Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy

BACKGROUND-: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. METHODS AND RESULTS-: We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. CONCLUSIONS-: Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families

Cardiac myosin-binding protein C mutations and hypertrophic cardiomyopathy haploinsufficiency, deranged phosphorylation, and cardiomyocyte dysfunction

Background-Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), are a frequent cause of familial hypertrophic cardiomyopathy. In the present study, we investigated whether protein composition and function of the sarcomere are altered in a homogeneous familial hypertrophic cardiomyopathy patient group with frameshift mutations in MYBPC3 (MYBPC3(mut)). Methods and Results-Comparisons were made between cardiac samples from MYBPC3 mutant carriers (c. 2373dupG, n=7; c. 2864_2865delCT, n=4) and nonfailing donors (n=13). Western blots with the use of antibodies directed against cMyBP-C did not reveal truncated cMyBP-C in MYBPC3(mut). Protein expression of cMyBP-C was significantly reduced in MYBPC3(mut) by 33 +/- 5%. Cardiac MyBP-C phosphorylation in MYBPC3(mut) samples was similar to the values in donor samples, whereas the phosphorylation status of cardiac troponin I was reduced by 84 +/- 5%, indicating divergent phosphorylation of the 2 main contractile target proteins of the beta-adrenergic pathway. Force measurements in mechanically isolated Triton-permeabilized cardiomyocytes demonstrated a decrease in maximal force per cross-sectional area of the myocytes in MYBPC3(mut) (20.2 +/- 2.7 kN/m(2)) compared with donor (34.5 +/- 1.1 kN/m(2)). Moreover, Ca2+ sensitivity was higher in MYBPC3(mut) (pCa(50)=5.62 +/- 0.04) than in donor (pCa(50)=5.54 +/- 0.02), consistent with reduced cardiac troponin I phosphorylation. Treatment with exogenous protein kinase A, to mimic beta-adrenergic stimulation, did not correct reduced maximal force but abolished the initial difference in Ca2+ sensitivity between MYBPC3(mut) (pCa(50)=5.46 +/- 0.03) and donor (pCa(50)=5.48 +/- 0.02). Conclusions-Frameshift MYBPC3 mutations cause haploinsufficiency, deranged phosphorylation of contractile proteins, and reduced maximal force-generating capacity of cardiomyocytes. The enhanced Ca2+ sensitivity in MYBPC3(mut) is due to hypophosphorylation of troponin I secondary to mutation-induced dysfunction. (Circulation. 2009; 119: 1473-1483.

Легочная гипертензия при диастолической дисфункции левого желудочка у больных с ишемической кардиомиопатией

На основании данных эхокардиографического исследования выявлена взаимосвязь между степенью легочной гипертензии и тяжестью диастолической дисфункции левого желудочка у больных с ишемической кардиомиопатией. Показано, что рестриктиное наполнение левого желудочка наблюдается в основном при выраженной легочной гипертензии.The findings of echocardiography were used to reveal interrelation between the degree of pulmonary hypertension and severity of diastolic dysfunction of the left ventricle in patients with ischemic cardiomyopathy. Restrictive filling of the left ventricle is shown to be observed in marked pulmonary hypertension

Truncating Titin (TTN) Variants in Chemotherapy-Induced Cardiomyopathy

Chemotherapy-induced cardiomyopathy (CCMP) is a complication of chemotherapy treatment occurring in 9% of patients treated with the use of anthracyclines. Currently, risk stratification is based on clinical risk factors that do not adequately account for variable individual susceptibility. This suggests the presence of other determinants. In this case series, we describe 2 women with breast cancer who developed severe heart failure within months after chemotherapy. Genetic screening revealed truncating frameshift mutations in TTN, encoding the myofilament titin, in both women. To our knowledge, this is the 1st report of an association between truncating TTN variants and CCMP. Because truncations in TTN are the most common cause of familial and sporadic dilated cardiomyopathy, further research is needed to establish their prevalence in patients presenting with CCMP

P62-positive aggregates are homogenously distributed in the myocardium and associated with the type of mutation in genetic cardiomyopathy

© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd Genetic cardiomyopathy is caused by mutations in various genes. The accumulation of potentially proteotoxic mutant protein aggregates due to insufficient autophagy is a possible mechanism of disease development. The objective of this study was to investigate the distribution in the myocardium of such aggregates in relation to specific pathogenic genetic mutations in cardiomyopathy hearts. Hearts from 32 genetic cardiomyopathy patients, 4 non-genetic cardiomyopathy patients and 5 controls were studied. Microscopic slices from an entire midventricular heart slice were stained for p62 (sequestosome-1, marker for aggregated proteins destined for autophagy). The percentage of cardiomyocytes with p62 accumulation was higher in cardiomyopathy hearts (median 3.3%) than in healthy controls (0.3%; P <.0001). p62 accumulation was highest in the desmin (15.6%) and phospholamban (7.2%) groups. P62 accumulation was homogeneously distributed in the myocardium. Fibrosis was not associated with p62 accumulation in subgroup analysis of phospholamban hearts. In conclusion, accumulation of p62-positive protein aggregates is homogeneously distributed in the myocardium independently of fibrosis distribution and associated with desmin and phospholamban cardiomyopathy. Proteotoxic protein accumulation is a diffuse process in the myocardium while a more localized second hit, such as local strain during exercise, might determine whether this leads to regional myocyte decay

Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy

Phospholamban (PLN) p.Arg14del cardiomyopathy is associated with an increased risk of malignant ventricular arrhythmias and severe heart failure and a poor prognosis from late adolescence. It can be diagnosed in whole heart specimens, but rarely in right ventricular biopsy specimens, by PLN immunohistochemistry showing PLN-containing aggregates concentrated in cardiomyocytes in dense perinuclear aggresomes. The purpose of this study was to determine whether PLN immunohistochemistry can be used to diagnose PLN p.Arg14del cardiomyopathy using apical left ventricular myocardial specimens harvested during left ventricular assist device (LVAD) implantation. At that stage, a genetic diagnosis, which may guide treatment and referral of family members for further investigation, is frequently not established yet. Included were myocardial specimens from 30 diverse genetic cardiomyopathy cases with known variants (9 carriers of the pathogenic PLN p.Arg14del variant, 18 cases with other pathogenic or likely pathogenic variants in cardiomyopathy-related genes, and 3 with only variants of unknown significance). Immunohistochemical analysis revealed typical dense perinuclear globular PLN-positive aggregates, representing aggresomes, in all nine PLN p.Arg14del cases. In 20 non-PLN cases, PLN-staining was absent. In one non-PLN case, one of the two independent observers misinterpreted PLN staining of heavily wrinkled nuclear membranes of cardiomyocytes as perinuclear PLN aggregates. In this genetic cardiomyopathy cohort, PLN Immunohistochemical analysis in LVAD biopsies was found to be a highly sensitive (100%) and specific (95%) method for demonstration of PLN protein aggregates in PLN p.Arg14del cardiomyopathy. In clinical practice, PLN immunohistochemical analysis of LVAD specimens can be of incremental value in the diagnostic workup of this cardiomyopathy, even more so if genetic analysis is not readily available

The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Diagnostic Task Force Criteria Impact of New Task Force Criteria

Background-Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. Methods and Results-In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS ≥55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No rel

Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. AIM: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. METHODS: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). RESULTS: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. CONCLUSION: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium