Gap junction protein beta 4 plays an important role in cardiac function in humans, rodents, and zebrafish.

AIMS: GJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function. METHODS AND RESULTS: We examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization. CONCLUSIONS: These results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.

Surgical pathology of subaortic septal myectomy: histology skips over clinical diagnosis.

BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload. Myectomy histopathology might be useful to enlighten the cause of the obstruction and establish the diagnosis. AIM: The aim was to describe the pathological findings of surgical septal myectomy specimens obtained from a group of patients with diverse clinical diagnosis, including HCM, severe aortic stenosis, and asymmetrical septal hypertrophy. METHODS: This was a retrospective study of 56 patients undergoing septal myectomy along a 10-year period at a tertiary cardiac surgical center. Clinical, interventional, and anatomopathological findings between patients with and without a preoperative diagnosis of HCM were analyzed and compared. RESULTS: Mean age at intervention was 67.5±20.5 years; 37 (66.1%) were female Preoperative diagnosis of sarcomeric obstructive HCM was assumed in 23 (41.1%) patients. All the other patients (58.9%) were referred for surgery with preoperative diagnosis of asymmetric septal hypertrophy, mainly in the context of severe aortic stenosis (24 patients). Twenty-seven (48.2%) patients had a greater than 30 mmHg intraventricular gradient at rest. Patients with presumed HCM were significantly younger (56.5±15.8 vs. 70.2±13.3 years, P<.001), had higher prevalence of significant intraventricular obstruction at rest [20 (87.0%) vs. 8 (34.8%), P<.001], and more frequently had moderate or severe mitral regurgitation [9 (39.1%) vs. 5(15.1%), P=.043]. All patients with aortic valve stenosis underwent both aortic valve replacement and septal myectomy. Twelve (52.1%) of the patients with obstructive HCM had isolated septal myectomy, while in the remaining 11, the procedure was combined with intervention on the mitral valve. Histopathological final diagnosis was of nonspecific reactive myocardial hypertrophy in all but 4 (92.2%) patients. In those, 2 (3.6%) had the final diagnosis of HCM and 2 (3.6%) the diagnosis of congenital subaortic membranous stenosis with reactive myocardial hypertrophy. Different grades of subendocardial fibroelastosis and myocardial fibrosis, mainly interstitial, were present [27 (48.2%) and 18 (32%) patients, respectively]. When microscopic data were compared between patients with or without a preoperative clinical diagnosis of HCM, no significant differences were found. CONCLUSION: In patients submitted to surgical septal myectomy, histology was mostly indistinctive among different clinical entities. Since different myocardial hypertrophy etiologies may share similar pathological expression, there is a need for detailed clinical assessment when trying to define the best strategy for clinical management.

Optimized pacing mode for hypertrophic cardiomyopathy: Impact of ECG fusion during pacing.

BACKGROUND: Electrocardiographic (ECG) fusion with intrinsic QRS could reduce the benefit of atrial synchronous biventricular pacing (AS-BiVP) in patients with hypertrophic obstructive cardiomyopathy (HOCM). OBJECTIVES: The purpose of this study was to assess the benefit of AS-BiVP and the influence of ECG fusion for reduction of left ventricular outflow tract gradient (LVOTG) in these patients. METHODS: Twenty-one symptomatic HOCM patients with severe LVOTG were included. Twelve patients were evaluated retrospectively for the prevalence of fusion and its influence on outcomes after AS-BiVP. Eleven patients (2 of the first population were also evaluated retrospectively) were prospectively included to evaluate the benefit of performing atrioventricular node ablation (AVNA) to achieve full ventricular capture if fusion was present during AS-BiVP. RESULTS: Seven of the first 12 patients (58%) had ECG fusion. After 54 ± 24 months of AS-BiVP, the presence of fusion was associated with lower values for reduction of resting, dynamic LVOTG and New York Heart Association (NYHA) class. In the prospectively evaluated patients, after 12 months of follow-up, resting LVOTG decreased from 98 ± 39 to 39 ± 24 mm Hg (P = .008); dynamic LVOTG decreased from 112 ± 38 to 60 ± 24 mm Hg (P = .013); NYHA class decreased from 2.8 ± 0.4 to 1.7 ± 0.6 (P = .014); endurance time during constant work rate cycling exercise (80% of peak oxygen consumption) increased from 399 ± 148 to 691 ± 249 seconds (P = .046); quality of life improved from 46 ± 22 to 22 ± 20 points (P = .02); and brain natriuretic peptide levels decreased from 318 ± 238 to 152 ± 118 pg/mL (P = .09). Eight of the 11 prospectively evaluated patients (73%) needed AVNA, which further decreased LVOTG from 108 ± 40 mm Hg at baseline to 89 ± 29 mm Hg after BiVP to 54 ± 22 mm Hg after AVNA (P = .003). CONCLUSION: As-BiVP that ensures no ECG fusion, by means of AVNA when needed, appears to be the optimal pacing mode in HOCM patients.

The Brockenbrough-Braunwald-Morrow sign.

