Within the intricate realm of cardiovascular health, the blueprint of our genes exerts a profound influence on the fate of our hearts. Inherited cardiomyopathies, a diverse group of conditions with a strong genetic basis, offer us a unique glimpse into the intricate interplay between our DNA and the intricate machinery of the heart. This comprehensive exploration embarks on a voyage through the genetic landscapes underlying inherited cardiomyopathies, shedding light on conditions like dilated cardiomyopathies (LMNA mutations), hypertrophic cardiomyopathy (HCM) with sarcomeric mutations, arrhythmic right ventricular cardiomyopathy (ARVC) caused by desmosomal genes, as well as the intriguing phenocopies like ATTR amyloidosis.
Dilated cardiomyopathy (DCM) is a disease of the heart muscle that makes it stretched with thin walls and enlarged LV cavity or dilated. With thinner walls, the heart becomes weaker and the amount of blood pumped with each heartbeat becomes lower and lower. The ejection fraction (EF) measured by echo or cardiac cath is lower (normal EF: 55-65%) and in some cases can become severely reduced (EF<20%). Some people have no symptoms at all, while others have symptoms of heart failure: tiredness, decreased exercise tolerance, difficulty breathing, swelling of the feet, palpitations, and sometimes chest pain. The diagnosis of cardiomyopathy is made by a combination of a physical exam, ECG, echo, stress test, and cardiac catheterization. After ruling out the most common causes of cardiomyopathy, such as ischemic, endocrine, medications/toxins, and tachycardia-induced factors, idiopathic cardiomyopathy can be divided as familial or non-familial. A genetic cause can be found in up to 50% of familial cardiomyopathy and genetic testing is advisable. More than fifty genes have been linked to DCM with 23 of them responsible for the majority of genetic DCM. These genes determine the structure and function of the heart muscle cell and can involve any of its components: sarcomere, desmosome, nuclear lamina, mitochondria, and ion channels. Overall, patients with DCM and carrying an abnormal gene usually have more heart failure symptoms and more arrhythmias compared to patients who do not carry an abnormal gene.
- Variants of the titin gene (TTN) are the most common cause of genetic DCM and account for up to 25% of familial cases. The progression of severe heart failure can be rapid with more use of LVAD, and heart transplantation at an earlier age.
- Sometimes cardiac disease can be related to the envelop protein A of the nucleus (LMNA). This type of genetic DCM has almost 100% penetrance and can present with malignant arrhythmias (Brady- or ventricular tachycardia) in addition to heart failure. One of our patients presented in 2009 with dilated cardiomyopathy with EF of 20%, normal coronaries, and VT storms. She was treated first with an ICD and 6 years later underwent a VT ablation and her ICD was upgraded to a BiV-ICD. Currently, guideline-directed medical therapy consisting of Sacubitril/Valsartan, metoprolol, empagliflozin, and spironolactone combined with amiodarone has been used with good results, minimal symptoms, and an improving EF of 30-35%. Her son carries the LMNA and NEXN genes and presented with severe heart failure and VT at the age of 17. He has undergone a heart transplant and doing well. She is still working with the genetic counselor to reconstitute her genealogical tree documenting an LMNA gene originating from her mother’s side.
- Among patients with inherited cardiomyopathy, 10% are affected by damaging variants of the gene of the cardiac desmosome. Traditionally these genes are associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy. When combined with LMNA variants, patients can present with high rates of ventricular arrhythmias or sudden death.
- SCN5A-related cardiomyopathies can affect the cardiac sodium channels and present with arrhythmias related to the Brugada syndrome, Long-QT syndrome, or familial atrial fibrillation. Successful treatment with sodium channel blockers such as Flecainide or propafenone (1C) has been used clinically.
Hypertrophic cardiomyopathy (HCM) is a disease of the heart muscle where the walls of the heart muscle become very thick. It can affect different parts of the wall of the heart but most frequently, the septal wall (between the LV and RV), is severely thickened and can cause an obstruction to the outflow of blood from the cardiac chamber and make the patient faint. This obstructive HCM is far more common than the non-obstructive form of HCM. It is a genetic cardiomyopathy where a change or variation in one or more genes is passed on to families in an autosomal dominant way. The variant gene can affect the myosin-binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), troponin T2 (TNNT2), and troponin I3 (TNNI3), alpha-actinin 2 (ACTN2), myosin light-chain 3 (MYL3) and tropomyosin alpha-1 chain (TPM1). A variant gene is found in approximately 40-50% of individuals undergoing genetic testing. The damaging variants in the genes affect the structure and function of the contractile heart muscle unit called the sarcomere. About one in 500 people are affected by this condition with most patients having no symptoms at all. Patients who test positive for a variant gene tend to present earlier in life with more arrhythmias (AFib or ventricular arrhythmias) and more heart failure. As the muscle wall thickens, the heart muscle becomes stiffer causing the pressure to rise inside the heart and the lungs, making the patients shorter of breath. Other symptoms include fainting, chest pain, and palpitations. A rare complication is a cardiac arrest or sudden death. For this reason, it is important to make the diagnosis of HCM and prevent sudden death at an early age.
The diagnosis is made by examining the patient since some individuals can develop a heart murmur that is dynamic at auscultation. Other patients can have mitral regurgitation. To follow in the investigation is an ECG, Holter or event monitors, echocardiogram with Doppler at rest and exercise, and where available, a cardiac MRI.
Management of HCM:
For patients with no or minimal symptoms, a healthy lifestyle consisting of regular exercise activity, eating a Mediterranean diet, maintaining a normal weight and blood pressure, and not smoking is probably the best advice. In one study, one-third of patients with HCM were obese and had more symptoms of shortness of breath, more outflow tract obstruction, more heart failure, and more atrial fibrillation. Patients who have cardiomyopathy and a gene variation are more susceptible to the myocardial depressant effect of alcohol and certain cardiotoxins such as anthracyclin and need careful monitoring of their heart function and abstinence from alcohol. Unlike patients with ARVC or certain DCM (LMNA and NEXN), most patients with HCM are now encouraged to exercise moderately or even vigorously. Shared decision-making between the patients, the cardiologist, and the genetic counselor can help individuals achieve the potential cardiac and overall health benefits of improved cardiopulmonary fitness.
For patients with obstructive HCM and mild to moderate symptoms, a beta-blocker or a calcium antagonist can be used to reduce the obstruction to the outflow tract. Disopyramide has been used as well but side effects are common. For patients with severe obstruction and symptoms, mavacamtan was approved by the FDA in 2022. It is a first-in-class, cardiac myosin inhibitor. In EXPLORER-HCM, mavacamtan decreased LVOT obstruction and improved objective and subjective functional capacity in patients with severe obstructive HCM. In patients who remain severely symptomatic despite medical therapy, an invasive septal myectomy can be offered to relieve the obstruction. It should be performed in experienced HCM centers. Other reasons to favor surgical myectomy include young adults with severe outflow obstruction (gradient >100 mmHg), debilitating outflow obstruction symptoms not responsive to medical therapy and affecting the quality of life, progressive pulmonary hypertension attributed to the outflow obstruction, and associated mitral regurgitation or repeated episodes of atrial fibrillation. When surgery is considered too high-risk, alcohol septal ablation can be performed in selected experienced centers. In high-risk HCM patients, a prophylactic ICD is recommended: Patients who had a first-degree relative with HCM and sudden death at a young age, patients with massive hypertrophy (wall thickness >30 mm in diameter), patients with more than one recent episode of syncope attributable to an arrhythmia, apical aneurysm or LV function <50%. With advanced end-stage HCM, a heart transplant can be considered.
HCM phenocopies or HCM look alike:
Genetic testing can differentiate sarcomeric disease from the so-called phenocopies. Some syndromic or infiltrative conditions are seen in the young (lysosomal and glycogen storage disease: Danon, Fabry, and Pompe’s disease), RASopathies (Noonan, Costello), and some are seen in adults (amyloidosis). These conditions manifest with cardiac changes similar to sarcomeric HCM. In a series of 343 patients evaluated for HCM, 9% were found to have cardiac amyloidosis: 3.5% had an amyloidosis-associated gene TTR and 17 patients had wild-type-TTR cardiac amyloidosis. In the US, 3.4% of African Americans exhibit a TTR variant (Val122Ile). Amyloidosis results from misfolding of proteins that collect into amyloid fibrils in the interstitial space of normal tissue. In cardiac amyloidosis, these abnormal proteins accumulate between the normal cardiac cells, precipitating damage to the cells and increasing heart muscle stiffness. The majority of cardiac amyloidosis results from the misfolding of either an immunoglobulin light chain produced in plasma cells of the bone marrow (AL-CM) or more frequently, the misfolding of pre-albumin or Transthyretin (ATTR-CM) with an increased prevalence as we get older.
The diagnosis of AL-amyloidosis requires the demonstration of amyloid in the tissue and evidence of plasma cell dyscrasia at bone marrow biopsy. Because the primary treatment requires chemotherapy or immunotherapy, it is important that the oncologist be involved and be an integral part of the heart team. The treatment targets the aberrant plasma cells reduces the production of amyloid protein production, and allows for the regression of amyloid tissue deposit. We have a patient with severe hypertrophic cardiomyopathy and severe symptoms from obstruction to the outflow tract. She underwent a surgical septectomy and was found to have amyloidosis on the pathology analysis of the septal cardiac muscle. A bone marrow biopsy was obtained and revealed AL amyloidosis. She was treated initially at the Mayo Clinic and has been maintained on a protease inhibitor, bortezomib (Velcade), and has been doing well without evidence of heart failure.
AL-amyloidosis can be excluded by obtaining a negative monoclonal protein screen: serum free light chain assay ( kappa/lambda ratio <2) as well as serum and urine samples for immunofixation electrophoresis to rule out a monoclonal protein. Cardiac scintigraphy with technetium Pyrophosphate (Tc-PYP) and SPECT/tomographic imaging can be used to help make the diagnosis of TTR-amyloidosis. It is not a perfect technique and sometimes cardiac MRI can be helpful. Genetic testing and counseling are essential to identify the presence or absence of a TTR variant for ATTR-CM. The only treatment available to treat ATTR cardiac amyloidosis is Tafamidis. It acts as a TTR stabilizer and slows the fibril formation and cardiac deposits.
This article was written in collaboration with Dr. Pankaj Arora, Director, UAB Cardiogenomics Clinic Program; Director, Cardiology Clinical and Translational Research Program, Associate Professor of Medicine, at University of Alabama at Birmingham.,