My name is Qiuhua Jennifer Zhang. I worked at the Sunland Cardiology Clinic in Memphis, Tennessee. My work is focused on heart failure, genetic cardiomyopsy. I have a background of research on angiogenesis. I published over 20 papers in cardiovascular disease. Today, my topic will focus on inheritable cardiomyopsy. In this module, we will focus on cardiomyopsy and genetic considerations. This is my disclosure. Through this module, we want to realize genetic links to cardiovascular disease. We will focus on two typical cardiomyopsies, hypertrophic cardiomyopsy and the left ventricular non-compaction. We will focus on the diagnosis and the treatment. Through the case study, we want to know that genetic testing will improve diagnosis, family screening, disease management, risk stratification, and prognosis. We will learn that possibly we will change the practice of the clinical cardiovascular medicine management. Also, the future genetic editing and modulation of signaling pathways will offer promising approach to management of inheritable cardiovascular disease. Cardiovascular genetic counseling has emerged as a specialty critical to the care of patients with inheritable cardiovascular disease. Currently, the most common condition for which genetic counseling was provided were cardiomyopsy, congenital heart disease, thoracic aorta aneurysm and dissection, arrhythmia like lung QT syndrome, and the familial hyperlipidemia. This lecture, we will focus on hypertrophic cardiomyopsy and left ventricular non-compaction. Genetic cardiomyopsies are defined as those solely or predominantly confined to heart muscle, not caused the secondary to coronary artery disease or systemic disease. Based on the region of cardiomyopsy and the structure, it can be divided to dilated cardiomyopsy, which is a left ventricular chamber size enlarged with a relative thin myocardium wall, which is associated with systolic dysfunction. Hypertrophic cardiomyopsy, which is typical of asymmetrical septal wall enlarged, the left ventricular wall thickness is over 15 millimeter, can be with or without obstruction. Restrictive cardiomyopsy, which is characterized by non-dilated, non-hypertrophic ventricles with moderate to severe biatrial enlargement, which is secondary to the elevated atrial pressure. Cardiomyopsy can be a result of external or intrinsic process. The external process is a secondary cause, which includes hypertension, valvular disease, ischemic disease, or secondary to systemic disease or inflammation. Intrinsic process in the cardiomyopsy is caused by the heart muscle problem itself. Basically, it is a genetic problem. Due to the genetic defect, heart muscle did not develop properly when it was developed in the mom's womb. The phenotype can be dilated cardiomyopsy, hypertrophic cardiomyopsy, or respiratory cardiomyopsy, restrictive cardiomyopsy, or left ventricular non-compaction. Dilated cardiomyopsy-causative genes are predominantly encode two major subgroups of proteins, cytoskeletal and sarcomeric proteins. It is not a single gene problem. It can be caused by the sarcomere protein genes, like titin, beta-myosin heavy chain, alpha-tropomyosin, cardiac troponin, or genes which the function is cardiomyocyte function, like dasmine, dystrophin, genes which are responsible for nuclear structure and function, like lamin A and C, RNA-binding multi-protein 20, or genes responsible for ion channel activity, like sodium voltage-gated channel alpha subunit 5, which is related to arrhythmia, genes which is related to protein turnover, like DAG3, and also gene related to calcium homostasis, like PLN. This gene mutation would result in depression of ventricular systolic contraction and impaired fourth generation. Hypertrophic cardiomyopsy is mainly a gene of mutation of sarcomere. It can cause increased fourth generation, ATP hydrolysis, and active myosin sliding velocities. It is the imbalance of the proportion of myosin heads that are in a disordered or super relaxed state. It is abnormal. Myocardium calcium homostasis can activate signaling cascades that accumulate in myocardial modeling with the development of pathology, hypertrophy, and fibrosis. The ACM genes, including the desmosomal protein, like DSG2, desmoplankin, DSP, plankoglobin, GUP, and the plantophilin, PKPC2. It can cause disruption of the intercellular junctions and cardiomyocyte detachment, which cause arrhythmogenic cardiomyopsy. Okay, this picture shows cardiomyocyte subcellular architecture and the location of key disease genes. For hypertrophic cardiomyopsy, these genes cluster in the sarcomere, the central inset, and arrhythmogenic cardiomyopsy is a desmosome in the right inset, like this part. Dilated cardiomyopsy disease genes are found in this region and also allow the access of false transmission that links to the sarcomere and extracellular matrix to set the skeletal components and nucleus with the left part. For patients with inherited cardiomyopsy, it is important to first establish a clinical diagnosis. Patients will need comprehensive assessment with medical history and genetic testing to identify all the factors that may be contributing to the disease. It will need a detailed assessment of cardiac phenotype using like EKG, echocardiogram, or cardiomyopsy. Also, a complete three-generation family history is needed. Any family member who had a history of cardiomyopsy diagnosis, arrhythmia, conduction abnormalities, like any family member who had a history of procedure, like ablation, cardioversion, pacemaker defibrillator, had a history of valve surgery or heart transplantation, or any members had a history of unexplained sudden cardiac death. Hypertrophic cardiomyopsy is a common genetic heart disease inherited in an autosomal dominant pattern. Currently, clinical diagnosis of hypertrophic cardiomyopsy is defined as a disease state in which morphology expression is confined solely to the heart. Mainly, only two criteria is needed to suggest a hypertrophic cardiomyopsy. One is the left ventricular wall thickness over 15 millimeter. The other is absence of another cause of hypertrophy, like hypertension. These two pictures show the normal heart and the hypertrophic cardiomyopsy. In the right, we can see the thickened septal wall. Among the patients with hypertrophic cardiomyopsy, about 30 to 60% have an identifiable pathogenic or likely pathogenic genetic variant. A substantial proportion of patients with hypertrophic cardiomyopsy are currently without any evidence of a genetic etiology to their disease, including a subgroup who also have no other affected family members. Possibly, new pathophysiology mechanism may be responsible to the affected patients with hypertrophic cardiomyopsy. Among patients with hypertrophic cardiomyopsy, there are two most common genes, a beta-myosin-hybrin gene 7, MYH7, and a myosin-binding protein C3, MYBPC3. These two proteins are responsible for about 70% of variant-positive patients. The other genes, like troponin, are only responsible for about 1% to 5% of the disease. Mutant sarcoma genes can trigger myocardial change, leading to hypertrophy and fibrosis, which ultimately result in a small, stiff ventricle with impaired systolic and dystolic function. In this picture, it shows the schematic structure of the sarcoma composed of thick and thin filaments and Z-disc. In the center, these are the thick filaments. These are thin filaments. These are Z-disc. Genes in thick filaments, like here, myosin-binding protein C3, beta-myosin-hybrin gene, is responsible for over half of the patients with familial hypertrophic cardiomyopsy. On the other hand, gene mutations in thin filament proteins, such as cardiac troponin 1 and alpha-tropomyosin, are relatively uncommon, only responsible about 1% to 5% of hypertrophic cardiomyopsy perceive this gene mutation because impaired biomechanical stress sensing, impaired calcium cycling and sensitivity, or altered energy homostasis, or increased fibrosis. This picture shows the pathophysiology of hypertrophic cardiomyopsy. The pathophysiology of hypertrophic cardiomyopsy consists of dynamic left ventricular outflow obstruction, mitral regurgitation, diastolic dysfunction, or myocardial ischemia. For left ventricular outflow obstruction, two components are responsible for that. One is septal wall thickness, which can lead to narrowing left ventricular outflow because of normal blood flow vector that dynamically displays the mitral valve leaflets anteriorly. The other is anatomic alteration in the mitral valve, which makes it more susceptible to the abnormal blood flow. Left ventricular outflow obstruction may cause worsened left ventricular hypertrophy, myocardial ischemia, and prolonged ventricular relaxation. A peak left ventricular outflow gradient of over 30 millimeter per mercury is considered to be indicative of obstruction. Also, high intra-cavity pressure may cause diastolic dysfunction, chamber stiffness fibrosis, left ventricular remodeling, which can cause exercise intolerance. Left ventricular outflow obstruction, systolic anterior motion of the mitral valve can cause mitral regurgitation. Factors that affect the severity of left ventricular outflow obstruction may affect the degree of mitral regurgitation. Also, we can see if we decrease the preload, decrease offload, and increase the heart muscle contractility can increase left ventricular outflow gradient. Also, patients with hypertrophic cardiomyopathy are susceptible to myocardial ischemia, attributable to a mismatch between myocardium oxygen supply and demand. Left ventricular hypertrophy, microvascular dysfunction with impaired coronary flow reserve. Blunted coronary flow reserve occurs even without