the 1A>G mutation (1). KLHL24-N28 is a shortened KLHL24 protein caused by this mutation (Figure 1B). Both patients had EBS and exhibited characteristic aplasia cutis congenita and skin fragility that improved with time. Furthermore, at the age of 17, the index patient (II:3) was diagnosed with a fast-progressing type of DCM, for which he had a heart transplant at the age of 18. His son (III:2), who was 18 years old at the time of the research, was still asymptomatic, but his echocardiography revealed clear indications of DCM, including left ventricular (LV) dilatation, decreased LVEF, and impaired global longitudinal systolic strain.
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Dr. Massar Omar works as a Doctor of Medicine and research fellow at the Mayo Clinic in Rochester Minnesota. In this podcast Dr. Omar discusses Hemodynamic Determinants of Activity Measured by Accelerometer in Patients With Stable Heart Failure.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jchf.2021.05.013
Abstract-
This study examined the link between accelerometer recordings and cardiac pathophysiology measured with right heart cauterization at rest and with exercise in patients with HFrEF.
Background
Patient-worn accelerometers are increasingly being used in patients with heart failure with reduced ejection fraction (HFrEF) to assess activity and serve as surrogate endpoints in heart failure trials.
Methods
Physical average daily activity (PADA) and total average daily activity according to accelerometer units were assessed in 63 patients (mean age 58 ± 10 years; mean ejection fraction 26% ± 4%). Patients underwent hemodynamic exercise testing and accelerometry. Patients were divided according to PADA in PADALow and PADAHigh activity level groups based on median counts per minute of physical activity.
Results
Patients in the PADALow group were older and more frequently treated with diuretics. At rest, the PADALow group was characterized by a lower cardiac index (2.2 ± 0.4 L/min/m2 vs 2.4 ± 0.4 L/min/m2; P = 0.01) and stroke volume (70 ± 19 mL vs 81 ± 17 mL; P = 0.02) but not pulmonary capillary wedge pressure (12 ± 5 mm Hg vs 11 ± 5 mm Hg; P = 0.3). The PADALow group reached a lower cardiac index (4.8 ± 1.7 L/min/m2 vs 6.6 ± 1.7 L/min/m2; P < 0.001) but not in pulmonary capillary wedge pressure (31 ± 12 mm Hg vs 27 ± 8 mm Hg; P = 0.2) at peak exercise. The attenuated increase was associated with an attenuated increase in stroke volume (94 ± 32 mL vs 121 ± 29 mL; P < 0.001) rather than a reduced increase in heart rate (42 ± 23 beats/min vs 52 ± 21 beats/min; P = 0.07). PADA and total average daily accelerometer units were associated with patient-reported functional impairment according to the Kansas City Cardiomyopathy Questionnaire but not with New York Heart Association functional class.
Conclusions
Among stable ambulatory patients with HFrEF, lower daily activity is associated with poorer cardiac index reserve and reduced cardiac index during exercise. (Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction; NCT03198585)
Dr. John W. Ostrominski is an internist at Brigham and Women's Hospital and Massachusetts General Hospital in Boston, Massachusetts. In this podcast Dr. Ostrominski discusses Cost and Value in Contemporary Heart Failure Clinical Guidance Documents.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jchf.2021.08.002
Abstract -
The researchers wanted to see if global longitudinal strain (GLS) is linked to the natural history of patients with heart failure (HF) who had a better ejection fraction (HFimpEF).
Background
The ejection fraction (EF) of the left ventricle (LV) generally improves in people who have a low EF. Patients with HFimpEF, on the other hand, have a wide range of clinical outcomes. GLS, a sensitive biomarker of LV systolic function, could help this population estimate the risk of future occurrences.
Methods
Retrospective examination of HF patients with LVEF greater than 40% on index echocardiography who had LVEF less than 40% on initial study and improved by 10%. On index echocardiography, GLS was measured using 2-dimensional speckle-tracking software. The primary outcome was the time it took for cardiovascular death or HF hospitalization/emergency treatment to occur for the first time.
Results
The median absolute values of GLS (aGLS) and LVEF from index echocardiogram were 12.7 percent (IQR: 10.8 percent-14.7 percent) and 52 percent (IQR: 46 percent -58 percent) for the 289 patients with HFimpEF, respectively. The primary endpoint occurred less frequently in patients with aGLS above the median than below it (21 percent vs 34 percent; P = 0.014); HR of 0.51; 95 percent CI: 0.33-0.81; P = 0.004; HR of 0.51; 95 percent CI: 0.33-0.81; P = 0.004; HR of 0.51; 95 percent CI: 0.33-0.81; P = 0.004; HR of 0.51; 95 percent CI: 0.3 When aGLS on index echocardiogram was assessed as a continuous variable, each 1% increase was associated with a lower likelihood of the composite endpoint; HR 0.86; 95 percent CI: 0.79-0.93; P 0.001, an association that persisted after multivariable adjustment; HR 0.90; 95 percent CI: 0.82-0.97; P = 0.01. Lower aGLS was linked to a higher chance of LVEF worsening.
