Francesca N. Delling

Heart Disease and Stroke Statistics—2018 Update: A Report From the American Heart Association

Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter. Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA’s My Life Check - Life’s Simple 7 (Figure1), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents …

Mitral valve disease—morphology and mechanisms

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Epidemiology and Pathophysiology of Mitral Valve Prolapse New Insights Into Disease Progression, Genetics, and Molecular Basis

Mitral valve (MV) prolapse (MVP) is a common disorder, afflicting 2% to 3% of the general population.1,2 It is characterized by typical fibromyxomatous changes in the mitral leaflet tissue with superior displacement of 1 or both leaflets into the left atrium.3,4 With a prevalence of 2% to 3%, MVP is expected to affect ≈7.8 million individuals in the United States and >176 million people worldwide. MVP can be associated with significant mitral regurgitation (MR), bacterial endocarditis, congestive heart failure, and even sudden death.5–7 MVP is a clinical entity that is not fully understood, despite being known for more than a century. A “midsystolic click” was first described in 1887 by Cuffer and Barbillon.8 In 1963, Barlow and Pocock9 demonstrated the presence of MR by angiography in patients with the “click-murmur” syndrome. Criley et al10 subsequently coined the term MVP. MVP may be familial or sporadic. Despite being the most common cause of isolated MR requiring surgical repair,11 little is known about the genetic mechanisms underlying the pathogenesis and progression of MVP. Studies on the heritable features of MVP have been limited by the analysis of relatively small pedigrees and by self-referral and selection biases, including a preponderance of data from hospital-based cohorts.12,13 Nonetheless, the majority of data favor an autosomal-dominant pattern of inheritance in a large proportion of individuals with MVP.12,13 Despite the variability in clinical features, familial MVP might be considered a prevalent mendelian cardiac abnormality in humans. Although filamin-A has been identified as causing an X-linked form of MVP,14 the causative genes for the more common form of autosomal-dominant MVP have yet to be defined. In this review, we summarize our current knowledge of the diagnosis, epidemiology, prognosis, …

Intermediate-Signal-Intensity Late Gadolinium Enhancement Predicts Ventricular Tachyarrhythmias in Patients With Hypertrophic Cardiomyopathy

Background— In hypertrophic cardiomyopathy (HCM), the arrhythmic potential associated with a variety of left ventricular myocardial signal intensities evident on contrast-enhanced cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is unresolved. Methods and Results— In 145 HCM patients (43±15 years old), visually identified areas of LGE in left ventricle were analyzed quantitatively for intermediate (≥4 but <6 SD) and high (≥6 SD above the mean signal intensity of normal myocardium) LGE signal intensity (LGE-SI). Ambulatory Holter ECGs were obtained within 7.8±8.3 weeks of cardiovascular magnetic resonance. HCM patients with nonsustained ventricular tachycardia, ventricular couplets, and premature ventricular contractions showed greater amounts of intermediate LGE-SI (17±7 versus 10±10 g, 16±10 versus 10±11 g, and 13±8 versus 10±13 g, respectively; P=0.003 to <0.001) and greater amounts of high LGE-SI (15±6 versus 10±8 g, 14±9 versus 10±12 g, and 12±7 versus 10±8 g, respectively; P=0.02–0.003) than patients without these arrhythmias. In HCM patients with either nonsustained ventricular tachycardia, couplets, or premature ventricular contractions, the extent of intermediate LGE-SI exceeded that of high LGE-SI (17±7 versus 15±6 g, 16±10 versus 14±9 g, and 13±8 versus 12±7 g, respectively; P=0.01–0.04). In addition, the receiver operating characteristic area under the curve established intermediate LGE-SI as a better discriminator of patients with nonsustained ventricular tachycardia than was high LGE-SI, with 7 additional patients with this arrhythmia identified. Conclusions— In patients with HCM, intermediate LGE-SI is a better predictor of ventricular tachyarrhythmias (including nonsustained ventricular tachycardia, a risk factor for sudden death) than is high LGE-SI. Longitudinal studies in larger HCM cohorts are justified to define the independent prognostic impact of intermediate LGE-SI.

Mutations in DCHS1 cause mitral valve prolapse.

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1+/− mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.

Tricuspid Regurgitation and Mortality in Patients With Transvenous Permanent Pacemaker Leads.