Hypertrophic cardiomyopathy is a relatively common genetic disorder and usually asymptomatic. However, approximately 25% of patients develop left ventricular outflow obstruction and can develop angina, syncope, or congestive heart failure. Initiation and titration of beta-blockade usually results in symptomatic improvement. Patients with medically refractory symptoms can see further symptomatic improvement and relief of obstruction with either surgical myectomy or alcohol septal ablation (ASA). Although surgical myectomy has been the gold standard, ASA has been shown in nonrandomized studies and a meta-analysis to be comparable. In patients undergoing ASA without a rest obstruction, the Brokenbrough-Braunwald-Morrow sign can be used to accurately determine the degree of left ventricular outflow tract (LVOT) obstruction prior to, during, and after ASA.

Dramatically different phenotypic expressions of hypertrophic cardiomyopathy in male cousins undergoing cardiac transplantation with identical disease-causing gene mutation.

Described herein are certain findings in 2 male cousins who underwent cardiac transplantation for severe heart failure (HF), one of the diastolic type (ejection fraction ≈65%), and one of the systolic type (ejection fraction ≈20%), both the consequence of hypertrophic cardiomyopathy (HC), and each had identical disease-causing gene mutations. The implanted heart in one had normal-sized ventricular cavities and no grossly visible ventricular wall lesions (except in one papillary muscle) and the other patient had severely dilated ventricular cavities and multiple extensive ventricular wall scars. The heart mass and the age of onset of symptoms was similar in each patient. A number of other family members had evidence of HC.

Apico-aortic conduit for severe hypertrophic cardiomyopathy: sudden death despite conduit patency 31 years postoperatively.

Although small experiences have been described with the use of apico-aortic valved conduit in the treatment of hypertrophic cardiomyopathy (HCM), the long-term follow-up has never been previously reported. In a young female patient with symptomatic HCM and a prognostically unfavorable phenotype, apico-aortic conduit was chosen instead of conventional myectomy because severe ventricular hypertrophy involved the whole ventricle, making outflow tract cavity virtually absent in systole. Close clinical and imaging follow-up was postoperatively performed. The patient remained asymptomatic, without cardioactive drug therapy for 30 years, also experiencing 2 successful pregnancies. A striking finding was the perfect patency of the conduit at the last follow-up control (31 years), with computed tomography and echocardiography showing no calcification of the porcine Hancock bioprosthesis inside the graft. Nevertheless, the disease slowly evolved towards the dilative phase and the patient experienced sudden death while scheduled for implantation of defibrillator in waiting list for heart transplant.The present case could suggest that, in selected cases of HCM not treatable by myectomy, apico-aortic conduit may be an option. The relief of the obstruction can provide even long-term freedom from symptoms, however, late evolution to end-stage cannot be prevented.

Mammary to innominate arteriovenous fistula: endovascular management of an anecdotal complication.

An internal thoracic artery pseudoaneurysm associated with an arteriovenous fistula to the innominate vein is a very rare complication after implantation of a cardioverter-defibrillator. We report the successful endovascular management of this unusual complication.

Profound left ventricular remodeling associated with LAMP2 cardiomyopathy.

Lysosome-associated membrane protein (LAMP2) cardiomyopathy is an X-linked and highly progressive myocardial storage disorder associated with diminished survival, which clinically resembles sarcomeric hypertrophic cardiomyopathy. As shown here in a young woman, the natural history of LAMP2 may demonstrate an extreme profile of left ventricular remodeling with regression of hypertrophy (i.e. marked wall thinning), chamber dilatation, and severe systolic dysfunction, all of which are associated with widespread transmural scarring.

The left and right ventricle of a patient with a R723G mutation of the beta-myosin heavy chain and severe hypertrophic cardiomyopathy show no differences in the expression of myosin mRNA.

BACKGROUND: In familial hypertrophic cardiomyopathy (FHC), asymmetric left ventricular (LV) hypertrophy has been considered to be the predominant phenotypic expression, whereas right ventricular (RV) involvement is still ambiguous. In most cases, the right ventricle remains unaffected until secondary pulmonary hypertension develops. Several FHC-causing mutations of genes encoding sarcomere-related proteins have been identified which are transmitted in an autosomal-dominant manner. METHODS: We report the case of a 61 year old member of a Catalan family with a Arg723Gly missense mutation of the ß-myosin heavy chain (ß-MHC), that is associated with a malignant phenotype characterized by sudden cardiac death and heart failure. Because of progressive systolic LV dysfunction, the patient received a heart transplant in 2003. RESULTS: Molecular analysis of the myocardial tissue of the explanted heart, taken from the left and right ventricle, showed a similar deviation of the ratio of mutant vs wild type mRNA of the ß-MHC of 71.8 ± 5% and 68.5 ± 3%, respectively. This finding was confirmed for LV biopsies of this patient on protein level, showing a similar proportion of mutated ß-myosin. But since the patient is heterozygous for the ß-MHC mutation and the mutation is located in a coding region, the relative increase of the expression of the mutant allele is unexpected. It has been demonstrated before by our group for several ß-MHC mutations that the relative abundance of mutated mRNA/protein correlates with the clinical severity of the disease. But since the right ventricle shows no (or only minor) manifestation in terms of hypertrophy or dysfunction, the level of mRNA and protein expression is not the only factor responsible for the development of the phenotype of FHC. CONCLUSIONS: Several mechanisms through which cardiac stresses may incite maladaptive cardiac remodeling primarily of the left ventricle that result in myocardial hypertrophy and heart failure are proposed. One of those triggers could be the enhanced work load of the left ventricle, especially if a LV outflow tract gradient is present, in contrast to the lesser demands to the right ventricle which is adapted to the low pressure system of the pulmonary circulation. Further studies are needed to confirm the results of this case, as well as functional studies involving both ventricles.