Conclusions
GLS is a powerful predictor of future HF episodes and heart function impairment in patients with HFimpEF.
From 2005 to 2011, Kieran Docherty studied medicine at the University of Glasgow. He is a Cardiology Specialist Registrar in the West of Scotland Deanery and a Clinical Research Fellow at the University of Glasgow's Institute of Cardiovascular and Medical Sciences. In this podcast Dr. Docherty discuss Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jchf.2021.09.002
Abstract-
Objectives
The authors wanted to see how dapagliflozin affected patients in the DAPA-HF study across the risk range.
Background
The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening HF events and cardiovascular death in individuals with HF and lower ejection fraction in the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial.
Methods
Patients were classified into risk quintiles using the MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) PREDICT-HF (Risk of Events and Death in the Contemporary Treatment of Heart Failure) risk models. The authors looked at rates of the key composite outcome of a worsening HF event or cardiovascular death, as well as its components and all-cause mortality, by risk quintile, to see if risk influenced dapagliflozin's effect.
Results
In DAPA-HF, the MAGGIC score was available for 4,740 patients out of 4,744 (median score 22 [IQR: 18–25]). A one-point rise in A1 was linked to an 8.2 percent (95 percent CI: 6.9%–9.4%) greater relative risk of the primary outcome (P 0.001). The primary endpoint advantage of dapagliflozin vs placebo was equal across the MAGGIC risk score spectrum (interaction P = 0.71). With dapagliflozin added to standard medication, the total relative risk reduction (26 percent) resulted in 7 fewer patients in the highest MAGGIC risk quintile experiencing a main outcome per 100 person-years of treatment, compared to 2 in the lowest quintile. The results were comparable with PREDICT-HF, however this model provided superior risk discrimination.
Conclusions
In DAPA-HF, the advantages of dapagliflozin were consistent over a wide range of baseline risk.
Introduction
Individual clinical factors such as age, creatinine, and left ventricular ejection fraction (LVEF) are poor predictors of risk in individuals with heart failure (HF) (1-5). When assessing patients clinically, physicians informally integrate variables, although the most often used measure, the New York Heart Association (NYHA) classification, focuses on functional limitation associated to symptoms. Because of the lack of uniformity and subjectivity, as well as the minimal number of categories accessible (i.e., most patients are put in either class II or class III, despite classes I to IV are theoretically available), NYHA class has a limited function in predicting risk (1-5). At one end of the NYHA functional class continuum, well-treated patients may have minimal symptoms and little functional impairment, but they are nonetheless at significant risk, as seen by previous trials recruiting patients mostly in NYHA functional class II (6). Patients in NYHA functional class IV, on the other hand, are rarely enrolled in studies since this is often a temporary state from which patients improve or deteriorate to the point of hospital admission or death. Scores that incorporate all important characteristics provide a more accurate risk assessment. The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) score is one of the most extensively utilized since it just requires conventional clinical characteristics seen in most health-care settings (6-10). However, it was created before natriuretic peptides were widely used, and the only proven outcome it predicts is all-cause death (7). The PARADIGM-HF, a new prediction tool, was just released (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) PREDICT-HF (Risk of Events and Death in the Contemporary Treatment of Heart Failure), which contains natriuretic peptides, was constructed using the PARADIGM-HF study and verified in other large data sets (11). Using the MAGGIC and PREDICT-HF risk scores, we assessed the baseline risk of participants in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure experiment. We also looked at the effect of dapagliflozin against placebo in terms of baseline risk.
Methods
DAPA-HF was a randomized, double-blind, controlled trial in patients with HF with decreased ejection fraction (HFrEF) that compared dapagliflozin 10 mg once day to placebo when added to usual therapy (12-14). The procedure was approved by ethics boards at each participating hospital, and all patients supplied written informed permission.
Patients in the research
Men and women in NYHA functional classes II–IV with an LVEF of less than 40%, a high NT-proBNP level, and who were receiving optimal pharmaceutical and device therapy were eligible for the study. Symptoms of hypotension or a systolic blood pressure (SBP) of less than 95 mm Hg, an eGFR of less than 30 mL/min/1.73 m2, type 1 diabetes mellitus, or another condition likely to prevent patient participation in the trial or severely limit life expectancy were among the key exclusion criteria (see the design paper for a complete list of exclusion criteria) (12).
Results of the research
The primary outcome was a composite of a worsening HF episode (unplanned hospitalization or an urgent visit culminating in HF IV therapy) or cardiovascular death, whichever came first. We looked at the primary composite outcome, its components, and the predetermined secondary endpoint of all-cause death in this study.
Adverse events leading to trial treatment discontinuation and adverse events of interest were included in pre-specified safety evaluations (ie, volume depletion, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, amputation).
The MAGGIC risk score is a measure of how dangerous a person is.
