Acute Coronary Syndromes - Acute Coronary Syndromes - 559 · acute-coronary-syndromes

Dr. Brendan Carry is an American Board of Internal Medicine certified Cardiologist who attended Thomas Jefferson University. In this video Dr. Carry will discuss Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records


Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.07.002


Abstract

Background
New treatments for transthyretin amyloidosis help patients live longer, but diagnosis is still difficult. Transthyretin amyloidosis is caused by pathogenic or probable pathogenic (P/LP) mutations in the transthyretin (TTR) gene, and genomic screening has been proposed to detect at-risk individuals. However, there is a lack of data on illness characteristics and penetrance to help determine the efficacy of population-based genomic screening for TTR.

Objectives
This study looked at the prevalence of P/LP variations in TTR discovered using exome sequencing, as well as the burden of disease associated with these variants based on electronic health records for people with these variants from a large (N = 134,753), mostly European-ancestry sample.

Methods
Individuals with and without P/LP TTR mutations were compared in terms of the frequency of common illness symptoms and cardiac imaging findings.

Results
We found P/LP TTR variations in 157 of 134,753 (0.12 percent) people (43 percent male, median age 52 [Q1-Q3: 37–61] years). All findings were accounted for by seven P/LP variations, the bulk of which were V122I. (p.V142I; 113, 0.08 percent ). African ancestry was found in approximately 60% (n = 91) of people with P/LP TTR mutations (all V122I). Although associated heart disease diagnoses, such as cardiomyopathy and heart failure, were considerably higher in individuals with P/LP TTR variations who were over 60 years old, amyloidosis diagnoses were rare (2 of 157 patients). Only one of the 14 percent (7 of 49) of people aged 60 or older with a P/LP TTR variation had cardiac disease and a ventricular septal thickness greater than 1.2 cm, and only one of them had amyloidosis.

Conclusions
Individuals with P/LP TTR variations discovered through genomic screening had a higher risk of heart disease after 60 years, despite the fact that amyloidosis is likely underdiagnosed without knowing the genetic variant.

Dr. Brendan Carry is an American Board of Internal Medicine certified Cardiologist who attended Thomas Jefferson University. In this video Dr. Carry will discuss Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records


Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.07.002


Abstract

Background
New treatments for transthyretin amyloidosis help patients live longer, but diagnosis is still difficult. Transthyretin amyloidosis is caused by pathogenic or probable pathogenic (P/LP) mutations in the transthyretin (TTR) gene, and genomic screening has been proposed to detect at-risk individuals. However, there is a lack of data on illness characteristics and penetrance to help determine the efficacy of population-based genomic screening for TTR.

Objectives
This study looked at the prevalence of P/LP variations in TTR discovered using exome sequencing, as well as the burden of disease associated with these variants based on electronic health records for people with these variants from a large (N = 134,753), mostly European-ancestry sample.

Methods
Individuals with and without P/LP TTR mutations were compared in terms of the frequency of common illness symptoms and cardiac imaging findings.

Results
We found P/LP TTR variations in 157 of 134,753 (0.12 percent) people (43 percent male, median age 52 [Q1-Q3: 37–61] years). All findings were accounted for by seven P/LP variations, the bulk of which were V122I. (p.V142I; 113, 0.08 percent ). African ancestry was found in approximately 60% (n = 91) of people with P/LP TTR mutations (all V122I). Although associated heart disease diagnoses, such as cardiomyopathy and heart failure, were considerably higher in individuals with P/LP TTR variations who were over 60 years old, amyloidosis diagnoses were rare (2 of 157 patients). Only one of the 14 percent (7 of 49) of people aged 60 or older with a P/LP TTR variation had cardiac disease and a ventricular septal thickness greater than 1.2 cm, and only one of them had amyloidosis.

Conclusions
Individuals with P/LP TTR variations discovered through genomic screening had a higher risk of heart disease after 60 years, despite the fact that amyloidosis is likely underdiagnosed without knowing the genetic variant.

Dr. Michael R. Jaff, Vice President of Clinical Affairs, Innovation, Technology, and Peripheral Interventions at Boston Scientific, is a world-renowned vascular medicine expert. In this video Dr. Jaff discusses the Primary Results of the Randomized Trial of Eluvia DES vs Bare Metal Stents.

Link to Abstract-
https://clinicaltrials.gov/ct2/show/study/NCT02921230

The EMINENT research is a prospective, multi-center trial that found the ELUVIA stent to be more effective than self-expanding bare nitinol stents in treating femoropopliteal artery lesions.

The EMINENT research is a prospective, multi-center study that found the ELUVIA stent to be more successful than Self-Expanding Bare Nitinol Stents in treating lesions 30-210 mm length in the femoropopliteal arteries in people with Rutherford classifications 2-4 symptoms.

The experiment is a controlled, single-blind, 2:1 randomized (ELUVIA vs. Self-Expanding Bare Nitinol Stents) superiority trial (RCT).

The study's goal is to confirm the greater effectiveness of the ELUVIA Drug-Eluting Vascular Stent System (ELUVIA Stent) in treating SFA and/or PPA lesions up to 210 mm in length when compared to bare metal stents, as well as collect other data, such as health economics data.

Dr. Borge Gronne Nordestgaard is a clinical biochemist, genetic epidemiologist, educator, and Danish National Board of Health certified clinical biochemistry specialist. He received the Boserup Foundation's prize in 1994, the Quentin's Foundation's prize in 2001, and the Carlsen's Foundation's prize in 2005. In this video Dr. Nordestgaard speaks on how Elevated remnant cholesterol increases the risk of peripheral artery disease, myocardial infarction, and ischaemic stroke.

Link to Abstract:
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab705/6399975?login=true


Aims
Cholesterol in triglyceride-rich lipoproteins, also known as residue cholesterol, is increasingly recognized for its atherogenic potential. Remaining cholesterol levels are linked to a higher risk of myocardial infarction and ischemic stroke. We investigated whether high residual cholesterol is linked to an increased risk of peripheral arterial disease (PAD).

