Mortality Risk Associated With Truncating Founder Mutations in Titin.

Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients. Methods Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. Results The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged ≥60 years. Conclusions The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.

Did Frédéric Chopin Die From Heart Failure?

On October 17, 1849, Poland's greatest composer, Frédéric Chopin (1810-1849) died aged 39. His cause of death remains unknown. An investigation of the documental sources was performed to reconstruct the medical history of the artist. Since his earliest years, his life had been dominated by poor health. Recurrent episodes of cough, fever, headaches, lymphadenopathy- a series of symptoms that may be attributed to viral respiratory infections- manifested in his teens. Later in life, he had chest pain, hemoptysis, hematemesis, neuralgia, and arthralgia. Exhaustion and breathlessness characterized all his adult life. Coughing, choking, and edema of the legs and ankles manifested four months before his death. Several hypotheses ranging from cystic fibrosis to alpha-1 anti-trypsin deficiency and pulmonary tuberculosis have been proposed to explain Chopin's lifelong illness. We suggest that Chopin had dilated cardiomyopathy with consequent heart failure and cirrhosis that caused his death.

The Remarkable 50 Years of Imaging in HCM and How it Has Changed Diagnosis and Management: From M-Mode Echocardiography to CMR.

The almost 50-year odyssey of cardiac imaging in hypertrophic cardiomyopathy (HCM), revisited and described here, has been remarkable, particularly when viewed in the timeline of advances that occurred during a single generation of investigators. At each step along the way, from M-mode to 2-dimensional echocardiography to Doppler imaging, and finally over the last 10 years with the emergence of high-resolution tomographic cardiac magnetic resonance (CMR), evolution of the images generated by each new technology constituted a paradigm change over what was previously available. Together, these advances have transformed the noninvasive diagnosis and management of HCM in a number of important clinical respects. These changes include a more complete definition of the phenotype, resulting in more reliable clinical identification of patients and family members, defining mechanisms (and magnitude) of left ventricular outflow obstruction, and novel myocardial tissue characterization (including in vivo detection of fibrosis/scarring); notably, these advances afford more precise recognition of at-risk patients who are potential candidates for life-saving primary prevention defibrillator therapy. This evolution in imaging as applied to HCM has indelibly changed cardiovascular practice for this morphologically and clinically complex genetic disease.

The contribution of South Africans to the subject of dilated cardiomyopathy - with reference to : cardiovascular collagenosis with parietal endocardial thrombosis : a clinicopathologic study of forty cases.

BACKGROUND: Dilated cardiomyopathy (DCM) is a heart muscle disease that is endemic in Africa. Over the past 50 years, South African investigators have made significant contributions to scientific elucidation of the condition. The objective of this review was to summarise their research on the subject of DCM. METHODS AND RESULTS: We searched PubMed for articles originating from South Africa and focusing on DCM or the related condition, peripartum cardiomyopathy (PCM). Reference lists and prominent South African researchers on DCM were also consulted. The prevalence of DCM is comparable in magnitude to that of other endemic heart conditions such as hypertension and rheumatic heart disease, although by comparison, DCM may cause disproportionate morbidity from heart failure. In the African context, malnutrition, excessive alcohol intake, prior myocarditis and genetic make-up have been proposed as aetiologies, and some or all of these factors may play an interrelated role in individual disease expression. The pathogenesis of DCM is partially due to the mechanical effects of fibrosis, and the immune response to myocardial damage likely affects disease progression. Small trials of pentoxifylline plus conventional therapy have demonstrated a trend towards reduced mortality from heart failure. CONCLUSIONS: Despite half a century of noteworthy research, the pathogenic mechanisms of DCM are still incompletely understood. South Africans have, however, played and should continue to play a critical role in advancing research on DCM.

A decade of discoveries in cardiac biology.

The heart is the first organ to form in the embryo, and all subsequent events in the life of the organism depend on its function. Inherited mutations in cardiac regulatory genes give rise to congenital heart disease, the most common form of human birth defects, and abnormalities of the adult heart represent the most prevalent cause of morbidity and mortality in the industrialized world. The past decade has marked a transition from physiological and functional studies of the heart toward a deeper understanding of cardiac function (and dysfunction) at genetic and molecular levels. These discoveries have provided new therapeutic approaches for prevention and palliation of cardiac disease and have raised new questions, challenges and opportunities for the future.

Maladaptive growth in the failing heart: the cardiomyopathy of overload.

The hypertrophic response to overload plays an important role in the progressive deterioration of the failing heart--the "Cardiomyopathy of Overload"--and so contributes to the poor prognosis in patients with heart failure. Although increased myocyte size reduces the load on individual sarcomeres, hypertrophy also has maladaptive features. The latter include molecular changes that weaken and impair relaxation in the overloaded heart, and accelerate cardiac myocyte death. Different types of overload lead to concentric and eccentric hypertrophy; as the latter tends to progress ("remodeling"), dilatation is associated with an especially poor prognosis. Concentric hypertrophy is due largely to cardiac myocyte thickening, while eccentric hypertrophy is caused by cell elongation. These differences, along with evidence that concentric hypertrophy is initiated by increased diastolic stretch while eccentric hypertrophy results from increased systolic stress, indicate that these growth responses are mediated by different signal transudation pathways. The beneficial effects of neurohumoral blockers in patients with heart failure are due partly to their ability to inhibit maladaptive features of overload-induced proliferative signaling. The molecular complexity of the hypertrophic response now being uncovered offers opportunities for the development of new therapy to inhibit remodeling and cell death in the failing heart.