In a nutshell, the MAGGIC score was created by examining 31 potential variables in 39,372 patients involved in 30 clinical trials and cohort studies using a multivariable risk model (7,15). Age (per 10 years), male sex, BMI (per 1 kg/m2 increase up to 30 kg/m2), current smoking, diabetes, SBP (per 10 mm Hg increase), NYHA functional class, LVEF (per 5% increase up to 40%), COPD, HF duration >18 months, creatinine (per 10 mol/L up to 350 mol/L), ACE inhibitor/ARB use, and -blocker use were identified as thirteen independent predictors of (significant interactions between LVEF and age and LVEF and SBP were also identified). The result was a simple integer score. The maximum score is 57, and a risk calculator (http://www.heartfailurerisk.org/) is available online.
PREDICT-HF is a risk assessment tool.
The PREDICT-HF risk calculator was created using a multivariable risk model based on an analysis of 63 candidate variables in 8,011 patients enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, and validated in 7,016 patients in the ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trial and 2,794 (11). Thirty independent predictors of death from any cause were discovered (Supplemental Table 1). The total of the multiplication of each variable in the model by the -coefficient was used to create a PREDICT-HF pseudoscore for this investigation. A constant from PARADIGM-HF, the derivation cohort, was then used to determine baseline survival. A PREDICT-HF score was multiplied by a factor of ten for comparison with the MAGGIC risk score. The highest score recorded was 83.8. There is an online risk calculator (http://www.predict-hf.com).
Analytical statistics
Each of the MAGGIC and PREDICT-HF scores were grouped into quintiles. In a Cox regression model, the effect of dapagliflozin versus placebo on each prespecified outcome throughout the risk spectrum was investigated. In a Cox regression model containing an interaction term between score quintile and treatment, the effect of risk and treatment on the occurrence of each outcome was investigated. We utilized a semiparametric proportional rates model to examine the treatment impact and quantify the treatment difference for the composite endpoint of total (including recurrent) HF hospitalizations and cardiovascular death. Predetermined adverse events were also investigated based on the risk score category. By including a risk score element in the models outlined above, the association between a 1-point rise in MAGGIC and PREDICT-HF scores and the probability of outcomes was investigated. Exponentiating the -coefficient for the score variable from these models yielded the increase in risk associated with a 1-point increase (ie, the hazard or rate ratio per 1-point increase in score).
Patients with HF for 18 months or longer receive 2 points on the MAGGIC score. In DAPA-HF, however, the duration of HF was classified as 0 to 3 months, 3 to 6 months, 6 to 12 months, 1 to 2 years, 2 to 5 years, and >5 years. In the main analysis, we added 2 points to a patient's score if they had HF for less than a year, and we did the same in a sensitivity analysis (Supplemental Table 2) if they had HF for more than two years.
DAPA-HF provided serum potassium, hemoglobin, bilirubin, aspartate aminotransferase, urea, and NT-proBNP values. The medians from the PARADIGM-HF cohort were utilized for the other laboratory data (albumin, uric acid, percent monocytes, absolute neutrophils, chloride, low-density lipoprotein, and triglycerides).
Harrell's C-statistic was used to examine model discrimination for all-cause death. STATA version 16.1 was used for all of the analyses. A statistically significant P value of 0.05 was used.
Results
A total of 4,744 patients, ranging in age from 22 to 94, were randomized. The average age of the participants was 66.3 years, with 76.6 percent of men, and 67.5 percent of patients in NYHA functional class II, 31.6 percent in functional class III, and 0.9 percent in functional class IV.
Dr. Marianna Fontana works as the Director at the Royal Free Hospital in the UCL CMR unit. She is a Honorary Consultant Cardiologist and Professor of Cardiology at the National Amyloidosis Centre at the University College London. In this video Dr. Fontana discusses the Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis.
https://www.jacc.org/doi/10.1016/j.jcmg.2021.06.022
Abstract
The goal of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of ATTR-CM patients; and investigate the relationship between LA pathology and mortality.
Background
The clinical importance of LA involvement in ATTR-CM is a hot topic in medicine.
Methods
In 5 explanted ATTR-CM atria, Congo red staining and immunohistochemistry were used to characterize the presence, type, and amount of amyloid and related alterations. In 906 individuals with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other), echo speckle tracking was employed to measure LA reservoir, conduit, contractile function, and stiffness.
Results
The 5 atria had a lot of ATTR amyloid infiltration, which caused loss of normal architecture, vascular remodeling, capillary disruption, and subendocardial fibrosis. After controlling for established predictors, echo speckle tracking in 906 patients with ATTR-CM revealed higher atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]), which remained independently linked with prognosis (lnLA stiff: HR: 1.23; 95 percent CI: 1.03-1.49; P = 0.029). The three phasic functional atrial components were severely harmed (reservoir 8.86 percent [5.94 percent -12.97 percent ]; conduit 6.5 percent [4.53 percent -9.28 percent ]; contraction function 4.0 percent [2.29 percent -6.56 percent ]). Atrial contraction was missing in 22.1 percent of patients with sinus rhythm (SR) "atrial electromechanical dissociation" on electrocardiograms (AEMD). Patients with AEMD had a worse outcome than those with SR and efficient mechanical contraction (P = 0.0018). Patients with atrial fibrillation who received AEMD had a similar prognosis.