Methods and outcomes
We looked at 106 937 people from the Copenhagen General Population Study who were recruited between 2003 and 2015. 1586 people were diagnosed with PAD, 2570 with myocardial infarction, and 2762 with ischemic stroke over the course of the study, which lasted up to 15 years. We also looked at 13 974 people who were part of the Copenhagen City Heart Study in 1976–78. During the study's 43-year follow-up, 1033 people were diagnosed with PAD, 2236 with MI, and 1976 with ischemic stroke. A conventional lipid profile was used to quantify residual cholesterol. The diagnoses came from national health registries in Denmark. In the Copenhagen General Population Study, people with residual cholesterol levels of 1.5 mmol/L (58 mg/dL) vs. 0.5 mmol/L (19 mg/dL) had a multivariable adjusted hazard ratio (HR) of 4.8 (95 percent confidence interval 3.1–7.5) had a greater risk of PAD. Myocardial infarction had a score of 4.2 (2.9–6.1) and ischemic stroke had a score of 1.8 (1.4–2.5). In the Copenhagen City Heart Study, the associated HRs for PAD, myocardial infarction, and ischemic stroke were 4.9 (2.9–8.5), 2.6 (1.8–3.8), and 2.1 (1.5–3.1).

Conclusion
In the general population, elevated residual cholesterol is linked to a five-fold greater risk of PAD, which is higher than the risk of myocardial infarction and ischemic stroke.

Dr. Borge Gronne Nordestgaard is a clinical biochemist, genetic epidemiologist, educator, and Danish National Board of Health certified clinical biochemistry specialist. He received the Boserup Foundation's prize in 1994, the Quentin's Foundation's prize in 2001, and the Carlsen's Foundation's prize in 2005. In this video Dr. Nordestgaard speaks on how Elevated remnant cholesterol increases the risk of peripheral artery disease, myocardial infarction, and ischaemic stroke.

Link to Abstract:
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab705/6399975?login=true


Aims
Cholesterol in triglyceride-rich lipoproteins, also known as residue cholesterol, is increasingly recognized for its atherogenic potential. Remaining cholesterol levels are linked to a higher risk of myocardial infarction and ischemic stroke. We investigated whether high residual cholesterol is linked to an increased risk of peripheral arterial disease (PAD).

Methods and outcomes
We looked at 106 937 people from the Copenhagen General Population Study who were recruited between 2003 and 2015. 1586 people were diagnosed with PAD, 2570 with myocardial infarction, and 2762 with ischemic stroke over the course of the study, which lasted up to 15 years. We also looked at 13 974 people who were part of the Copenhagen City Heart Study in 1976–78. During the study's 43-year follow-up, 1033 people were diagnosed with PAD, 2236 with MI, and 1976 with ischemic stroke. A conventional lipid profile was used to quantify residual cholesterol. The diagnoses came from national health registries in Denmark. In the Copenhagen General Population Study, people with residual cholesterol levels of 1.5 mmol/L (58 mg/dL) vs. 0.5 mmol/L (19 mg/dL) had a multivariable adjusted hazard ratio (HR) of 4.8 (95 percent confidence interval 3.1–7.5) had a greater risk of PAD. Myocardial infarction had a score of 4.2 (2.9–6.1) and ischemic stroke had a score of 1.8 (1.4–2.5). In the Copenhagen City Heart Study, the associated HRs for PAD, myocardial infarction, and ischemic stroke were 4.9 (2.9–8.5), 2.6 (1.8–3.8), and 2.1 (1.5–3.1).

Conclusion
In the general population, elevated residual cholesterol is linked to a five-fold greater risk of PAD, which is higher than the risk of myocardial infarction and ischemic stroke.

Dr. Artur Fedorowski earned his MD and PhD in internal medicine and cardiology from the Wroclaw Medical University in Poland. Since 2013, he has worked as an Associate Professor at Lund University, and since 2016, he has been a Fellow of the European Society of Cardiology. Dr. Fedorowski has vast experience in cardiology and cardiovascular medicine. In this video Dr. Fedorowski speaks about Thrombosis and fibrinolysis in atherosclerotic cardiovascular disease.

Link to Article:
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab710/6408927

Walter Bradford Cannon (1871–1945) developed the term "homeostasis," which refers to "any self-regulating process by which biological systems strive to preserve stability while responding to conditions that are optimal for survival." If homeostasis is achieved, life continues; if it is not, disaster or death follows' (Encyclopaedia Britannica; www.britannica.com). Haemostatic capacity, which prevents bleeding while preserving unobstructed blood flow, is one of the most important aspects of human homeostasis. Platelets and the coagulation system are two key components of haemostasis, working together to form a haemostatic plug when vascular continuity is interrupted. Coagulation and platelet activity are turned off by circulating inhibitors and proteolytic feedback loops to reduce the danger of arterial occlusion. 2 Otherwise, uncontrolled haemostatic activity will cause thrombo-embolic problems, leading to 'disaster or death' in the worst-case scenario. Prothrombotic and fibrinolytic forces are thus intertwined, resulting in a homeostatic steady state that responds to vascular emergencies.

DeFilippis et al.3 present a prospective study based on a multi-ethnic cohort of 5800 adults (mean age 63 years) without a history of atherosclerotic cardiovascular disease (ASCVD) from six communities in the United States in this issue of the European Heart Journal. The participants were recruited between 2000 and 2002 and monitored for 15 years, during which time 15% of them had a cardiovascular event. Blood samples were taken at the start of the study to look for circulating prothrombotic and fibrinolytic factors to see if there was a biomarker pattern that could predict incident ASCVD. The authors' technique is unique in that it uses two composite variables called thrombotic and fibrinolytic factors. Five biomarkers contributed to the thrombotic factor [fibrinogen, plasmin–antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a)], and two contributed to the fibrinolytic factor [plasminogen and oxidized phospholipids on plasminogen (OxPL-PLG)]. The authors discovered that a higher thrombotic factor score and a lower fibrinolytic factor score suggested the highest risk of incident atherothrombotic events (Graphical Abstract).

