Francesca Nesta

New Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 13 Clinical Insights From Genetic Studies

Background—Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation, endocarditis, heart failure, and sudden death. To date, 2 MVP loci have been described, but the defective genes have yet to be discovered. In the present study, we analyzed a large family segregating MVP, and identified a new locus, MMVP3. This study and others have enabled us to explore mitral valve morphological variations of currently uncertain clinical significance. Methods and Results—Echocardiograms and blood samples were obtained from 43 individuals who were classified by the extent and pattern of displacement. Genotypic analyses were performed with polymorphic microsatellite markers. Evidence of linkage was obtained on chromosome 13q31.3-q32.1, with a peak nonparametric linkage score of 18.41 (P<0.0007). Multipoint parametric analysis gave a logarithm of odds score of 3.17 at marker D13S132. Of the 6 related individuals with mitral valve morphologies not meeting diagnostic criteria but resembling fully developed forms, 5 carried all or part of the haplotype linked to MVP. Conclusions—The mapping of a new MVP locus to chromosome 13 confirms the observed genetic heterogeneity and represents an important step toward gene identification. Furthermore, the genetic analysis provides clinical lessons with regard to previously nondiagnostic morphologies. In the familial context, these may represent early expression in gene carriers. Early recognition of gene carriers could potentially enhance the clinical evaluation of patients at risk of full expression, with the ultimate aim of developing interventions to reduce progression.

A Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 11p15.4

Mitral valve prolapse (MVP) is a common cardiovascular abnormality in the United States, occurring in approximately 2.4% of the general population. Clinically, patients with MVP exhibit fibromyxomatous changes in one or both of the mitral leaflets that result in superior displacement of the leaflets into the left atrium. Although often clinically benign, MVP can be associated with important accompanying sequelae, including mitral regurgitation, bacterial endocarditis, congestive heart failure, atrial fibrillation, and even sudden death. MVP is genetically heterogeneous and is inherited as an autosomal dominant trait that exhibits both sex- and age-dependent penetrance. In this report, we describe the results of a genome scan and show that a locus for MVP maps to chromosome 11p15.4. Multipoint parametric analysis performed by use of GENEHUNTER gave a maximum LOD score of 3.12 for the chromosomal region immediately surrounding the four-marker haplotype D11S4124-D11S2349-D11S1338-D11S1323, and multipoint nonparametric analysis (NPL) confirms this finding (NPL=38.59; P=.000397). Haplotype analysis across this region defines a 4.3-cM region between the markers D11S1923 and D11S1331 as the location of a new MVP locus, MMVP2, and confirms the genetic heterogeneity of this disorder. The discovery of genes involved in the pathogenesis of this common disease is crucial to understanding the marked variability in disease expression and mortality seen in MVP.

Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling: Failure of Hypertrophic Compensation

OBJECTIVES We examined whether mitral regurgitation (MR) augments post-myocardial infarction (MI) remodeling. BACKGROUND MR doubles mortality after MI, but its additive contribution to left ventricular (LV) remodeling is debated and has not been addressed in a controlled fashion. METHODS Apical MIs were created in 12 sheep, and 6 had an LV-to-left atrial shunt implanted, consistently producing regurgitant fractions of approximately 30%. The groups were compared at baseline, 1, and 3 months. RESULTS Left ventricular end-systolic volume progressively increased by 190% with MR versus 90% without MR (p < 0.02). Pre-load-recruitable stroke work declined by 82 +/- 13% versus 25 +/- 16% (p < 0.01) with MR, with decreased remote-zone sarcoplasmic reticulum Ca(2+)-ATPase levels (0.56 +/- 0.03 vs. 0.76 +/- 0.02, p < 0.001), and decreased isolated myocyte contractility. In remote zones, pro-hypertrophic Akt and gp130 were upregulated in both groups at 1 month, but significantly lower and below baseline in the MR group at 3 months. Pro-apoptotic caspase 3 remained high in both groups. Matrix metalloproteinase (MMP)-13 and membrane-type MMP-1 were increased in remote zones of MR versus infarct-only animals at 1 month, then fell below baseline. The MMP tissue inhibitors rose from baseline to 3 months in all animals, rising higher in the MI + MR-group border zone. CONCLUSIONS In this controlled model, moderate MR worsens post-MI remodeling, with reduced contractility. Pro-hypertrophic pathways are initially upregulated but subsequently fall below infarct-only levels and baseline; with sustained caspase 3 elevation, transformation to a failure phenotype occurs. Extracellular matrix turnover increases in MR animals. Therefore, MR can precipitate an earlier onset of dilated heart failure.

A Framework for the Analysis of Acoustical Cardiac Signals

Skilled cardiologists perform cardiac auscultation, acquiring and interpreting heart sounds, by implicitly carrying out a sequence of steps. These include discarding clinically irrelevant beats, selectively tuning in to particular frequencies and aggregating information across time to make a diagnosis. In this paper, we formalize a series of analytical stages for processing heart sounds, propose algorithms to enable computers to approximate these steps, and investigate the effectiveness of each step in extracting relevant information from actual patient data. Through such reasoning, we provide insight into the relative difficulty of the various tasks involved in the accurate interpretation of heart sounds. We also evaluate the contribution of each analytical stage in the overall assessment of patients. We expect our framework and associated software to be useful to educators wanting to teach cardiac auscultation, and to primary care physicians, who can benefit from presentation tools for computer-assisted diagnosis of cardiac disorders. Researchers may also employ the comprehensive processing provided by our framework to develop more powerful, fully automated auscultation applications

Audio-Visual Tools for Computer-Assisted Diagnosis of Cardiac Disorders

The process of interpreting heart sounds is restricted by human auditory limitations. Shortcomings such as insensitivity to frequency changes, slow responses to rapidly occurring changes in acoustic signals and an inability to discriminate the presence of soft pathological sounds are the source of inaccuracies and persist even with experience. This restricts both the practice and teaching of auscultation. In this paper we propose and evaluate a suite of presentation tools for computer-assisted auscultation. We explore the use of digital signal processing techniques to slow down heart sounds while preserving frequency content, differential enhancement across frequency scales to amplify pathological disease signatures, visualization of the signal to measure changes in signal energy across time and presentation of a representative prototypical signal for the patient

Software Enhanced Learning of Cardiac Auscultation

Listening to heart sounds during physical exams can offer useful clues to the presence of cardiac disease. Cardiac auscultation is non-invasive, inexpensive and fast. It is also highly unreliable, and requires good hearing and considerable expertise. In this paper, we describe an audio-visual tool designed to help people learn to be better at cardiac auscultation. The use of digital signal processing techniques makes pathological findings more recognizable in both audio and visual representations. This reduces dependence on the ability of people to hear relevant information