Conclusions
ATTR-CM has a phenotype that includes considerable atrial infiltration, gradual loss of atrial function, and increasing stiffness, all of which are strong independent predictors of death. AEMD has developed as a distinct trait that can be used to identify patients in SR who have a bad prognosis.
Latest Videos
Prakriti Gaba, MD, Cardiology Fellow at Harvard Medical School. In this video, she speaks about the Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.
Outline
Origins:
REDUCE-IT was a double-blind experiment in which 8,179 statin-treated individuals with reduced low-density lipoprotein cholesterol and moderately increased triglycerides were randomly assigned to icosapent ethyl (IPE) or placebo. The primary objective, including death from cardiovascular (CV) causes, was significantly reduced. It was uncertain what effect IPE has on people who had previously had a myocardial infarction (MI).
Goals:
In REDUCE-IT, we wanted to look at the effect of IPE on ischemic events in patients who had previously had a MI.
Methodology:
We conducted post-hoc analysis on patients who had previously experienced MI. CV mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina were the primary endpoints. The most important secondary outcome was CV death, MI, or stroke.
Outcomes:
A total of 3,693 patients had a previous MI. With IPE vs placebo, the primary endpoint was lowered from 26.1 percent to 20.2 percent; HR: 0.74 (95 percent CI: 0.65-0.85; P = 0.00001). The main secondary endpoint was lowered from 18.0% to 13.3%; HR: 0.71 (95 percent CI: 0.61-0.84; P = 0.00006). There was also a substantial 35% relative risk reduction in total ischemia events (P = 0.0000001), 34% reduction in MI (P = 0.00009), 30% reduction in CV death (P = 0.01), and a 20% reduction in all-cause mortality (P = 0.054), despite a modest rise in atrial fibrillation. Sudden cardiac death and cardiac arrest were also drastically reduced by 40% and 56%, respectively.
Inferences:
Patients in REDUCE-IT with a history of recent MI who were treated with IPE had large and significant relative and absolute risk reductions in ischemic events, including CV mortality. (AMR101 Study to Assess Its Ability to Reduce Cardiovascular Events in High-Risk Patients With Hypertriglyceridemia and Statin Use. The primary goal is to assess the effect of 4 g/day AMR101 on the occurrence of a first major cardiovascular event. NCT01492361; [REDUCE-IT])
Ibrahim Sultan, MD, Associate Professor of Cardiothoracic Surgery, Director, Center for Thoracic Aortic Disease, Surgical Director, Center for Heart Valve Disease, UPMC Heart and Vascular Institute at UPMC. In this video, he speaks about Transfusion of non–red blood cell blood products does not reduce survival following cardiac surgery.
Outline
Goals:
The evidence suggests that patients undergoing cardiac surgery who receive perioperative packed red blood cell (pRBC) transfusions have an increased risk of death. The current investigation is to determine whether there is a link between non–pRBC blood product transfusions and higher mortality.
Methodology:
Patients who underwent heart surgery between 2010 and 2018 were included in data from our center's Society of Thoracic Surgeons database. Patients requiring pRBC infusions or experiencing circulatory arrest were excluded. Propensity matching (1:1; caliper = 0.2 times the standard deviation of logit of propensity score) was used. Cox regression and Kaplan–Meier estimates were utilized. This study excluded individuals with cardiac transplants, ventricular assist devices, transcatheter aortic valves, and circulatory arrest.
Outcomes:
A total of 8042 patients met the analytic requirements. 395 patients requiring perioperative non–pRBC blood products (platelets, fresh-frozen plasma, and cryoprecipitate) were matched with 395 nontransfusion patients using propensity matching (1:1), resulting in equitable patient cohorts. The median duration of follow-up was 4.5 (3.0-6.4) years. Platelets (327 [82.8 percent]), fresh-frozen plasma (141 [35.7 percent]), and cryoprecipitate were given to patients (60 [15.2 percent ]). There was no statistically significant difference in postoperative mortality (6 [1.5%] vs 4 [1.0%]; P =.52). The transfusion group had higher rates of reoperation (20 [5.0 percent] vs 8 [2.0 percent]; P.02) and prolonged ventilation (36 [9.1 percent] vs 19 [4.8 percent]; P.02). Blood product use was strongly linked with emergent surgery (odds ratio [OR] 2.86 [1.72-4.78]; P.001), intra-aortic balloon pump (OR 3.24 [1.64-6.39]; P.001), and multivalve surgery (OR 4.34 [2.83-6.67]; P.001). Blood product transfusion (hazard ratio: 1.15 [0.89-1.48]; P =.3) was not related with an increased risk of death. There was no significant difference in long-term survival between groups.
Findings:
Those undergoing cardiac surgery who require blood products alone, without pRBC transfusion, have comparable postoperative and long-term survival to patients who do not require blood products. These findings are based on a small number of patients, and further research will help to improve the generalizability of these findings.
Andrea Natale M.D., F.A.C.C., F.H.R.S., F.E.S.C., Executive Medical Director, Texas Cardiac Arrhythmia Institute at St. David’s Medical Center at Texas Cardiac Arrhythmia. In this video, he speaks about Endocardial Scar-Homogenization With vs Without Epicardial Ablation in VT Patients With Ischemic Cardiomyopathy.