Higher levels of fibrinogen, D-dimer, plasmin–antiplasmin, factor VIII, and Lp(a) have previously been linked to an increased risk of CV events, therefore the findings of this significant study3 were not entirely unexpected.

4–7 Importantly, circulating levels of both plasminogen and OxPLs, which indicate reduced fibrinolytic activity, were significantly lower in patients with incident myocardial infarction at baseline compared to stable coronary artery disease patients and unaffected subjects, but increased immediately after percutaneous coronary intervention. 8 What's new is that assessing the balance between the competing processes of thrombosis and fibrinolysis should help forecast CV events more precisely. The authors underline that when the two biomarker sets are evaluated combined, they provide additional information. It was proved in a statistical model where the relative risks were increased once both factors were input at the same time. Notably, there was a moderately positive association between these two variables, implying that increased thrombotic propensity is frequently counterbalanced by increased fibrinolytic propensity. When thrombotic propensity and fibrinolytic propensity were uneven, i.e. when an elevated thrombotic factor was associated with a low fibrinolytic factor, the risk of CV events was highest. As a result, patients with high fibrinolytic factor and low thrombotic factor values had the lowest risk of CV events. It's worth noting that the two factors had no effect on coronary artery calcification.

Adding thrombotic and fibrinolytic components to a multivariable Cox model using variables from the American Heart Association (AHA)–American College of Cardiology (ACC) CV disease risk prediction calculators resulted in a minor (albeit statistically significant) improvement in model fit (C-index increase from 0.718 to 0.721). As a result, the proposed model based on integrated coagulation biomarkers has the potential to provide extra information on CV risk prediction beyond what can be determined only from traditional risk variables. However, the question arises as to whether measuring the balance between thrombosis and fibrinolysis has therapeutic value when applied to well-established clinical risk models in a broad and perhaps arbitrary manner. Indeed, a recent study of community-dwelling middle-aged people found that a high CHA2DS2-VASc score, which was designed for patients with atrial fibrillation, was also a sensitive measure for predicting bad CV outcomes in people who did not have atrial fibrillation. 9

DeFilippis et al.3 claim that the new thrombotic and fibrinolytic factors allow for a more complete assessment of the balance between thrombosis and fibrinolysis, which determines the risk of atherothrombosis, and that the new factors have promise for predicting an individual's propensity to form thrombus, based on their findings. As a result, the model should integrate into precision medicine and has the ability to select individuals for antithrombotic therapy by weighing the risk of iatrogenic bleeding against the advantages of reducing atherothrombotic events. For primary CV prevention, such a tailored medicine strategy appears to be quite appealing. Despite this, the path from epidemiological observation to clinical application is typically protracted, with just a few biomarkers making it into current clinical practice. The primary difficulty here will be to show that the suggested composite biomarker prediction model is capable of selecting candidates for more or less aggressive CV disease prevention, beyond what can be clinically determined in conjunction with traditional risk assessment scores.

However, it should be highlighted that other major atherothrombotic risk factors, such as platelet indices and platelet reactivity, as well as atherosclerotic indicators, were not considered in DeFilippis et al.3's investigation (Graphical Abstract). Individuals with an increased platelet count at baseline had a significantly greater risk of death and severe CV events throughout a 16-year follow-up in the prospective Malmö Diet and Cancer cohort, regardless of the presence of CV disease. 10 Higher platelet aggregability, as well as pathways connected to atherosclerosis onset, progression, and complications in people with high platelet counts, could explain these findings. Furthermore, a study of the same cohort found that clustering of blood cell count abnormalities (e.g., anemia, leucocytosis, and thrombocytosis), a condition commonly seen in people with a high inflammatory milieu, poor health, or frailty, was linked to increased mortality and the risk of future CV events. 11 These findings, together with the findings of DeFilippis et al.3, raise the question of whether anticoagulants such as low-dose rivaroxaban12, rather than aspirin13, should be explored in primary CV prevention in those with a high prothrombotic profile.

DeFilippis et al.3's study has several clear strengths: robustness of data gathered prospectively from a large, representative population; independent and meticulous event adjudication; long follow-up duration; and long-term stability of healthcare and reporting systems. However, there are some significant restrictions. First, because the investigators only looked at baseline blood samples, the dynamic nature of atherothrombotic biomarkers was not investigated. Second, data on platelet reactivity, which is important for assessing atherothrombotic risk, were not available, and aetiological subtyping of CV events (for example, atherothrombotic vs. non-atherothrombotic myocardial infarction) was not done. The danger of residual confounding and a lack of detailed information on concomitant disorders or undiscovered diseases that could cause changes in coagulation patterns at baseline are two other drawbacks. Importantly, the relationships found by DeFilippis et al.3 do not prove causation and must be confirmed in separate cohorts. Furthermore, due to the demand for seven laboratory measurements, the model's relevance in the real world should be acknowledged. Finally, it will be interesting to see how thrombotic and fibrinolytic variables vary over time and how these changes relate to cardiovascular events.

Taken together, our findings support the notion that the use of multi-biomarker technologies can help to improve CV risk prevention even more. Different mechanisms (e.g. thrombosis, inflammation, and lipid plaque development) may coexist in the pathophysiology of atherothrombosis, with varied roles for each of these mechanisms in different individuals (Graphical Abstract). As a result, the best prediction model would combine data from the coagulation system, lipid metabolism, and inflammation. As a result, a two-step approach may be beneficial: first, individual clinical risk stratification to identify people at moderate to high risk of CV events, then multi-biomarker examination to determine which pathogenetic process (thrombosis vs. inflammation vs. lipid problems) is dominant. The latter may help the practitioner choose whether preventive strategies should be used on an individual basis. A machine learning approach may also be effective for developing multi-parametric models due to its accuracy in analyzing competitive hazards. 14 Another major concern is whether prothrombotic vs. fibrinolytic activity should be assessed separately.