abicardial stenosis. The presence of myocardial ischemia may lead to infarction. Left ventricular aneurysm or increase the risk of heart failure and arrhythmia. So there are questions when we met with hypertrophic cardiomyopathy, question to ask them, what brings them on? How long have they been occurring? What physical activity or exercise is part of their daily life? Symptom onset for patients with hypertrophic cardiomyopathy tend to be very gradual or unrecognized, but some may be present with syncope or sudden cardiac arrest. When coming to diagnosis, there are several questions. Some patients are present only with pathogenic genes, no image to support the left ventricular hypertrophy. Some with positive genes, but genetic testing with variant insignificance or negative. Clinically, genotype and phenotype may inconsistently correlated. Some sarcomia variant are unreliable to give diagnosis. At the same time, when they rule out amyloidosis, fibroid disease. The hypertrophic cardiomyopathy too include a lot like echocardiogram, cardiomi, cardiac CT, heart monitor. The echo sometimes may underestimate the maximum wall sickness at an interlateral left ventricular wall, posterior septum and apex. Echo sometime may overestimate left ventricular wall sickness. So in this condition, cardiomi is a good diagnosis too for hypertrophic cardiomyopathy. Also for exercise, stress testing is recommended for the detection and the quantification of dynamic left ventricular outflow obstruction to determine the functional capacity and provide a prognostic image. This is to show the cardiomyopathy is a golden tool to diagnose hypertrophic cardiomyopathy to avoid echocardiogram sometimes overestimated or underestimated. It's a great technique for hypertrophic cardiomyopathy diagnosis and management. It can also assessment of family members may it is related to the management strategies for invasive septal reduction. For example, patient need the surgery, we need to get a cardiomyopsy to see the detailed myopsy. Cardiomyopsy should be considered as part of the initial evaluation in nearly all hypertrophic cardiomyopsy patients. It is indicated that one ankle is inclusive to differentiate it with alternative diagnoses like infiltrative storage disease, athlete heart, to assess the high risk of sudden cardiac death, to assess the burden of fibrosis, maximum left ventricular wall thickness, or left ventricular apical aneurysm. So to diagnose hypertrophic cardiomyopsy, we should have the differential diagnosis like cardiac amyloidosis, fibroid disease, Noonan syndrome. Cardiac amyloidosis is characterized by right ventricular free wall thickening. It has a typical apical sparing longitudinal strain. There is a discordance of wall thickness and EKG voltage. There is a thickened interatrial septum and cardiac valves. It also has global hypokinesia. For fibroid disease, it usually involves right ventricular free wall thickening. It has a concentric distribution. There is a global hypokinesia and also thickened mitral and tricuspid valves. Noonan syndrome is characterized by right ventricular outflow tract obstruction. So for hypertrophic cardiomyopsy, we should have a sudden cardiac death risk assessment and prevention. When the patient has a high risk, we should give the patient ICD. Usually, if the patient has a history of cardiac arrest, history of syncope or presyncope episode, any family members have a history of sudden cardiac death or die at early year. No cause, maximum left ventricular wall thickness over 30 mm. Patient with heart monitor has a non-susceptible episode on heart monitor. Also, when the left ventricular systolic dysfunction is less than 50%, we should consider, the patient will increase the risk of sudden cardiac death. We should note here, left ventricular systolic dysfunction is a little different than a normal patient, no hypertrophic with heart failure diagnosis, which is 40. Here is 50. So in this condition, it is reasonable to consider primary prevention to give the patient ICD. So for hypertrophic cardiomyopsy, there are some complicated diseases. The patient sometimes with symptoms with obstructive hypertrophic cardiomyopsy. And also, we should know the patient with heart failure with preservative injection fraction, patient have hypertrophic cardiomyopsy and atrial fibrillation, patient who has hypertrophic cardiomyopsy and ventricular arrhythmia, also patient who has hypertrophic cardiomyopsy and advanced heart failure. The next few slides, we will focus on this disease with hypertrophic cardiomyopsy. Management is a little different. So for patient with obstruction, patient have symptoms, patient have shortness of breath, fatigue when exertion themselves. We should give the patient pharmacological management like non-vasodilating blood blocker, non-dihydropyridine calcium channel