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Observation -
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Goals:
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The authors of this study compared the success of scar homogeneity with a mixed (epicarddial + endocardial) vs endocardial-only technique for ventricular tachycardia (VT) in patients with ischemic cardiomyopathy (ICM) at 5 years of follow-up.
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Origins:
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The best ablation strategy for achieving long-term success in VT patients with ICM is unknown.
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Methodology:
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Patients with ICM who underwent VT ablation at our center were divided into two groups: endocardial + epicardial scar homogenization and endocardial scar homogenization. Patients who had already undergone open heart surgery were not eligible. Despite the fact that all group 1 patients were noninducible following endocardial ablation, epicardial ablation was done. All patients received bipolar substrate mapping with conventional scar settings of >1.5 mV for normal tissue and 0.5 mV for severe scar. The procedure\'s endpoint in both groups was noninducibility of monomorphic VT. Implantable device interrogations were performed on patients every 4 months for 5 years.
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Outcomes:
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The study included 361 participants (n = 70 in group 1 and n = 291 in group 2). At 5 years, 81.4 percent (n = 57/70) of group 1 patients and 66.3 percent (n = 193/291) of group 2 patients were arrhythmia-free (P = 0.01). Anti-arrhythmic medications (AAD) were used by 26 of 57 (45.6 percent) and 172 of 193 (89.1 percent) of the patients in groups 1 and 2 (log-rank P 0.001). Endo-epicarddial scar homogeneity was linked with a substantial reduction in arrhythmia recurrence after controlling for age, gender, and obstructive sleep apnea (HR: 0.48; 95 percent CI: 0.27-0.86; P = 0.02).
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Observations:
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Despite being noninducible following endocardial ablation, epicardial substrate was found in all group 1 patients in this series of patients with ICM and VT. Furthermore, when compared to endocardial ablation alone, combined endo-epicarddial scar homogeneity was linked with a much higher success rate at 5 years of follow-up and a significantly lower demand for antiarrhythmic medicines after the treatment.
Scott Wright, MD, Professor of Medicine, Chair of the IRB at the Mayo Clinic. In this video, he speaks about the Phase III ORION-9,10, and 11 Studies.
In summary:
This is a placebo-controlled, double-blind, randomized Phase III research in patients with ASCVD with increased LDL-C despite the maximum tolerated dose of LDL-C lowering treatments to assess the efficacy, safety, and tolerability of subcutaneous (SC) inclisiran injection (s). The study will be conducted in multiple locations across the United States.
Amyloidosis
Dr. Oscar M. Westin is a PHd student and a medical doctor at the University Hospital of Copenhagen's Heart Center, Rigshospitalet. In this Podcast Dr. Westin speaks on the Two Decades of Cardiac Amyloidosis: A Danish Nationwide Study.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Cardiac amyloidosis (CA) is linked to a bad prognosis. According to screening studies, CA is often ignored, especially in the elderly. Recent therapy improvements have drawn attention to the condition, although data on CA epidemiology across time is scarce.
Objectives
The goal of this study was to describe all CA patients in Denmark from 1998 to 2017, as well as to look at changes in patient characteristics over time.
Methods
In Danish nationwide registries, all patients with any kind of amyloidosis diagnosed between 1998 and 2017, as well as their comorbidities and medication, were identified. Any diagnosis code for amyloidosis paired with a diagnosis code for heart failure, cardiomyopathy, or atrial fibrillation, or a procedural code for pacemaker installation, regardless of order, was classified as CA. The index date was established as the date on which those criteria were met. By index date, patients were separated into 5-year segments. We also included control subjects (1:4 ratio) from the general population as a comparison.
Results
619 patients met the CA requirements. The median age at baseline grew from 67.4 years (interquartile range [IQR]: 53.9-75.2 years) in 1998-2002 to 72.3 years in 2013-2017. (IQR: 66.0-79.3 years). Male patients grew from 62.1 percent to 66.2 percent of all patients. In the Danish population aged 65 years, the incidence of CA increased from 0.88 to 3.56 per 100,000 person-years, whereas 2-year mortality reduced from 82.6 percent (IQR: 69.9 percent -90.5 percent) to 50.2 percent (IQR: 43.1 percent -56.9 percent ). CA patients had a considerably greater mortality rate than control participants (log-rank test: P 0.0001).
Conclusions
On a nationwide scale, CA, as defined in this study, was becoming more prevalent. The rising number of male patients and median age indicate that wild-type transthyretin amyloidosis is to blame. The fact that earlier, less advanced illnesses are being recognized more often could explain the lower fatality rate.
Dr. Marianna Fontana works as the Director at the Royal Free Hospital in the UCL CMR unit. She is a Honorary Consultant Cardiologist and Professor of Cardiology at the National Amyloidosis Centre at the University College London. In this video Dr. Fontana discusses the Clinical Importance of Left Atrial Infiltration in Cardiac Transthyretin Amyloidosis.
https://www.jacc.org/doi/10.1016/j.jcmg.2021.06.022
Abstract
The goal of this study was to characterize left atrial (LA) pathology in explanted hearts with transthyretin amyloid cardiomyopathy (ATTR-CM); LA mechanics using echocardiographic speckle-tracking in a large cohort of ATTR-CM patients; and investigate the relationship between LA pathology and mortality.