Dr. Artur Fedorowski earned his MD and PhD in internal medicine and cardiology from the Wroclaw Medical University in Poland. Since 2013, he has worked as an Associate Professor at Lund University, and since 2016, he has been a Fellow of the European Society of Cardiology. Dr. Fedorowski has vast experience in cardiology and cardiovascular medicine. In this video Dr. Fedorowski speaks about Thrombosis and fibrinolysis in atherosclerotic cardiovascular disease.

Link to Article:
https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab710/6408927

Walter Bradford Cannon (1871–1945) developed the term "homeostasis," which refers to "any self-regulating process by which biological systems strive to preserve stability while responding to conditions that are optimal for survival." If homeostasis is achieved, life continues; if it is not, disaster or death follows' (Encyclopaedia Britannica; www.britannica.com). Haemostatic capacity, which prevents bleeding while preserving unobstructed blood flow, is one of the most important aspects of human homeostasis. Platelets and the coagulation system are two key components of haemostasis, working together to form a haemostatic plug when vascular continuity is interrupted. Coagulation and platelet activity are turned off by circulating inhibitors and proteolytic feedback loops to reduce the danger of arterial occlusion. 2 Otherwise, uncontrolled haemostatic activity will cause thrombo-embolic problems, leading to 'disaster or death' in the worst-case scenario. Prothrombotic and fibrinolytic forces are thus intertwined, resulting in a homeostatic steady state that responds to vascular emergencies.

DeFilippis et al.3 present a prospective study based on a multi-ethnic cohort of 5800 adults (mean age 63 years) without a history of atherosclerotic cardiovascular disease (ASCVD) from six communities in the United States in this issue of the European Heart Journal. The participants were recruited between 2000 and 2002 and monitored for 15 years, during which time 15% of them had a cardiovascular event. Blood samples were taken at the start of the study to look for circulating prothrombotic and fibrinolytic factors to see if there was a biomarker pattern that could predict incident ASCVD. The authors' technique is unique in that it uses two composite variables called thrombotic and fibrinolytic factors. Five biomarkers contributed to the thrombotic factor [fibrinogen, plasmin–antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a)], and two contributed to the fibrinolytic factor [plasminogen and oxidized phospholipids on plasminogen (OxPL-PLG)]. The authors discovered that a higher thrombotic factor score and a lower fibrinolytic factor score suggested the highest risk of incident atherothrombotic events (Graphical Abstract).

Higher levels of fibrinogen, D-dimer, plasmin–antiplasmin, factor VIII, and Lp(a) have previously been linked to an increased risk of CV events, therefore the findings of this significant study3 were not entirely unexpected.

4–7 Importantly, circulating levels of both plasminogen and OxPLs, which indicate reduced fibrinolytic activity, were significantly lower in patients with incident myocardial infarction at baseline compared to stable coronary artery disease patients and unaffected subjects, but increased immediately after percutaneous coronary intervention. 8 What's new is that assessing the balance between the competing processes of thrombosis and fibrinolysis should help forecast CV events more precisely. The authors underline that when the two biomarker sets are evaluated combined, they provide additional information. It was proved in a statistical model where the relative risks were increased once both factors were input at the same time. Notably, there was a moderately positive association between these two variables, implying that increased thrombotic propensity is frequently counterbalanced by increased fibrinolytic propensity. When thrombotic propensity and fibrinolytic propensity were uneven, i.e. when an elevated thrombotic factor was associated with a low fibrinolytic factor, the risk of CV events was highest. As a result, patients with high fibrinolytic factor and low thrombotic factor values had the lowest risk of CV events. It's worth noting that the two factors had no effect on coronary artery calcification.

Adding thrombotic and fibrinolytic components to a multivariable Cox model using variables from the American Heart Association (AHA)–American College of Cardiology (ACC) CV disease risk prediction calculators resulted in a minor (albeit statistically significant) improvement in model fit (C-index increase from 0.718 to 0.721). As a result, the proposed model based on integrated coagulation biomarkers has the potential to provide extra information on CV risk prediction beyond what can be determined only from traditional risk variables. However, the question arises as to whether measuring the balance between thrombosis and fibrinolysis has therapeutic value when applied to well-established clinical risk models in a broad and perhaps arbitrary manner. Indeed, a recent study of community-dwelling middle-aged people found that a high CHA2DS2-VASc score, which was designed for patients with atrial fibrillation, was also a sensitive measure for predicting bad CV outcomes in people who did not have atrial fibrillation. 9

DeFilippis et al.3 claim that the new thrombotic and fibrinolytic factors allow for a more complete assessment of the balance between thrombosis and fibrinolysis, which determines the risk of atherothrombosis, and that the new factors have promise for predicting an individual's propensity to form thrombus, based on their findings. As a result, the model should integrate into precision medicine and has the ability to select individuals for antithrombotic therapy by weighing the risk of iatrogenic bleeding against the advantages of reducing atherothrombotic events. For primary CV prevention, such a tailored medicine strategy appears to be quite appealing. Despite this, the path from epidemiological observation to clinical application is typically protracted, with just a few biomarkers making it into current clinical practice. The primary difficulty here will be to show that the suggested composite biomarker prediction model is capable of selecting candidates for more or less aggressive CV disease prevention, beyond what can be clinically determined in conjunction with traditional risk assessment scores.

However, it should be highlighted that other major atherothrombotic risk factors, such as platelet indices and platelet reactivity, as well as atherosclerotic indicators, were not considered in DeFilippis et al.3's investigation (Graphical Abstract). Individuals with an increased platelet count at baseline had a significantly greater risk of death and severe CV events throughout a 16-year follow-up in the prospective Malmö Diet and Cancer cohort, regardless of the presence of CV disease. 10 Higher platelet aggregability, as well as pathways connected to atherosclerosis onset, progression, and complications in people with high platelet counts, could explain these findings. Furthermore, a study of the same cohort found that clustering of blood cell count abnormalities (e.g., anemia, leucocytosis, and thrombocytosis), a condition commonly seen in people with a high inflammatory milieu, poor health, or frailty, was linked to increased mortality and the risk of future CV events. 11 These findings, together with the findings of DeFilippis et al.3, raise the question of whether anticoagulants such as low-dose rivaroxaban12, rather than aspirin13, should be explored in primary CV prevention in those with a high prothrombotic profile.