blocker. If the patient with blood blocker and calcium channel blocker, no symptom relief, we will consider adding disoperamide. Also, patient, when patient have fluid retention, patient should use diuretics. We should pay special attention to this kind of patients because usually diuretics is contraindicated to hypertrophic cardiomyopsy. We should discontinue all vasodilators like ACE inhibitors or ARB. There is a new medication called melacontin is a mild inhibitor. It's a new medication used in hypertrophic cardiomyopsy, which we will mention in the next few slides. For patients with pharmacological management, there is no improvement. We should consider invasive treatment like septal reduction therapy. If patient with associated cardio disease requiring surgical treatment, surgical myotomy is recommended at the same time. So for patients with non-obstructive hypertrophic cardiomyopsy, if the ventricular outflow gradient is not increased, patient with preserved ejection fraction, but patient have symptoms with symptoms of exertional angina or dyspnea, we should consider beta blocker, non-dihydropyridine calcium channel blocker, or disoperamide. Or patient still have symptoms with the medication, we should consider adding oral diuretics. ACE inhibitor or ARB is not indicated in this kind of patients. So for the patient with atrial fibrillation, there is a little different management compared with patient with no hypertrophic cardiomyopsy, only atrial fibrillation. In patients with hypertrophic cardiomyopsy and clinical atrial fibrillation, anticoagulation is recommended independent of chest vascular score. Also subclinical atrial fibrillation detected by auto monitor of over 24 hours duration for given episode, we will recommend DUAC. If episode over 5 minutes but less than 24 hours duration for given period, we should consider no DUAC can be beneficial. In patients with atrial fibrillation in whom rate control strategy is planned, neither beta blocker, varopamil, or diltiazem are recommended. In patients with hypertrophic cardiomyopsy and poorly tolerated atrial fibrillation, rhythm control strategy with cardioversion or antiarrhythmic drug can be beneficial. If with all these management patients still have atrial fibrillation, we should consider cancer ablation. Also surgical atrial fibrillation ablation is required when patients have surgical myotomy. Also patients with hypertrophic cardiomyopsy at the same time with ventricular arrhythmia, sometimes we consider heart transplant antiarrhythmic drug therapy or programming anti-tachycardia pacing or cancer ablation to reduce arrhythmia burden. When hypertrophic cardiomyopsy patients develop to advance heart failure, it's similar as heart failure treatment. We can use guideline-directed therapy. We can use CPX testing to quantify the LVAD or advance the heart failure treatment criteria. To discontinue previous indicated negative amyotrophs like calcium channel blocker, do patients have the indication for ICD, CRTD or left ventricular assistive device is similar with heart failure patients. For most patients with hypertrophic cardiomyopsy, mild to moderate intensity exercise is beneficial to improve cardiorespiratory fitness, physical functioning and quality of life. There is no certainty regarding the degree to which risk may be increased during sports participation in isolates with hypertrophic cardiomyopsy. Precise risk for participating in sports for individuals with hypertrophic cardiomyopsy is not easily quantifiable. Evaluation and shared decision should be considered and repeated at least on any base. For women with clinical stable hypertrophic cardiomyopsy who wish to become pregnant, it is reasonable to advise that pregnancy is generally safe as part of a shared decision regarding potential maternal and fetal risks. Also, the clinician should monitor and counsel patients to prevention and treatment of complicated conditions that can worsen severity of hypertrophic cardiomyopsy like artery disease, obesity, hypertension and sleep apnea. Genetic testing is recommended for all patients with hypertrophic cardiomyopsy. The results of genetic testing include pathogenic, variant uncertain significance and negative. If a clinically pathogenic or likely pathogenic variant is found in the case, then adult family members should be detested to determine whether or not they carry this specific variant. This can be used for the specific center sequencing and the testing for the full gene panel is not needed. Variants that have uncertain significance are not clinically actionable and cascade testing of these variants in family members is not recommended. But in the research field, family genotyping may be undertaken. Also, other family members also need echo and EKG screen. Also, periodic re-evaluation is needed and this may change over time and new family members become affected. These genes most are related to hypertrophic cardiomyopsy of beta-myosin hyphen gene, titan-myosin binding protein genes. If the genetic tests come out in negative, does that mean it is safe? No, we only test the gene panel based on the current medicine research. So this will include our hypertrophic cardiomyopsy topic. The above lecture summarizes the hypertrophic cardiomyopsy genetics, pathogenesis, diagnosis, clinical cause and therapy of hypertrophic cardiomyopsy as well as treatment plan and prognosis. Next, we will focus on left ventricular non-compaction. It is characterized by abnormal trabeculation in the left ventricle, most frequently at the apex. Cardiomyopathy criteria developed by Peterson to accurately diagnose pathologic non-compaction is based on a non-compaction to compaction ratio at end-diastole of over 2.3. This picture shows the embryonic development of left ventricle non-compaction. During the early embryologic development, myocardium is a loose meshwork of trabeculations. Progress at week 5 to form compacted outer and inner smooth muscle layer. In left ventricular non-compaction, the lower part, there is retarded myocardial morphogenesis and persistence of the trabeculation meshwork. The severity of myocardial non-compaction is dependent on the stage at which the arrest of the normal embryonic myocardial maturation takes place. The compaction process is triggered by vascular endothelial growth factor or angiopointing. Cardiomyopathy morphogenesis genes are responsible for the myocardium development. Sarcomeric gene mutations are also the most common one. This picture shows the left ventricular non-compaction diagnosis criteria. Absence of coexisting cardiac abnormalities, non-compaction to compaction ratio of over 2 at end-diastole, segmental thickening of the left ventricular myocardium with the thin compacted endocardial layer with trabeculation and deep recesses. Also, color-doctor evidence of deep inter-trabeculation results is required, predominant localization in the apical, mid-lateral, and mid-inferior regions. Left ventricular non-compaction, like dilated cardiomyopathy or hypertrophic cardiomyopathy, obviously no specific gene. In this model, myocardial morphogenesis is central to the three phenotypes, non-compaction, hypertrophy, or dilation. Genomic factors, probably interacting with hemodynamic, environmental, and other factors, determine the phenotype of the myocardium. The resulting physiology may be pathological and present with symptoms and major cardiovascular events, such as systolic dysfunction and or increased contractility, diastolic dysfunction, or arrhythmia and heart failure. Left ventricular non-compaction remains a heterogeneous disease with multiple possible concomitant phenotypes. It can be divided into nine distinct subtypes. Briefly, these subtypes are as follows. The isolated or benign form of left ventricular non-compaction, the unrestricted form, the dilated form, the hypertrophic form, the mixed form of left ventricular non-compaction, the restricted form, the biventricular form, the right ventricular hypertrophy correlation with normal LV form, and the congenital heart disease form. Left ventricular non-compaction is associated with several chromosomal defects and syndromes. Primary pathways or development pathways such as NODGE are affected. Often there are disturbances of protein-protein binding caused by the primary genetic mutation. Gene mutation may be in the Z-line protein, may be sarcomia-encoding gene like beta-myosin-hyphen-chain-7 or myosin-binding protein C or may be involved in a sodium channel gene, SCN5A, or gene responsible for cytoskeletal protein, dystrophin, or mitochondrial genome mutation. There are only limited data available about treatment options for left ventricular non-compaction. The crucial points of treatment are physiotherapy, including heart transplantation, antiarrhythmic therapy, ablation, and implantation of a defibrillator for oral anticoagulation. In practice, high thrombotic risks associated with left ventricular non-compaction are unknown. Antiplatelets and oral anticoagulation therapy were only considered when ventricular and atrium are enlarged. Heart failure in left ventricular non-compaction should be treated in the same way as heart failure because of other causes. Outcomes of patients with left ventricular non-compaction are largely associated with a presence of myocardial dysfunction or clinically significant arrhythmias or both. Despite progress in diagnosis and treatment in the past 10 years, understanding of the disorder and outcome needs to be improved. These are my references. Thank you.

inheritable cardiomyopathy

hypertrophic cardiomyopathy

left ventricular non-compaction

genetic conditions

genetic testing

diagnostic methods

treatment options