Background
The clinical importance of LA involvement in ATTR-CM is a hot topic in medicine.
Methods
In 5 explanted ATTR-CM atria, Congo red staining and immunohistochemistry were used to characterize the presence, type, and amount of amyloid and related alterations. In 906 individuals with ATTR-CM (551 wild-type (wt)-ATTR-CM; 93 T60A-ATTR-CM; 241 V122I-ATTR-CM; 21 other), echo speckle tracking was employed to measure LA reservoir, conduit, contractile function, and stiffness.
Results
The 5 atria had a lot of ATTR amyloid infiltration, which caused loss of normal architecture, vascular remodeling, capillary disruption, and subendocardial fibrosis. After controlling for established predictors, echo speckle tracking in 906 patients with ATTR-CM revealed higher atrial stiffness (median [25th-75th quartile] 1.83 [1.15-2.92]), which remained independently linked with prognosis (lnLA stiff: HR: 1.23; 95 percent CI: 1.03-1.49; P = 0.029). The three phasic functional atrial components were severely harmed (reservoir 8.86 percent [5.94 percent -12.97 percent ]; conduit 6.5 percent [4.53 percent -9.28 percent ]; contraction function 4.0 percent [2.29 percent -6.56 percent ]). Atrial contraction was missing in 22.1 percent of patients with sinus rhythm (SR) "atrial electromechanical dissociation" on electrocardiograms (AEMD). Patients with AEMD had a worse outcome than those with SR and efficient mechanical contraction (P = 0.0018). Patients with atrial fibrillation who received AEMD had a similar prognosis.
Conclusions
ATTR-CM has a phenotype that includes considerable atrial infiltration, gradual loss of atrial function, and increasing stiffness, all of which are strong independent predictors of death. AEMD has developed as a distinct trait that can be used to identify patients in SR who have a bad prognosis.
Dr. Alexander is a cardiologist with advanced training in heart failure. He also works at Stanford University School of Medicine as an Assistant Professor of Cardiovascular Medicine. Dr. Alexander sees a wide range of patients and specializes in the care of severe heart failure and transplant situations. He also runs a research center that studies various types of heart failure. In this video Dr. Alexander discusses Using Bone Scintigraphy to Diagnose Cardiac Amyloidosis in Patients With a Monoclonal Gammopathy.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.06.002
Abstract-
Introduction
When amyloid fibrils invade the myocardial interstitium, causing a stiffened myocardium and restrictive cardiomyopathy, cardiac amyloidosis (CA) develops. CA is caused by systemic light chain amyloidosis (AL) or transthyretin amyloidosis in more than 95% of cases (ATTR). A clonal plasma cell dyscrasia that produces amyloidogenic monoclonal immunoglobulins causes AL amyloidosis. These immunoglobulins then misfold and deposit in the heart, kidneys, liver, gastrointestinal tract, and peripheral nerves, among other organs (1). Transthyretin (2), a liver-derived thyroid hormone and retinol protein transporter, experiences tetramer dissociation, misfolds, and produces amyloid fibrils in various distant organs, resulting in ATTR amyloidosis (3).
It's critical to distinguish between AL and ATTR amyloidosis since their clinical outcomes and therapies are vastly different. Continued amyloid accumulation promotes greater organ damage, hence delays in diagnosis result in poorer results. Furthermore, diagnostic ambiguity may cause a delay in the start of amyloid-directed treatment.
As a result, a high index of clinical suspicion combined with adequate diagnostic sequencing can lead to an accurate and rapid diagnosis of CA. We provide a patient case that demonstrates the difficulties that can arise when 99mtechnetium pyrophosphate scintigraphy (99mTc-PYP) scanning is used inappropriately to identify ATTR-CA in a patient with suspected CA and a plasma cell dyscrasia.
Description of the Situation
A 63-year-old man with bilateral carpal tunnel syndrome reported with dyspnea on exertion, positional lightheadedness, and chest pain to an outpatient facility. He had a mildly increased troponin I level of 0.23 ng/mL during his first episode of chest pain (reference range: 0-0.09 ng/mL). He had 510 pg/mL of N-terminal pro–B-type natriuretic peptide (reference range: 100 pg/mL). In leads II, III, and aVF, an electrocardiogram indicated sinus rhythm, a right bundle branch block, and Q waves. A left ventricular ejection fraction of 55%, bi-atrial enlargement, concentric left ventricular hypertrophy, and grade II diastolic dysfunction were discovered on an echocardiography. Coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient was prescribed furosemide, metoprolol, lisinopril, and spironolactone after being diagnosed with heart failure with preserved ejection fraction due to hypertension. However, due to hypotension, metoprolol was quickly withdrawn, and he was switched to midodrine. Despite medical treatment, the patient had many outpatient visits and was admitted to the hospital for dyspnea and chest pain on multiple occasions.