DeFilippis et al.3's study has several clear strengths: robustness of data gathered prospectively from a large, representative population; independent and meticulous event adjudication; long follow-up duration; and long-term stability of healthcare and reporting systems. However, there are some significant restrictions. First, because the investigators only looked at baseline blood samples, the dynamic nature of atherothrombotic biomarkers was not investigated. Second, data on platelet reactivity, which is important for assessing atherothrombotic risk, were not available, and aetiological subtyping of CV events (for example, atherothrombotic vs. non-atherothrombotic myocardial infarction) was not done. The danger of residual confounding and a lack of detailed information on concomitant disorders or undiscovered diseases that could cause changes in coagulation patterns at baseline are two other drawbacks. Importantly, the relationships found by DeFilippis et al.3 do not prove causation and must be confirmed in separate cohorts. Furthermore, due to the demand for seven laboratory measurements, the model's relevance in the real world should be acknowledged. Finally, it will be interesting to see how thrombotic and fibrinolytic variables vary over time and how these changes relate to cardiovascular events.

Taken together, our findings support the notion that the use of multi-biomarker technologies can help to improve CV risk prevention even more. Different mechanisms (e.g. thrombosis, inflammation, and lipid plaque development) may coexist in the pathophysiology of atherothrombosis, with varied roles for each of these mechanisms in different individuals (Graphical Abstract). As a result, the best prediction model would combine data from the coagulation system, lipid metabolism, and inflammation. As a result, a two-step approach may be beneficial: first, individual clinical risk stratification to identify people at moderate to high risk of CV events, then multi-biomarker examination to determine which pathogenetic process (thrombosis vs. inflammation vs. lipid problems) is dominant. The latter may help the practitioner choose whether preventive strategies should be used on an individual basis. A machine learning approach may also be effective for developing multi-parametric models due to its accuracy in analyzing competitive hazards. 14 Another major concern is whether prothrombotic vs. fibrinolytic activity should be assessed separately.

Dr. Rupal O'Quinn is a cardiologist in Philadelphia who is affiliated with both Penn Presbyterian Medical Center and Pennsylvania Hospital. She graduated from Rutgers Robert Wood Johnson Medical School with her medical degree. In this video Dr. O'Quinn speaks about her research in Cardiac Magnetic Resonance in Cardio-Oncology: Advantages, Importance of Expediency, and Considerations to Navigate Pre-Authorization.


Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.04.011

Abstract-
As the scope of cardio-oncology expands dramatically, both in terms of the number of people impacted and the sorts of therapy it involves, diagnosing acute and late cardiotoxicity from cancer therapeutics has become increasingly crucial. Cardiac magnetic resonance (CMR) is a tool that can provide unequaled diagnostic information when compared to other imaging modalities, however due to the need for insurance pre-authorization, its use is frequently delayed, at the price of patient care. This paper discusses when CMR should be used as a diagnostic tool and gives examples of diagnoses that are more likely to be approved by insurance companies. It also contains specific cardio-oncology diagnoses and questions to assist the clinical cardio-oncologist with the pre-authorization process.
Highlights

• While evolving cancer medicines improve patient survival, they can also cause cardiotoxicity.

• CMR can help diagnose, prognosticate, and provide insight into cardiotoxicity management.

Why Insurance companies' use of pre-authorization for CMR frequently results in delays in patient care.

• Insurance payers and providers must be educated and advocated for in order to overcome these barriers.

Introduction

Cardio-oncology is a rapidly growing discipline that is constantly evolving. Part of this rapid growth can be attributed to breakthroughs in oncology, which have resulted in new treatments that are raising survival and cure rates. Many innovative therapies are linked to cardiovascular side effects. Anthracyclines were once thought to offer the highest risk to patients, although this risk was thought to be "manageable" if the dose was kept below a certain threshold (1). Following that, even at modest dosages, anthracyclines have been shown to cause significant cardiotoxicity. Newer medications feature a variety of cardiac adverse effects, ranging from severe hypertension with tyrosine kinase inhibitors to life-threatening myocarditis with immune checkpoint inhibitors (ICIs), and severe shock-like dysfunction with chimeric antigen receptor T cell therapy, notwithstanding their benefits (2). Chemotherapy–related cardiac dysfunction (CTRCD) can arise early in the course of cancer treatment (3) and can be delayed in the case of radiation therapy, especially when radiation fields include incidental dosage to cardiac tissues or the major arteries (4). Furthermore, newer evidence suggests a substantial risk of major adverse cardiovascular events (MACE) in the first few years after cardiac radiation exposure (5). Both the cardiovascular and oncologic communities are concerned about the necessity to diagnose these toxicities quickly and accurately. It is predicted that 30% of all cancer patients will experience some type of cardiovascular problem as a result of their treatment; additionally, cardiovascular illness is the primary cause of morbidity and mortality in the years after cancer treatment (6).

The changing paradigm of cancer as a chronic disease requiring long-term follow-up for persistent cardiovascular harm necessitates long-term follow-up. As more cancer patients are treated, remission is achieved, and survivorship begins, it is necessary to identify those who are at risk and develop ways for monitoring long-term cancer therapy–related cardiac illness. The number of cancer survivors in the United States is expected to rise by approximately 11 million in the next 25 years, from 15.5 million in 2016 to 26.1 million in 2040. Notably, the percentage of survivors aged 65 and up will rise from 61 percent to 73 percent. Only 18% of cancer survivors will be between the ages of 50 and 64 years old by 2040, and only 8% will be under the age of 50. As a result, the majority of survivors are older people who may have had cardiotoxic therapy but are still at risk for cardiovascular disease as a result of aging or other concomitant conditions. This is the so-called "silver tsunami" demographic, which will surely necessitate cardiovascular imaging and treatment options (7).

