Cardiomyopathies are a distinct class of heart disease and are the third most common cause of heart failure. These conditions are generally characterized by remodeling of the left ventricle; however, the molecular mechanisms leading to the pathological states are still not fully understood. Mutated genes encoding for sarcomeric proteins have been shown to influence the development of cardiomyopathies. Missense mutations in alpha-cardiac actin (ACTC) have been associated with both hypertrophic and dilated cardiomyopathies (HCM and DCM respectively). Twelve of these mutations contribute to the onset of HCM: E99K, P164A, A331P, Y166C, A230V, A295S, M305L, S271F, H88Y, R95C, F90del and R312C while two contribute to the onset of DCM: E361G and R312H. These mutations are proposed to have detrimental effects on the structure and function of alpha-cardiac actin, thus leading to the diseased state. A295S ACTC did not exhibit intrinsic defects in protein folding and polymerization as seen with other ACTC variants with subdomain 3 mutations. Actin-activated ATPase rates measured showed the E99K ACTC variant increased the ATPase rate of skeletal myosin by approximately 30% compared to WT ACTC. E99K ACTC also exhibited decreased filament motility approximately 40-50% slower that WT ACTC at all ionic and ATP conditions examined demonstrating a reduction in force generation. These results demonstrate deficiencies in myosin binding of the E99K ACTC variant, providing insight into the primary molecular disruptions leading to the development of cardiomyopathies. / Heart and Stroke Foundation

Cardiomyopathy accounts for 20-30% of acute heart failure cases in adult Africans. Several types of cardiomyopathy have been identified; this study focused primarily on the genetic causes of arrhythmogenic right ventricular cardiomyopathy (ARVC). Many genes are implicated in ARVC pathogenesis, but many remain to be identified. We investigated a South African family (ACM2) with autosomal dominant ARVC, for whom the genetic cause of disease was unknown. Extensive genetic analysis was previously performed using genome-wide linkage analysis, but no disease-causing genetic variant was identified. We subsequently performed candidate gene screening of the phospholamban (PLN) gene, genome-wide copy number variant (CNV) analysis and whole exome sequencing to identify the causal genetic variant. The ACM2 family harboured no disease-causing PLN variants. However, on screening all cardiomyopathy cases in our registry (ARVC, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy and peripartum cardiomyopathy), we identified a known pathogenic PLN variant (c.25C>T; p.R9C) in a DCM family of European descent. This variant was reported in an American DCM family of European descent. Haplotype analysis revealed independent variant origins in these families. CNV analysis revealed no disease-causing variants in the ACM2 family. Whole exome sequencing of two affected ACM2 family members revealed 38 variants shared by these individuals. Variants were verified in family members and population controls by high resolution melt analysis and Sanger sequencing, and by bioinformatics analysis to predict variant pathogenicity. A novel N-cadherin (CDH2) c.686A>C (p.Q229P) variant segregated with ARVC in the ACM2 family and was bioinformatically predicted to be deleterious. An additional pathogenic CDH2 variant (c.1219G>A (p.D407N)) was identified in another individual with ARVC after screening 85 cases. These CDH2 variants were absent in normal population controls. Furthermore, alterations in Cdh2 are known to cause cardiomyopathy in rodent models. Taken together, these findings support the causal role of N-cadherin gene variants in human cardiomyopathy.

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AIM: Subsequent pregnancies (SSPs) in patients with peripartum cardiomyopathy (PPCM) have a high risk of heart failure relapse. We report on outcome of SSPs in PPCM patients in South Africa. METHODS AND RESULTS: Of the 18 PPCM patients with a SSP, 3 patients died within 6-months follow-up. Overall relapse rate, left ventricular ejection fraction (LVEF) <50% or death after at least 6 months follow-up, was 30%, with 16% (3/18) mortality. Persistently reduced LVEF (<50%) before entering SSP was present in 44% of patients, while full recovery (LVEF≥ 50%) was present in 85%. Persistently reduced LVEF before SSP was associated with a higher mortality (27% vs 0%) and a lower rate of full recovery at follow-up. Patients obtaining standard therapy for heart failure and bromocriptine immediately after delivery displayed significantly better LVEF at follow-up and a higher rate of full recovery, with no patient dying, compared with patients obtaining standard therapy for heart failure alone. CONCLUSION: Full recovery of LVEF before SSP was associated with lower mortality and better cardiac function at follow-up. Addition of bromocriptine to standard therapy for heart failure immediately after delivery was safe and appeared to be associated with better outcome of SSP in our patients.

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/ or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.

INTRODUCTION:Newly developed antineoplastic drugs have resulted in improvements in morbidity and mortality from many forms of cancers. However, some of these new chemotherapeutic agents have potentially lethal side effects, which are now being exposed with their widespread use. Gemcitabine is a nucleoside analog, which is a commonly used agent for various solid organ malignancies. Phase 1 and 2 trials with gemcitabine did not show significant risk for cardiotoxicity / however, with its widespread clinical use over the last decade, a few cases of cardiotoxicity related to gemcitabine use have been reported. Cardiomyopathy after the use of gemcitabine monotherapy is extremely rare / and only one such case has been reported in detail previously.CASE PRESENTATION:We report a case of a 56-year-old African American man with pancreatic cancer who presented with signs and symptoms of congestive heart failure after being treated with gemcitabine for two cycles (six doses). A two-dimensional echocardiography showed left ventricular ejection fraction of 15 to 20 percent with global hypokinesia. With the absence of significant risk factors for coronary artery disease and a strong temporal relationship with the initiation of chemotherapy, it was concluded that our patient's cardiomyopathy was related to the use of gemcitabine. Gemcitabine was discontinued and our patient responded well to standard heart failure therapy. Two months later, a repeat echocardiogram showed significant improvements in left ventricular systolic function.CONCLUSIONS:Gemcitabine should be considered as a potential cause of cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into potential mechanisms and treatments of gemcitabine-induced cardiac dysfunction.

This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene(s) in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.

Mutations in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, cardiac disease caused by mutations in non-sarcomeric proteins exhibit remarkably similar phenotypes, suggesting that common modes of pathogenesis might exist. It is of particular interest whether non-sarcomeric mutations result in impaired contractile function akin to sarcomeric diseases. Accordingly, this thesis describes the effect of cardiomyopathy-causing mutations to an energy sensing protein (AMPK &gamma;2) and a small heat shock protein (&alpha;B-crystallin) on cardiac myofilament biomechanics and Ca²⁺ handling. Mutations in the regulatory &gamma;2 subunit of AMP-activated kinase (AMPK), encoded by the PRKAG2 gene, cause a cardiomyopathy characterized by ventricular hypertrophy, electrophysiological abnormalities, and glycogen accumulation. Data from animal models in which the mutant transgene is overexpressed suggest that the electrophysiological aspects might be caused by excess glycogen, but that this is insufficient to account for all facets of the phenotype. A novel knock-in mouse expressing R299Q AMPK &gamma;2 (homologous to the human R302Q mutation) was generated to model PRKAG2 cardiomyopathy more accurately. Assessment of the cardiac phenotype at two months to determine the early events in disease pathogenesis revealed systolic and diastolic dysfunction in mutant animals, with no excess glycogen detected. Analysis of acetyl-CoA carboxylase phosphorylation at S79 suggested increased basal AMPK activity in mutant animals. Increased sarcomeric Ca^2&plus; sensitivity of contractile activation was observed in demembranated cardiac trabeculae from mutant animals, associated with decreased phosphorylation of cardiac troponin I at S23/S24 and increased phosphorylation at S150. Treatment with protein kinase A normalized this difference in Ca^2&plus; sensitivity, suggesting that reduced PKA phosphorylation is the primary abnormality in mutant tissue. Cardiomyocytes from mutant animals exhibited slowed contractile and Ca^2&plus; reuptake rates, associated with reduced phosphorylation of phospholamban and myosin binding protein C, as well as an increased response to isoproterenol. The lack of glycogen accumulation in these animals, combined with abnormal contractile and Ca²⁺ handling properties, reveals a more nuanced interpretation of the mechanism of PRKAG2 cardiomyopathy development. Further, the newly identified interaction between energy- (AMPK) and stress- (PKA) signalling networks may be of importance in numerous additional disease pathways. This thesis clarifies the role of &alpha;B-crystallin, and its cardiomyopathy-causing mutant (R157H), in regulating cardiac muscle stiffness. Specifically, mass spectrometry data revealed that &alpha;B-crystallin forms large oligomers and binds to titin Ig domains. Nuclear magnetic resonance confirmed this binding and suggested that &alpha;B-crystallin's C-terminal is responsible for titin binding. A viscoelastic model was developed to match stress relaxation in cardiac muscle fibres. Measurements using this model indicated that &alpha;B-crystallin significantly increases myocardial stiffness and that the R157H mutation weakens this effect. Further, a 9-AA peptide from &alpha;B-crystallin's C-terminus was shown to bind titin and increase overall muscle stiffness. These results reveal a novel method of cardiac muscle stiffness regulation that might contribute to the pathogenesis of cardiomyopathy.

ABSTRACT Introduction: Peripartum cardiomyopathy (PPCM) is defined as a disorder of unknown aetiology that occurs between one month antepartum and five months postpartum in women without pre-existing heart disease. While the incidence of PPCM has been reported between 1: 2392 and 15000 live births in the USA, the disease is ubiquitous on the African continent with an incidence ranging from 1: 100 to 1: 1000 deliveries. The mortality rate ranges between 15 and 40.7%, while 23 to 54% of patients recover completely. Aim of this thesis was to describe the clinical profile of 100 PPCM patients, identify predictors of negative outcome, analyze differences in kinetics of cardiac function biomarkers, pro-inflammatory cytokines, markers of re-modeling and prolactin in cardiac function improvers versus non-improvers and investigate a possible autoimmune component in the pathogenesis of PPCM. Methods: We conducted a single centre, prospective study of 100 newly diagnosed patients meeting diagnostic criteria for PPCM. All patients received standard anti-failure therapy with diuretics (furosemide, aldactone), the β-blocker carvedilol, ACE-inhibitor perindopril and digoxin if indicated. Clinical assessment, 2-dimensional echocardiographic studies and blood analysis were systematically performed at time of presentation, after six and twelve months of therapy. Findings: Fifteen patients died within the follow-up period of six months and eight were not available for full follow-up since they moved to remote areas. Patients who completed six months of treatment showed a significant reduction of heart rate, left ventricular dimensions and significant improvement in scintigraphically and echocardiographically derived values for left ventricular ejection fraction (p< 0.0001) and NYHA functional class (p< 0.001). However, normalization of LVEF (>50%) was only observed in 18 (23%) of the patients. Baseline plasma levels of Fas/Apo-1 (OR = 3.56, CI 95% = 1.35–9.42) and NYHA FC (OR = 2.67, CI 95% = 1.04–6.83) were independent predictors of death.extra-cellular loop (RAESDE and DEARRCY), while those from DCMO patients bind to epitopes on the first (30%) and second extra-cellular loop (ARRCYND and PKCCDF). The β1-adrenoreceptor agonist-like antibodies identified in PPCM patients are part of the IgG2 and IgG3 subclass, while those from DCMO patients belong to the IgG2 subclass. Furthermore we demonstrated that β1-adrenoreceptor antibodies in serum of PPCM patients prevented desensitization of the receptor. The β1-adrenoreceptor antibodies in serum of PPCM patients were not detectable in serum of non PPCM peripartum controls and are different from those found in patients with DCMO, suggesting that PPCM forms a distinct disease entity. We demonstrated a positive correlation between the activity of the β1-adrenoreceptor antibodies and serum expression levels of the marker of cardiac function NT-proBNP from baseline to twelve months (rs=0.58, 2- tailed P=0.0228), 95% CI (0.10 to 0.84). Investigating the cause for high prolactin expression levels in serum of PPCM patients, we identified a STAT3 deficit in a PPCM mouse model. Significantly increased levels of cathepsin D cause the cleavage of the physiological 23-kDa form of prolactin into a 16-kDa form in PPCM patients, but not in non-PPCM peripartum controls. This initiated another clinical study, investigating the effect of the prolactin-inhibitor bromocriptine in addition to standard heart failure therapy in known PPCM patients, presenting with a subsequent pregnancy. Comparison of clinical and echocardiographic data of these patients to others on standard heart failure therapy demonstrated preservation or improvement of left ventricular dimensions and systolic function as well as NYHA FC. Conclusion: While a wide range of parameters, reflecting cardiac dysfunction and pro-inflammatory immune activation, were elevated in all PPCM patients at time of first presentation, indicating their involvement in the initiation of the disease, we found significant differences over time between cardiac function improvers and nonimprovers for ΔIFN-gamma (P=0.0181) serum levels, suggesting their role in disease progression. Heightened IFN-gamma expression could indicate an ongoing T-cell mediated autoimmune response and an insult to the cardiac muscle, resulting in fibrosis and inability to improve left ventricular systolic function. Prolactin represents a stimulatory link between the neuroendocrine and immune systems, promoting proinflammatory immune responses. Interestingly, we found significantly higher (P<0.0001) serum prolactin levels in PPCM patients at time of first presentation than in peripartum controls, suggesting the hormone’s role during the initial acute phase of PPCM. Several authors have described the induction of IFN-gamma by prolactin. Disease progression and the ongoing autoimmune insult by beta1-adrenergic autoantibodies appear to be driven by IFN-gamma. This pro-inflammatory cytokine remained high in PPCM nonimprovers, decreased in improvers, was previously implicated in the development of autoimmune disease and its suppression leads to desensitization of β-adrenoreceptors. Together with the β1-adrenoreceptor autoantibodies that we have identified in PPCM patients and their demonstrated property to also prevent desensitization of β1-adrenoreceptors, patients experience an adrenergic overdrive, leading to cardiac myocyte insult. 10 While the pathogenesis of PPCM appears to be multifactorial, our task as scientists remains to find out, how the monolith was erected. Specifically, it appears promising to investigate the effects of bromocriptine in addition to standard heart failure therapy in a randomised, double-blinded clinical study. Although one could argue that prolactin regulated expression of IFN-gamma and other cytokines may explain the gender-specific differences in autoimmunity, it has been shown that elevated serum prolactin concentrations are associated with accelerated autoimmune disease in both female and male mice. Possibly, prolactin does not only play a role in the pathogenesis of PPCM, but also in other forms of cardiomyopathy, affecting males and females alike. It would be interesting to study prolactin serum expression levels in male and female patients with idiopathic DCMO. Clearly, further studies into the unfolding pathogenesis of PPCM are indicated.