The patient was evaluated for ischemia again two years later. During exercise, an exercise treadmill test revealed no inducible ischemia but did reveal paroxysmal supraventricular tachycardia and infrequent premature ventricular contractions. In a second Zio Patch (iRhythm Technologies, Inc) investigation, nonsustained ventricular tachycardia was discovered, with the longest episode lasting 39 beats. A second coronary angiography revealed that there was no evidence of obstructive coronary artery disease. The patient's nonischemic cardiomyopathy was subsequently investigated further using cardiac magnetic resonance imaging (CMR). A left ventricular ejection fraction of 39%, modest concentric left ventricular hypertrophy, and diffuse late gadolinium enhancement with an inability to null the blood pool were all found on CMR imaging, all of which were problematic for CA.
Following these findings, the CMR report indicated that hematologic testing for monoclonal gammopathy and a 99mTc-PYP scan be conducted in parallel. An aberrant immunoglobulin G lambda monoclonal protein was discovered by serum electrophoresis with immunofixation. A serum free lambda of 152.03 mg/L (reference range: 5.71-26.30 mg/L), a serum free kappa of 8.91 mg/L (reference range: 3.30-19.40 mg/L), and a kappa:lambda ratio of 0.06 were found in serum free light chains (reference range: 0.26-1.65). When taken together, these findings point to a lambda monoclonal gammopathy. The patient also had a 99mTc-PYP scan during this time, which exhibited a heart/contralateral lung ratio of 1.47 and was read as grade 2 myocardial uptake (myocardial tracer uptake equals rib uptake) (Figure 1). However, single-photon emission computed tomography (SPECT) imaging with obvious myocardial uptake was inconclusive. His team identified him with wild-type ATTR amyloidosis based on the 99mTc-PYP scan and TTR genetic testing that came out negative for a variation.
Our center was referred to the patient for further treatment. The patient underwent an endomyocardial biopsy two months following the 99mTc-PYP scan due to the existence of a monoclonal gammopathy, which proved CA. When mass spectrometry was used to subtype amyloid, it discovered a peptide profile that was compatible with AL (lambda)-type amyloid deposition rather than ATTR amyloidosis. A later bone marrow biopsy indicated a lambda-restricted plasma cell population of 10% to 20%. As a result, the patient was diagnosed with AL-CA. The initial misdiagnosis of ATTR-CA was due to the incorrect use and interpretation of 99mTc-PYP imaging. As a result, there was a three-month gap between the initial identification of a monoclonal gammopathy and the start of AL-CA treatment.
Bortezomib, cyclophosphamide, and dexamethasone were given to the patient as an anti-plasma cell therapy. Daratumumab was later added to the mix. Hematologic remission was achieved for the patient. Despite his hematologic remission, he nevertheless had considerable limitations as a result of his cardiac condition (New York Heart Association functional class III heart failure symptoms and orthostasis, requiring midodrine).
Discussion
This instance illustrates the dangers of using and interpreting 99mTc-PYP scans incorrectly during a CA examination. It also underlines the significance of early detection and therapy in AL-CA in order to reverse the myocardium's consequences of light chain toxicity and fibril deposition. For detecting ATTR amyloidosis, bone scintigraphy has emerged as a viable noninvasive alternative to endomyocardial biopsy. Endomyocardial biopsy has long been the gold standard for confirming ATTR amyloidosis histologically. This treatment, however, can result in problems like as tamponade and valvular injury, and should only be performed by experienced clinicians. Bone scintigraphy, on the other hand, is simpler to perform and more widely available in most clinical settings. As a result, bone scintigraphy may make it easier to diagnose ATTR amyloidosis, a previously underdiagnosed but curable cause of heart failure (2).
Expert guidelines and consensus recommendations underline the need of excluding AL amyloidosis when scheduling a bone scintigraphy scan because >20 percent of patients with AL-CA will have grade 2 or 3 radiotracer uptake (4,5). If a monoclonal gammopathy is ruled out via serum and urine testing, grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy provides a 100 percent specificity and positive predictive value for ATTR-CA (6). It's crucial to get SPECT pictures for bone scintigraphy scans in addition to ruling out AL amyloidosis. Planar scintigraphy can result in false-positive scan results if radiotracer blood pooling occurs and is mistaken for myocardial uptake (7). According to follow-up SPECT imaging, the false-positive rate in individuals with grade 2 uptake on planar images is 64 percent due to blood pooling or a lack of myocardial uptake (8).
In situations of monoclonal gammopathy, a biopsy (e.g., endomyocardial) should be used instead of a 99mTc-PYP scan to confirm the presence of CA and correctly characterize the amyloid subtype. Because many older individuals with ATTR-CA can also have an unrelated monoclonal gammopathy, biopsy is still required in many cases in lieu of a 99mTc-PYP scan to confirm an ATTR-CA diagnosis (9).