CMR imaging is an important tool for detecting early and late cardiotoxic effects (8); however, there are various obstacles to getting these tests done on time, which can have an impact on patient care both in the acute and survival stages. Pre-authorization burdens imposed by insurance companies, in particular, have been noted as having an increasingly negative impact on patient treatment (9). We collaborated with members of the American College of Cardiology (ACC) Cardio-Cancer Section to identify key barriers to CMR adoption in oncology patients. Most cancer patients are likely to be affected during the early stages of treatment with newer, more effective medicines, as well as throughout follow-up as survival rates continue to rise.

This paper describes the scale of the problem, the circumstances in which CMR is most useful, and justifications for removing onerous pre-authorization requirements that delay therapy and place a significant burden on practicing physicians, particularly in the field of cardio-oncology and cancer care. When ordering a CMR for a cardio-oncology patient, we also go through useful nomenclature and indications.

The Pre-authorization Burden's Scope
The use of pre-authorization for testing as a cost-cutting tool has exploded in recent years. Many practices are forced to repeatedly request testing or medications for their patients, only to be denied. Insurance companies frequently create their own guidelines to make coverage determinations, which are often not transparent or publicly available, forcing many practices to request testing or medications for their patients, only to be denied. The American Medical Association (AMA) conducted a web-based poll in 2020 of 1,000 practicing physicians who offer patient care for more than 20 hours per week; 40% were primary care physicians and 60% were specialists. Almost 86 percent of practices said the administrative burden of prior authorization requests has increased in the last five years, and 86 percent said the burden is "very or extremely high." A medical practice completes 33 prior authorization requests per physician each week on average, which take 14.4 hours to process, and 30% of physicians hire staff to focus only on prior authorizations. Nearly 26% of physicians wait an average of 3 to 5 days for authorization, and 7% wait more than 5 days (9).

The fact that a delay in therapy is linked to unfavorable outcomes is a major worry for physicians caring for cancer patients suspected of having cardiotoxicity. The following is taken from the same poll (nine):

Pre-authorization delays are said to have caused substantial patient damage in 24% of cases.

Unnecessary hospitalizations were reported by 16 percent of respondents.

Pre-authorization, according to 91% of respondents, caused a delay in receiving care.
Pre-authorization prompted 74 percent of patients to forego recommended care because to the delay.

The burden of pre-authorization has also piqued the ACC's interest. Members who were practicing cardiologists were questioned how pre-authorization was affecting their practice patterns in response to an ACC Advocacy call to action. Several themes emerged from the data (H. McCants, personal communication, May 2019):

Peer-to-peer conversation was required in 25% of cases after the initial prior authorization denial.

In 42 percent of denials, it was suggested that a new (less expensive) test be performed instead of the original request;

45 percent of instances required more than 30 minutes on the phone to settle, and 30% of cases required the ordering physician's intervention to handle the authorization.

60 percent of filed cases resulted in care being delayed or rescheduled.

Despite the fact that these data were not particular to CMR, CMR was widely mentioned as a test that required pre-authorization.

Dr. Rupal O'Quinn is a cardiologist in Philadelphia who is affiliated with both Penn Presbyterian Medical Center and Pennsylvania Hospital. She graduated from Rutgers Robert Wood Johnson Medical School with her medical degree. In this video Dr. O'Quinn speaks about her research in Cardiac Magnetic Resonance in Cardio-Oncology: Advantages, Importance of Expediency, and Considerations to Navigate Pre-Authorization.


Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.04.011

Abstract-
As the scope of cardio-oncology expands dramatically, both in terms of the number of people impacted and the sorts of therapy it involves, diagnosing acute and late cardiotoxicity from cancer therapeutics has become increasingly crucial. Cardiac magnetic resonance (CMR) is a tool that can provide unequaled diagnostic information when compared to other imaging modalities, however due to the need for insurance pre-authorization, its use is frequently delayed, at the price of patient care. This paper discusses when CMR should be used as a diagnostic tool and gives examples of diagnoses that are more likely to be approved by insurance companies. It also contains specific cardio-oncology diagnoses and questions to assist the clinical cardio-oncologist with the pre-authorization process.
Highlights

• While evolving cancer medicines improve patient survival, they can also cause cardiotoxicity.

• CMR can help diagnose, prognosticate, and provide insight into cardiotoxicity management.

Why Insurance companies' use of pre-authorization for CMR frequently results in delays in patient care.

• Insurance payers and providers must be educated and advocated for in order to overcome these barriers.

Introduction

Cardio-oncology is a rapidly growing discipline that is constantly evolving. Part of this rapid growth can be attributed to breakthroughs in oncology, which have resulted in new treatments that are raising survival and cure rates. Many innovative therapies are linked to cardiovascular side effects. Anthracyclines were once thought to offer the highest risk to patients, although this risk was thought to be "manageable" if the dose was kept below a certain threshold (1). Following that, even at modest dosages, anthracyclines have been shown to cause significant cardiotoxicity. Newer medications feature a variety of cardiac adverse effects, ranging from severe hypertension with tyrosine kinase inhibitors to life-threatening myocarditis with immune checkpoint inhibitors (ICIs), and severe shock-like dysfunction with chimeric antigen receptor T cell therapy, notwithstanding their benefits (2). Chemotherapy–related cardiac dysfunction (CTRCD) can arise early in the course of cancer treatment (3) and can be delayed in the case of radiation therapy, especially when radiation fields include incidental dosage to cardiac tissues or the major arteries (4). Furthermore, newer evidence suggests a substantial risk of major adverse cardiovascular events (MACE) in the first few years after cardiac radiation exposure (5). Both the cardiovascular and oncologic communities are concerned about the necessity to diagnose these toxicities quickly and accurately. It is predicted that 30% of all cancer patients will experience some type of cardiovascular problem as a result of their treatment; additionally, cardiovascular illness is the primary cause of morbidity and mortality in the years after cancer treatment (6).

