Cardiovascular Disorders Associated with a Genetic Component

Genetic disorders, while important in their own right, have contributed greatly to our fundamental understanding of the pathogenesis, etiology, and treatment of coronary artery disease (CAD). The observation that familial hypercholesterolemia is associated with premature CAD has provided pivotal evidence that cholesterol is a major cause of coronary artery disease. Cholesterol has since become a major therapeutic target, leading to the development of statins and other lipid-lowering therapies. Similarly, the discovery that mutations in the gene responsible for proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with altered risk for CAD led to the development of a new class of lipid-lowering drugs, namely inhibitors of PCSK9.

In this issue of the Methodist DeBakey Cardiovascular Journal, we focus on the genetic components of cardiovascular disease through nine literature reviews, all authored by worldwide experts in their field.

The first five articles focus on the prevention and treatment of CAD in relationship to lipid disorders. To kick us off, Drs. Iulia Iatan and Jacques Genest discuss the need for increased awareness of familial hypercholesterolemia, the title of their review. The hereditary basis of this disorder, its clinical diagnosis, and the role of genetic screening are comprehensively elucidated. The authors emphasize the importance of early diagnosis and proper management of familial hypercholesterolemia to significantly reduce the risk of premature coronary artery disease.

In the second review, Dr. Allan Sniderman raises the question, “Is the Commitment to LDL-C Eternal?” and explores the possibility of measuring apolipoprotein B (apoB) rather than the conventional method of only calculating LDL-C levels. While it’s well-recognized that the number of particles of LDL-C determines the risk for CAD, apoB further quantifies the number of LDL-C particles, thus offering a more accurate predictor of CAD risk than plasma LDL-C. The author makes a strong scientific and passionate plea to substitute apoB for plasma LDL-C.

In my literature review, titled “Cholesterol Facts and Opinions by a Non-lipid Cardiologist,” I also explain my position on using statins given that over 80% of the cholesterol circulating in the blood is synthesized in excess of the cell’s needs and ultimately transported to the liver to be metabolized and excreted into the small intestine. Patients who receive this lifetime lipid-lowering therapy can find comfort in its safety and efficacy record over the past three decades.

Next, Drs. Christie Ballantyne, Yakubu Bene-Alhasan, and colleagues expand on “Targeting Lipoprotein(a): A New Era in Cardiovascular Disease Prevention.” The authors review the strong scientific evidence supporting lipoprotein(a) as an independent risk factor for CAD, with over 90% of its plasma level controlled by genetics. Clinical management of lipoprotein(a) offers renewed hope, with new therapies showing efficacy in randomly designed clinical trials.

In the final article related to CAD prevention, “Genetic and Conventional Risk Stratification are Complementary for Primary Prevention of CAD,” MacKenna Roberts, MA, and I emphasize that risk for CAD is 50% genetic. These genetic risk variants for CAD have been encrypted on a microarray (polygenic risk score, or PRS) to screen for risk of CAD. Individuals with a PRS in the top 20% have a one- to threefold increased risk for CAD—genetic risk that is randomly assigned at conception and does not change over a person’s lifetime. In contrast to conventional risk factors, which often do not present until the sixth or seventh decade, genetic risk can be determined at birth or anytime thereafter. This article explores using PRS to screen asymptomatic young individuals to detect those at high risk for CAD who would benefit most from early primary prevention.

Moving to “Hypertrophic Cardiomyopathy is a Disease of Sarcomere Proteins,” Dr. A.J. Marian provides a comprehensive discussion of the genetic basis and pathogenesis of hypertrophic cardiomyopathy (HCM), a condition that continues to both fascinate and frustrate cardiologists. Although therapeutic advances have emerged, including several promising agents in clinical trials, HCM remains a significant cause of sudden cardiac death in young individuals. The role of genetic screening, particularly in young athletes, is still evolving as our understanding of the disease deepens.

Next, in “Genetic Dilated Cardiomyopathies,” Drs. Luisa Mestroni, Madelyn Boslough, and colleagues remind us that dilated cardiomyopathy is still the most common cause of heart failure due to nonischemic causes. It has a prevalence of 0.4% in the general population and remains a leading cause of sudden cardiac death. This review discusses in detail the genetic variants known to cause dilated cardiomyopathy and the indications for genetic screening. It also explores clinical management, novel therapies, and the future direction of current research.

Dr. Ramon Brugada follows with a comprehensive review of the “Genetic Determinants of Inherited Cardiac Arrhythmias,” a group of disorders that remain a major cause of premature sudden cardiac death. He outlines the many genetic variants responsible for these syndromes and explains how this diversity affects molecules from cardiac ion channels to intercellular junctions. He also highlights advances in diagnosis, risk stratification, and family screening as well as the clinical implications of these inherited cardiac arrhythmias.

In our final review, “Genetics of Thoracic Aneurysm,” Drs. Rachel Wittenberg and Mark Lindsay present an overview of the various inherited syndromes together with the known genetic risk variants responsible for these disorders. The non-syndromic category, meaning those with a family history without other phenotypes, is also included along with possible explanations. The role of genetic screening in the medical and surgical management of these disorders is increasing as more pathogenetic variants are discovered.

My deepest thanks to each of the authors, whose expertise and clarity deepen our understanding of the genetic foundations of cardiovascular disease. Their work reminds us why this topic is so compelling: genetics continues to reshape how we think about pathogenesis, risk, and therapy across the full spectrum of cardiovascular disorders. The insights shared here help clarify where we stand today and illuminate the most promising directions for tomorrow. As our field moves steadily toward more precise diagnosis and earlier intervention, a deeper grasp of cardiovascular genetics is essential. It brings us closer to the ultimate goal that unites clinicians and scientists alike: transforming care through prevention, and improving the lives of the patients and families we serve.

Robert Roberts, MD

Dr. Roberts’ accomplished career as a geneticist and cardiologist includes leading the cardiology department at Baylor College of Medicine in Houston for 23 years, serving as the President and CEO of the University of Ottawa Heart Institute, and working with NASA as a cardiology consultant where he cleared Astronaut John Glenn to take flight into space.

In recent years, he has served as executive director of The Heart and Vascular Institute and director of Cardiovascular Genetics and Genomics at Dignity Health at St Joseph’s Hospital & Medical Center, chair of the International Society of Cardiovascular Translational Research at the University of Arizona College of Medicine, and professor of medicine at the University of Arizona College of Medicine.

During his extensive research, Dr. Roberts discovered the first gene for heart attacks and pioneered the MBCK Test, which has been used as the gold standard to diagnose heart attacks for the past three decades. In total, he has co-discovered more than 60 genes associated with coronary artery disease. His appearances as a keynote speaker in over 35 countries include the Opening Plenary Address of the American College of Cardiology, the Japanese College of Cardiology, and the Australian and New Zealand Heart Association.