Ventricular fibrillation following autologous intramyocardial cell therapy for inherited cardiomyopathy.

A 41-year-old male with cardiomyopathy from an inherited beta myosin heavy-chain mutation underwent treatment for heart failure with intramyocardial cell transplantation. He received direct injections into his heart of autologous precursor cells isolated from his blood. He immediately suffered ventricular fibrillation. Although he was resuscitated, he experienced a prolonged downward course that prohibited his undergoing transplantation. His autopsy revealed marked fibrosis throughout the myocardium with areas of mononuclear cell infiltrate. This case highlights the potential adverse effects associated with intramyocardial therapy in the cardiomyopathic heart.

Mitral valve abnormalities in hypertrophic cardiomyopathy: echocardiographic features and surgical outcomes.

BACKGROUND: Functional and intrinsic mitral valve (MV) abnormalities are common in hypertrophic cardiomyopathy (HCM); however, morphologic characteristics constituting indications for surgical intervention are incompletely defined. This study was conducted to define the echocardiographic features of MV pathology in patients with HCM and relate these to repairability of the MV, MV procedures performed, durability of repair, and survival. METHODS: From 1986 to 2003, 851 patients with HCM underwent operation, and 115 had a concomitant MV procedure. Detailed analysis of their 784 transthoracic and transesophageal echocardiograms, performed intraoperatively and postoperatively, was conducted. Outcomes were assessed by cross-sectional follow-up. RESULTS: Sixty-seven patients (58%) underwent MV repair, and 48 (42%) had MV replacement. The mean left ventricular outflow tract peak gradient was 70 +/- 50 mm Hg. Systolic anterior motion was present in 95%. Valve abnormalities were degenerative in 36 (31%), myxomatous in 23 (20%), papillary muscle in 23 (20%), restrictive chordal in 22 (19%), restrictive leaflet in 80 (70%), and long leaflet in 64 (56%). Patients undergoing MV repair had higher prevalence of long leaflets and degenerative MV pathology. The anterior mitral leaflet was 3.0 +/- 0.49 cm in the repair group vs 2.5 +/- 0.40 cm in the replacement group (p = 0.0001). MV replacement patients were older, more symptomatic, and had more renal dysfunction and lower hematocrits. By 3 years, 91% of patients with a repair were free of reoperation. CONCLUSIONS: Intrinsic MV pathology is frequently observed in HCM patients with symptomatic obstruction who undergo myectomy. Echocardiography can identify MV features predictive of successful valve repair. Repair, although durable, is feasible in only about half of patients.

Returning hypertrophy after surgery in a patient with hypertrophic cardiomyopathy caused by a myosin-binding protein C mutation.

We report a 13-year follow-up of a patient who underwent both myectomy and septal ablation due to hypertrophic cardiomyopathy caused by a cardiac myosin-binding protein C gene mutation. After myectomy the patient again developed significant septal hypertrophy at the operated septal area with a need for a second interventional therapy. This exceptional case underscores the remarkable ability of the heart muscle to show a continuous hypertrophic process over many years.

Children are not small adults: some differences between pediatric and adult cardiac transplantation.

Cardiac transplantation is a viable therapy for end-stage heart disease in both adults and children. Overall posttransplant survival in the pediatric age group (birth up to 18 years of age) is excellent (greater than 65% at 5 years for all age groups), comparable with the overall survival in the adult transplant recipients. Important differences exist regarding indications, evaluation, surgical technique, and posttransplant management. Indications for transplant in pediatric patients include metabolic and genetic forms of cardiomyopathy and structural congenital heart disease. Evaluation should include a metabolic workup, because potential etiologic factors include mitochondrial disorders, and genetic studies if indicated by phenotypic appearance or family pedigree. Children referred for transplantation with congenital heart disease have often had multiple attempts at palliative surgery, which increase peritransplant surgical risks. Key pediatric issues after transplantation include psychosocial support for the patient and family with regard to school, growth, development, and future expectations.

Hypertrophic cardiomyopathy and mtDNA depletion. Successful treatment with heart transplantation.

Cardiomyopathy associated with a mitochondrial DNA depletion syndrome is a rare condition. We report on a child with a hypertrophic cardiomyopathy and a mitochondrial depletion syndrome who was successfully treated by heart transplantation, given the tissue-specific nature of her mitochondrial disorder.