Estimates of the prevalence and importance of significant tricuspid regurgitation (STR) related to implantable device leads are based mainly on case reports, small observational studies, or mixed samples that include defibrillators. We sought to assess whether patients with permanent pacemaker (PPM) leads have an increased risk of STR and to determine mortality associated with PPM-related TR in a large longitudinal single-center cohort. We examined the prevalence of STR (defined as moderate-severe or ≥3+) among all echocardiograms performed from 2005 to 2011 excluding those with defibrillators. We then examined mortality risk according to the prevalence of PPM and STR after adjusting for cardiac co-morbidities, left ventricular systolic/diastolic function, and pulmonary artery hypertension. We screened 93,592 echocardiograms (1,245 with PPM) in 58,556 individual patients (634 with PPM). The prevalence of STR was higher in patients after PPM placement (mean age 79 ± 3 years; 54% men) compared with those without a PPM (adjusted odds ratio 2.32; 95% confidence interval [CI] 1.54 to 3.49; p <0.0001). Among patients with a PPM lead, the presence of STR was associated with increased mortality (adjusted hazard ratio 1.40; 95% CI 1.04 to 2.11, p = 0.027, vs no STR). Compared with having neither a PPM lead nor STR, adjusted hazard ratios for death were 2.13 (95% CI 1.93 to 2.34) for STR but no PPM, 1.04 (0.89 to 1.22) for PPM without STR, and 1.55 (1.13 to 2.14) for PPM with STR. In conclusion, in a sample comprising >58,000 individual patients, PPM leads are associated with higher risk of STR after adjustment for left ventricular systolic/diastolic function and pulmonary artery hypertension; similarly to STR from other cardiac pathologies, PPM-related STR is associated with increased mortality.

Familial Clustering of Mitral Valve Prolapse in the Community

Background— Knowledge of mitral valve prolapse (MVP) inheritance is based on pedigree observation and M-mode echocardiography. The extent of familial clustering of MVP among unselected individuals in the community using current, more specific echocardiographic criteria is unknown. In addition, the importance of nondiagnostic MVP morphologies (NDMs; first described in large pedigrees) has not been investigated in the general population. We hypothesized that parental MVP and NDMs increase the risk of offspring MVP. Methods and Results— Study participants were 3679 Generation 3 individuals with available parental data in the Offspring or the New Offspring Spouse cohorts. MVP and NDMs were distinguished by leaflet displacement >2 versus ⩽2 mm beyond the mitral annulus, respectively. We compared MVP prevalence in Generation 3 participants with at least 1 parent with MVP (n=186) with that in individuals without parental MVP (n=3493). Among 3679 participants (53% women; mean age, 40±9 years), 49 (1%) had MVP. Parental MVP was associated with a higher prevalence of MVP in Generation 3 participants (10 of 186, 5.4%) compared with no parental MVP (39 of 3493, 1.1%; adjusted odds ratio, 4.51; 95% confidence interval, 2.13–9.54; P<0.0001). When parental NDMs were examined alone, the prevalence of Generation 3 MVP remained higher (12 of 484, 2.5%) compared with those without parental MVP or NDMs (27 of 3009, 0.9%; adjusted odds ratio, 2.52; 95% confidence interval, 1.25–5.10; P=0.01). Conclusions— Parental MVP and NDMs are associated with increased prevalence of offspring MVP, highlighting the genetic substrate of MVP and the potential clinical significance of NDMs in the community.

CMR Predictors of Mitral Regurgitation in Mitral Valve Prolapse

OBJECTIVES We sought to assess the correlation between mitral valve characteristics and severity of mitral regurgitation (MR) in subjects with mitral valve prolapse (MVP) undergoing cardiac magnetic resonance (CMR) imaging. BACKGROUND Compared with extensive echocardiographic studies, CMR predictors of MVP-related MR are unknown. The severity of MR at the time of diagnosis has prognostic implication for patients; therefore, the identification of determinants of MR and its progression may be important for risk stratification, follow-up recommendations, and surgical decision making. METHODS Seventy-one MVP patients (age 54 ± 11 years, 58% males, left ventricular [LV] ejection fraction 65 ± 5%) underwent cine CMR to assess annular dimensions, maximum systolic anterior and posterior leaflet displacement, papillary muscle (PM) distance to coaptation point and prolapsed leaflets, as well as diastolic anterior and posterior leaflet thickness and length, and LV volumes and mass. Velocity-encoded CMR was used to obtain aortic outflow and to quantify MR volume. RESULTS Using multiple linear regression analysis including all variables, LV mass (p < 0.001), anterior leaflet length (p = 0.006), and posterior displacement (p = 0.01) were the best determinants of MR volume with a model-adjusted R(2) = 0.6. When the analysis was restricted to valvular characteristics, MR volume correlated with anterior mitral leaflet length (p < 0.001), posterior mitral leaflet displacement (p = 0.003), posterior leaflet thickness (p = 0.008), and the presence of flail (p = 0.005) with a model-adjusted R(2) = 0.5. We also demonstrated acceptable intraobserver and interobserver variability in these measurements. CONCLUSIONS Anterior leaflet length, posterior leaflet displacement, posterior leaflet thickness, and the presence of flail are the best CMR valvular determinants of MVP-related MR. The acceptable intraobserver and interobserver variability of our measurements confirms the role of CMR as an imaging modality for assessment of MVP patients with significant MR.

Evolution of Mitral Valve Prolapse Insights From the Framingham Heart Study

Background— Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. Methods and Results— We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P <0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P <0.05). Conclusions— NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression. # CLINICAL PERSPECTIVES {#article-title-33}Background— Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. Methods and Results— We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P<0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P<0.05). Conclusions— NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression.