MYH7 variants cause complex congenital heart disease.

MYH7, encoding the myosin heavy chain sarcomeric ß-myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Herein, we present a single center's experience of complex CHD due to MYH7 variants. Three probands with a history of CHD, LVNC, and/or arrhythmias were identified to have MYH7 variants through multigene panel testing or exome sequencing. These three patients collectively had 12 affected family members, four with a history of Ebstein anomaly and seven with a history of LVNC. These findings suggest a wider phenotypic spectrum in MYH7-related CHD than previously understood. Further investigation into the possible role of MYH7 in CHD and mechanism of disease is necessary to fully delineate the phenotypic spectrum of MYH7-related cardiac disease. MYH7 should be considered for families with multiple individuals with complex CHD in the setting of a family history of LVNC or arrhythmias.

Cardiovascular Genetics: The Role of Genetics in Predicting Risk.

Many cardiovascular disorders have underlying genetic causes. Clinical genetic testing for cardiovascular disease has become widely available and can be useful for diagnosis, management, and cascade screening in selected conditions and circumstances. This article gives an overview of the current state of genetic testing in inherited cardiovascular conditions, who can benefit from it, and the associated challenges.

Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP).

BACKGROUND: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. METHODS: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with "pathogenic" or "likely pathogenic" variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. RESULTS: Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). CONCLUSIONS: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.

Left Ventricular Hypertrophy and Hypertrophic Cardiomyopathy in Adult Solid Organ Transplant Recipients.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) in pediatric solid organ transplant recipients has been reported in association with use of calcineurin inhibitors. However, data on the incidence and prevalence of HCM in adult posttransplant patients are limited. We sought to describe the clinical characteristics of solid organ transplant recipients who were diagnosed with HCM from 2011 to 2021 at a single center. METHODS: Patients who had undergone solid organ transplant and exhibited left ventricular hypertrophy with left ventricular wall thickness ≥13 mm on transthoracic echocardiography were included. Clinical history, pedigree analysis, clinical genetic testing, transthoracic echocardiography, cardiac magnetic resonance imaging, treatment, and follow-up testing results were collected. Categorical variables were described as n (%). Continuous variables were described with medians and interquartile ranges and compared using the Wilcoxon rank-sum and Kruskal-Wallis tests. A 2-sided P < 0.05 was considered statistically significant. RESULTS: Three lung, 5 kidney, and 4 liver transplant recipients from 12 different families were included. Seven patients (58%) did not carry a preexisting diagnosis of hypertension, and none had a history of aortic or subaortic stenosis. A majority of patients exhibited asymmetric septal hypertrophy (67%; medial septal thickness versus left ventricular posterior wall thickness 17 versus 13 mm; P < 0.001) and dynamic left ventricular outflow tract (LVOT) obstruction (58%). All patients were managed long term with calcineurin inhibitors. Clinical genetic testing in 6 patients identified 2 with disease-causing variants in 2 sarcomere genes, myosin binding protein-C and myosin heavy chain 7. Four patients (33%) underwent successful septal reduction therapy for treatment of symptomatic LVOT obstruction. CONCLUSIONS: Symptomatic HCM with dynamic LVOT obstruction can develop in solid organ transplant recipients, and genetic testing can identify individuals with sarcomeric HCM. Medical management and septal reduction therapies are treatment options for severe symptomatic disease.

Antepartum Diagnosis and Management of Lamin A/C Disease.

Lamin A/C cardiac disease is a genetic cardiomyopathy and arrhythmia syndrome caused by alterations in the function of the nuclear lamin A and C proteins. It is inherited in an autosomal dominant manner and usually presents in mid- to late adulthood with atrioventricular conduction abnormalities, atrial and ventricular arrhythmias, biventricular dysfunction, and advanced heart failure. While rare, women of childbearing age can exhibit an aggressive disease course, and appropriate risk stratification and management are critical. Here, we present a case of newly diagnosed lamin A/C cardiac disease in a pregnant woman.

Cardiac Amyloidosis Masked as Hypertrophic Cardiomyopathy: A Case Report.

It is well known that cardiac amyloidosis and hypertrophic cardiomyopathy (HCM) have different physiologies and pathologies. However, it might be difficult to differentiate cardiac amyloidosis from HCM in certain clinical situations.

Modifiable factors associated with sleep dysfunction in adults with heart failure.

BACKGROUND: Sleep dysfunction contributes to poor quality of life in adults with heart failure (HF). The purpose of this study was to identify factors associated with sleep dysfunction that may be modifiable. METHODS: Data were collected from 266 subjects enrolled from three sites in the U.S. Sleep dysfunction was measured over the past month with the Pittsburgh sleep quality index, using a score > 10 to indicate sleep dysfunction. Potentially modifiable clinical, behavioral, and psychological factors thought to be associated with sleep dysfunction were analyzed with hierarchical logistic regression analysis. RESULTS: When covariates of age, gender, race, data collection site, and New York Heart Association (NYHA) functional class were entered on the first step, only NYHA was a significant correlate of sleep dysfunction. When the clinical, behavioral, and psychological factors were entered, correlates of sleep dysfunction were the number of drugs known to cause daytime somnolence (OR = 2.08), depression (OR = 1.83), worse overall perceived health (OR = 1.64), and better sleep hygiene (OR = 1.40). Although most (54%) subjects had sleep disordered breathing (SDB), SDB was not a significant predictor of sleep dysfunction. DISCUSSION: Factors associated with sleep dysfunction in HF include medications with sleepiness as a side-effect, depression, poorer health perceptions, and better sleep hygiene. Sleep dysfunction may motivate HF patients to address sleep hygiene. Eliminating medications with sleepiness as a side-effect, treating depression and perceptions of poor health may improve sleep quality in HF patients.