The changing paradigm of cancer as a chronic disease requiring long-term follow-up for persistent cardiovascular harm necessitates long-term follow-up. As more cancer patients are treated, remission is achieved, and survivorship begins, it is necessary to identify those who are at risk and develop ways for monitoring long-term cancer therapy–related cardiac illness. The number of cancer survivors in the United States is expected to rise by approximately 11 million in the next 25 years, from 15.5 million in 2016 to 26.1 million in 2040. Notably, the percentage of survivors aged 65 and up will rise from 61 percent to 73 percent. Only 18% of cancer survivors will be between the ages of 50 and 64 years old by 2040, and only 8% will be under the age of 50. As a result, the majority of survivors are older people who may have had cardiotoxic therapy but are still at risk for cardiovascular disease as a result of aging or other concomitant conditions. This is the so-called "silver tsunami" demographic, which will surely necessitate cardiovascular imaging and treatment options (7).

CMR imaging is an important tool for detecting early and late cardiotoxic effects (8); however, there are various obstacles to getting these tests done on time, which can have an impact on patient care both in the acute and survival stages. Pre-authorization burdens imposed by insurance companies, in particular, have been noted as having an increasingly negative impact on patient treatment (9). We collaborated with members of the American College of Cardiology (ACC) Cardio-Cancer Section to identify key barriers to CMR adoption in oncology patients. Most cancer patients are likely to be affected during the early stages of treatment with newer, more effective medicines, as well as throughout follow-up as survival rates continue to rise.

This paper describes the scale of the problem, the circumstances in which CMR is most useful, and justifications for removing onerous pre-authorization requirements that delay therapy and place a significant burden on practicing physicians, particularly in the field of cardio-oncology and cancer care. When ordering a CMR for a cardio-oncology patient, we also go through useful nomenclature and indications.

The Pre-authorization Burden's Scope
The use of pre-authorization for testing as a cost-cutting tool has exploded in recent years. Many practices are forced to repeatedly request testing or medications for their patients, only to be denied. Insurance companies frequently create their own guidelines to make coverage determinations, which are often not transparent or publicly available, forcing many practices to request testing or medications for their patients, only to be denied. The American Medical Association (AMA) conducted a web-based poll in 2020 of 1,000 practicing physicians who offer patient care for more than 20 hours per week; 40% were primary care physicians and 60% were specialists. Almost 86 percent of practices said the administrative burden of prior authorization requests has increased in the last five years, and 86 percent said the burden is "very or extremely high." A medical practice completes 33 prior authorization requests per physician each week on average, which take 14.4 hours to process, and 30% of physicians hire staff to focus only on prior authorizations. Nearly 26% of physicians wait an average of 3 to 5 days for authorization, and 7% wait more than 5 days (9).

The fact that a delay in therapy is linked to unfavorable outcomes is a major worry for physicians caring for cancer patients suspected of having cardiotoxicity. The following is taken from the same poll (nine):

Pre-authorization delays are said to have caused substantial patient damage in 24% of cases.

Unnecessary hospitalizations were reported by 16 percent of respondents.

Pre-authorization, according to 91% of respondents, caused a delay in receiving care.
Pre-authorization prompted 74 percent of patients to forego recommended care because to the delay.

The burden of pre-authorization has also piqued the ACC's interest. Members who were practicing cardiologists were questioned how pre-authorization was affecting their practice patterns in response to an ACC Advocacy call to action. Several themes emerged from the data (H. McCants, personal communication, May 2019):

Peer-to-peer conversation was required in 25% of cases after the initial prior authorization denial.

In 42 percent of denials, it was suggested that a new (less expensive) test be performed instead of the original request;

45 percent of instances required more than 30 minutes on the phone to settle, and 30% of cases required the ordering physician's intervention to handle the authorization.

60 percent of filed cases resulted in care being delayed or rescheduled.

Despite the fact that these data were not particular to CMR, CMR was widely mentioned as a test that required pre-authorization.

Dr. Allen is the medical director of the Shands Emergency Room at UF Health. The emergency department scribe program, observation medicine, emergency department quality and throughput innovation, and cardiac biomarkers research are some of his main interests. In this video Dr. Allen talks about his research with the Diagnostic Performance of High-Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite US Cohort.


Link to Abstract-
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.049298

Abstract-

Background:
Low high-sensitivity troponin (hs-cTn) readings or a 0/1-hour (0/1-h) strategy for myocardial infarction are recommended in Europe to rule out major adverse cardiac events (MACEs) in patients with suspected acute coronary syndrome. However, there is just limited data from the United States to back up these techniques. In a multisite US population, researchers looked at the diagnostic performance of an initial hs-cTnT value below the limit of quantification (LOQ: 6 ng/L), a 0/1-h methodology, and their combination with history, ECG, age, risk factors, and initial troponin (HEART) scores for eliminating MACE.


Methods:
Adult patients in the emergency department with symptoms suggestive of acute coronary syndrome but no ST-elevation on ECG were enrolled in a prospective cohort study at eight US sites. hs-cTnT (Roche; Basel, Switzerland) was evaluated using baseline and 1-hour blood samples. HEART scores were determined prospectively by treating clinicians who were blinded to the hs-cTnT data. At 30 days, MACE (cardiac death, myocardial infarction, and coronary revascularization) was determined. A 0/1-h approach was used to determine the proportion of individuals with first hs-cTnT measurements below the LOQ and risk. When both techniques were applied alone and with a HEART score, the negative predictive value (NPV) was obtained.


Results:
46.4 percent (678 of 1462) of the 1462 participants with initial hs-cTnT measurements were women, and 37.1 percent (542 of 1462) were Black, with a mean age of 57.612.9 (SD) years. MACEs occurred in 14.4% (210 of 1462) of participants after 30 days. Initial hs-cTnT measurements below the LOQ were found in 32.8 percent (479 of 1462), resulting in a 30-day MACE NPV of 98.3 percent (95 percent CI, 96.7–99.3). A low-risk HEART score with an initial hs-cTnT below the LOQ was found in 20.1 percent (294 of 1462), resulting in a 30-day MACE NPV of 99.0 percent (95 percent CI, 97.0–99.8). In 1430 patients, a 0/1-h algorithm was completed, ruling out 57.8% (826 of 1430) of 30-day MACEs with an NPV of 97.2 percent (95 percent CI, 95.9–98.2). When a low HEART score was included to the 0/1-h methodology, 30.8 percent (441 of 1430) of 30-day MACEs were ruled out, with an NPV of 98.4 percent (95 percent CI, 96.8–99.4).

Conclusions:
An initial hs-cTnT below the LOQ combined with a low-risk HEART score provides a 99 percent NPV for 30-day MACEs in a prospective multisite US population. When employed alone or with a HEART score, the 0/1-h hs-cTnT algorithm did not produce an NPV >99 percent for 30-day MACEs.

Dr. Allen is the medical director of the Shands Emergency Room at UF Health. The emergency department scribe program, observation medicine, emergency department quality and throughput innovation, and cardiac biomarkers research are some of his main interests. In this video Dr. Allen talks about his research with the Diagnostic Performance of High-Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite US Cohort.


Link to Abstract-
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.049298

Abstract-

Background:
Low high-sensitivity troponin (hs-cTn) readings or a 0/1-hour (0/1-h) strategy for myocardial infarction are recommended in Europe to rule out major adverse cardiac events (MACEs) in patients with suspected acute coronary syndrome. However, there is just limited data from the United States to back up these techniques. In a multisite US population, researchers looked at the diagnostic performance of an initial hs-cTnT value below the limit of quantification (LOQ: 6 ng/L), a 0/1-h methodology, and their combination with history, ECG, age, risk factors, and initial troponin (HEART) scores for eliminating MACE.


Methods:
Adult patients in the emergency department with symptoms suggestive of acute coronary syndrome but no ST-elevation on ECG were enrolled in a prospective cohort study at eight US sites. hs-cTnT (Roche; Basel, Switzerland) was evaluated using baseline and 1-hour blood samples. HEART scores were determined prospectively by treating clinicians who were blinded to the hs-cTnT data. At 30 days, MACE (cardiac death, myocardial infarction, and coronary revascularization) was determined. A 0/1-h approach was used to determine the proportion of individuals with first hs-cTnT measurements below the LOQ and risk. When both techniques were applied alone and with a HEART score, the negative predictive value (NPV) was obtained.


Results:
46.4 percent (678 of 1462) of the 1462 participants with initial hs-cTnT measurements were women, and 37.1 percent (542 of 1462) were Black, with a mean age of 57.612.9 (SD) years. MACEs occurred in 14.4% (210 of 1462) of participants after 30 days. Initial hs-cTnT measurements below the LOQ were found in 32.8 percent (479 of 1462), resulting in a 30-day MACE NPV of 98.3 percent (95 percent CI, 96.7–99.3). A low-risk HEART score with an initial hs-cTnT below the LOQ was found in 20.1 percent (294 of 1462), resulting in a 30-day MACE NPV of 99.0 percent (95 percent CI, 97.0–99.8). In 1430 patients, a 0/1-h algorithm was completed, ruling out 57.8% (826 of 1430) of 30-day MACEs with an NPV of 97.2 percent (95 percent CI, 95.9–98.2). When a low HEART score was included to the 0/1-h methodology, 30.8 percent (441 of 1430) of 30-day MACEs were ruled out, with an NPV of 98.4 percent (95 percent CI, 96.8–99.4).

Conclusions:
An initial hs-cTnT below the LOQ combined with a low-risk HEART score provides a 99 percent NPV for 30-day MACEs in a prospective multisite US population. When employed alone or with a HEART score, the 0/1-h hs-cTnT algorithm did not produce an NPV >99 percent for 30-day MACEs.

Dr. Javier Valero-Elizondo works as a Research Associate at the Center for Outcomes Research at the Houston Methodist Research Institute. In this video Dr. Valero-Elizondo speaks about Atherosclerotic Cardiovascular Disease, Cancer, and Financial Toxicity Among Adults in the United States.

Link to Abstract-
https://www.jacc.org/doi/10.1016/j.jaccao.2021.02.006


Abstract

Background
Financial toxicity (FT) is a well-known adverse effect of the high costs of cancer treatment. According to recent studies, a considerable proportion of people with atherosclerotic cardiovascular disease (ASCVD) suffer from FT and its effects.

Objectives
The goal of this study was to compare FT in those who had neither ASCVD nor cancer, as well as those who had ASCVD but not cancer, cancer but not ASCVD, and both ASCVD and cancer.

Methods
We identified persons with self-reported ASCVD and/or cancer from the National Health Interview Survey between 2013 and 2018, stratifying data by nonelderly (age 65 years) and elderly (age 65 years). Any trouble paying medical bills, substantial financial distress, cost-related medication nonadherence, food insecurity, and/or foregone/delayed care due to cost were all indicators of FT.

Results
When comparing individuals with ASCVD to those with cancer, the prevalence of FT was higher (54 percent vs. 41 percent; p 0.001). In adjusted analyses, those with ASCVD were more likely to have any difficulty paying medical bills (OR: 1.22; 95 percent confidence interval [CI]: 1.09 to 1.36), inability to pay bills (OR: 1.25; 95 percent CI: 1.04 to 1.50), cost-related medication nonadherence (OR: 1.28; 95 percent CI: 1.08 to 1.51), food insecurity (OR: 1.39; 95 percent CI: 1.17 to 1.64), and foregone/delayed care (OR: 1.17; 95 percent CI: 1.01 to 1.36). When comparing individuals with ASCVD and those with both ASCVD and cancer to those without cancer, the presence of three of these variables was considerably greater (23 percent vs. 30 percent vs. 13 percent, respectively; p 0.001). In the older population, the results were comparable.

Conclusions
Our findings show that FT is more common in individuals with ASCVD than in those with cancer, with those with both diseases having the highest burden.