It's critical to follow diagnostic standards to guarantee a thorough and accurate assessment of CA (10). Understanding the appropriate usage and caveats of interpreting bone scintigraphy will be critical to avoid misdiagnosis as ATTR-CA becomes more widely recognized and 99mTc-PYP scans become more extensively used. When there is a clinical suspicion of CA based on history, electrocardiography, echocardiography, CMR imaging, or biomarkers, consensus recommendations call for CA screening. Many clinical indicators were present in our patient, including intolerance to heart failure medicines and orthostatic hypotension needing midodrine. He also experienced bilateral carpal tunnel syndrome and a low-level positive troponin reading for a long time. Although ATTR was suspected, the initial step was to rule out the presence of a monoclonal gammopathy, as finding a monoclonal protein would necessitate an endomyocardial biopsy to rule for AL amyloidosis. A positive 99mTc-PYP scan must be evaluated in the context of ruling out AL amyloid while screening for a monoclonal gammopathy and undergoing 99mTc-PYP. Furthermore, whereas 99mTc-PYP planar pictures demonstrated grade 2 tracer uptake in our patient, SPECT imaging revealed no obvious myocardial uptake, increasing the possibility of a false-positive finding due to blood pool uptake. Despite the existence of a gammopathy, the patient was wrongly diagnosed with ATTR-CA because the 99mTc-PYP scan indicated radiotracer uptake. After a later endomyocardial biopsy and amyloid subtyping using mass spectrometry, the actual diagnosis of AL amyloidosis was made.
Conclusions
In patients with signs of monoclonal gammopathy, an endomyocardial biopsy is required for a proper diagnosis of CA. Bone scintigraphy imaging is a potentially noninvasive technology that has the potential to improve ATTR-CA diagnosis, a previously unknown but now curable cause of heart failure. A clear framework for CA evaluations, on the other hand, is critical for avoiding diagnostic delays and increasing outcomes. This is especially important for AL-CA, which has a median survival time of 6 months if left untreated (11). Our example highlights the dangers of using and interpreting bone scintigraphy imaging for CA incorrectly, as well as the significance of checking for an underlying plasma cell dyscrasia. Providers will need to follow a systematic diagnostic strategy as knowledge of CA and novel therapeutics rises, in order to minimize undue financial hardship and diagnostic delay.
Dr. Jan Griffin is a cardiologist at New York-Presbyterian/Columbia University Irving Medical Center in New York, NY. She graduated from the Royal College of Surgeons of Ireland with a medical degree. In this video Dr. Griffin discusses ATTR Amyloidosis: Current and Emerging Management Strategies.
Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.05.004
Abstract-
Because of noninvasive imaging and increased awareness, transthyretin cardiac amyloidosis (ATTR-CA) is becoming more common. Because pathogenic alleles do not have complete clinical penetrance, there is a substantial population of asymptomatic transthyretin variant carriers. More research is needed into screening techniques, monitoring, and therapy of subclinical ATTR-CA. The development of effective medicines based on a scientific understanding of ATTR-CA pathogenesis is perhaps the most significant translational success. These include recently established transthyretin protein stabilization and transthyretin production suppression methods. Data on neurohormonal blocking in ATTR-CA is scarce, with medical treatment focusing primarily on fluid management. Atrial fibrillation is a frequent condition that necessitates anticoagulation due to the risk of thrombus formation. Although conduction disorders and ventricular arrhythmias are common, little is known about the best ways to treat them. Finally, because aortic stenosis and ATTR-CA are usually seen together, transcatheter valve replacement is the chosen treatment option.
Highlights
• ATTR-CA is becoming more well-known as a result of increased awareness and the development of noninvasive diagnostic approaches.
• Clinical penetrance of harmful alleles is incomplete, with inadequate data for asymptomatic carriers' screening or care.
• Biological understanding of ATTR-CA pathophysiology has led to effective TTR stabilizers and silencers as targeted therapeutics.
• Future treatments could involve CRISPR, amyloid extraction/degradation, and amyloid seeding inhibition.
Introduction
Over the last decade, the field of transthyretin cardiac amyloidosis (ATTR-CA) has undergone a transformation, with an increasing recognition that many ATTR-CA patients were previously undiagnosed and instead assumed to have hypertension, heart failure with preserved ejection fraction (HFpEF), or hypertrophic cardiomyopathy (1). Delays in diagnosis were almost prevalent, and they still exist today, sadly (2). However, with increased awareness of clinical clues and the ability to diagnose ATTR-CA without a biopsy (3), reports have shown ATTR-CA in patients hospitalized with HFpEF (13%) (4), patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR) (16%) (5), and up to 40% of high-risk populations, such as Afro-Caribbeans with heart failure and increased ventricular wall thickness undergoing TAVR (6). As a result, every cardiologist has come across patients with ATTR-CA, whether they are aware of it or not. Despite the exponential increase in the use of cardiac bone scintigraphy and multisocietal guidelines supporting nonbiopsy diagnosis (7,8), there are certain major traps to avoid. Failure to check for monoclonal proteins or an over-reliance on planar imaging are two examples (9). The development of effective medicines based on a biological understanding of the underlying pathophysiology has been the most significant "translational victory" (10). These treatments have a significant impact on the quality and quantity of life for those who are afflicted. This article focuses on the treatment of ATTR-CA patients and the evolving therapy landscape (Central Illustration).