Sex Differences and Similarities in Valvular Heart Disease.

As populations age worldwide, the burden of valvular heart disease has grown exponentially, and so has the proportion of affected women. Although rheumatic valve disease is declining in high-income countries, degenerative age-related causes are rising. Calcific aortic stenosis and degenerative mitral regurgitation affect a significant proportion of elderly women, particularly those with comorbidities. Women with valvular heart disease have been underrepresented in many of the landmark studies which form the basis for guideline recommendations. As a consequence, surgical referrals in women have often been delayed, with worse postoperative outcomes compared with men. As described in this review, a more recent effort to include women in research studies and clinical trials has increased our knowledge about sex-based differences in epidemiology, pathophysiology, diagnostic criteria, treatment options, outcomes, and prognosis.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease. RESULTS: Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association's 2020 Impact Goals. RESULTS: Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

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.

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study.

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001). Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

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 performance of high-resolution late gadolinium enhancement imaging with compressed sensing.

PURPOSE: To evaluate diagnostic image quality of 3D late gadolinium enhancement (LGE) with high isotropic spatial resolution (∼1.4 mm3 ) images reconstructed from randomly undersampled k-space using LOw-dimensional-structure Self-learning and Thresholding (LOST). MATERIALS AND METHODS: We prospectively enrolled 270 patients (181 men; 55 ± 14 years) referred for myocardial viability assessment. 3D LGE with isotropic spatial resolution of 1.4 ± 0.1 mm3 was acquired at 1.5T using a LOST acceleration rate of 3 to 5. In a subset of 121 patients, 3D LGE or phase-sensitive LGE were acquired with parallel imaging with an acceleration rate of 2 for comparison. Two readers evaluated image quality using a scale of 1 (poor) to 4 (excellent) and assessed for scar presence. The McNemar test statistic was used to compare the proportion of detected scar between the two sequences. We assessed the association between image quality and characteristics (age, gender, torso dimension, weight, heart rate), using generalized linear models. RESULTS: Overall, LGE detection proportions for 3D LGE with LOST were similar between readers 1 and 2 (16.30% vs. 18.15%). For image quality, readers gave 85.9% and 80.0%, respectively, for images categorized as good or excellent. Overall proportion of scar presence was not statistically different from conventional 3D LGE (28% vs. 33% [P = 0.17] for reader 1 and 26% vs. 31% [P = 0.37] for reader 2). Increasing subject heart rate was associated with lower image quality (estimated slope = -0.009 (P = 0.001)). CONCLUSION: High-resolution 3D LGE with LOST yields good to excellent image quality in >80% of patients and identifies patients with LV scar at the same rate as conventional 3D LGE. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1829-1838.

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.

Relationship between native papillary muscle T1 time and severity of functional mitral regurgitation in patients with non-ischemic dilated cardiomyopathy.

BACKGROUND: Functional mitral regurgitation is one of the severe complications of non-ischemic dilated cardiomyopathy (DCM). Non-contrast native T1 mapping has emerged as a non-invasive method to evaluate myocardial fibrosis. We sought to evaluate the potential relationship between papillary muscle T1 time and mitral regurgitation in DCM patients. METHODS: Forty DCM patients (55 ± 13 years) and 20 healthy adult control subjects (54 ± 13 years) were studied. Native T1 mapping was performed using a slice interleaved T1 mapping sequence (STONE) which enables acquisition of 5 slices in the short-axis plane within a 90 s free-breathing scan. We measured papillary muscle diameter, length and shortening. DCM patients were allocated into 2 groups based on the presence or absence of functional mitral regurgitation. RESULTS: Papillary muscle T1 time was significantly elevated in DCM patients with mitral regurgitation (n = 22) in comparison to those without mitral regurgitation (n = 18) (anterior papillary muscle: 1127 ± 36 msec vs 1063 ± 16 msec, p < 0.05; posterior papillary muscle: 1124 ± 30 msec vs 1062 ± 19 msec, p < 0.05), but LV T1 time was similar (1129 ± 38 msec vs 1134 ± 58 msec, p = 0.93). Multivariate linear regression analysis showed that papillary muscle native T1 time (ß = 0.10, 95 % CI: 0.05-0.17, p < 0.05) is significantly correlated with mitral regurgitant fraction. Elevated papillary muscle T1 time was associated with larger diameter, longer length and decreased papillary muscle shortening (all p values <0.05). CONCLUSIONS: In DCM, papillary muscle native T1 time is significantly elevated and related to mitral regurgitant fraction.

Cannabis use and incident atrial fibrillation in a longitudinal cohort.

BACKGROUND: Cannabis use is increasing worldwide. While prior studies have reported an association between cannabis use and a higher risk of atrial fibrillation (AF), most were cross-sectional and generally relied on diagnostic coding to identify cannabis users, which may not be representative of the typical recreational cannabis user. OBJECTIVE: The purpose of this study was to examine the association between recreational cannabis use and lifetime AF risk. METHODS: We evaluated the AF risk of participants of the UK Biobank cohort who completed the cannabis use lifestyle questionnaire. Cannabis exposure was categorized as "Occasional Use" for less than 100 times used, "Frequent Use" for more than 100 times used, and "Never" users. AF events were identified using International Classification of Diseases codes. Cox models were used to estimate the hazard ratios (HRs) between cannabis use and incident AF and were subsequently adjusted for age, sex, race, alcohol, coffee, smoking, education, and baseline cardiovascular comorbidities. RESULTS: A total of 150,554 participants (mean age 63.4 ± 7.7 years; 86,487 (57.4%) female; and 33,442 (22.2%) using cannabis at least once) were followed for a mean period of 6.1 ± 0.6 years. After multivariable adjustment, there were no statistically significant differences in incident AF among occasional users (HR 0.98; 95% confidence interval 0.89-1.08) nor frequent users (HR 1.03; 95% confidence interval 0.81-1.32) as compared with never users. CONCLUSION: In a large prospective cohort study, there was no evidence that cannabis use was associated with a higher risk of incident AF. An evaluation of cannabis ingestion methods and quantification was not possible using the current data set.

Primary Atriopathy in Mitral Valve Prolapse: Echocardiographic Evidence and Clinical Implications.

BACKGROUND: Prominent multi-scallop systolic leaflet displacement toward the left atrium (atrialization) is typically observed in bileaflet mitral valve prolapse (MVP) with mitral annular disjunction. We hypothesized that mitral leaflet atrialization is associated with an underlying left atrial (LA) myopathy characterized by progressive structural and functional abnormalities, irrespective of mitral regurgitation (MR) severity. METHODS: We identified 334 consecutive patients with MVP, no prior atrial fibrillation, and comprehensive clinical and echocardiographic data. LA function was assessed by LA reservoir strain, LA function index, and LA emptying fraction. We also classified the stage of LA remodeling based on LA enlargement and LA reservoir strain (stage 1: no remodeling; stage 2: mild remodeling; stage 3: moderate remodeling; and stage 4: severe remodeling). The primary end point was the composite risk of sudden arrhythmic death, heart failure hospitalization, or the new onset of atrial fibrillation. RESULTS: Bileaflet MVP with no or mild MR had a lower LA reservoir strain (P=0.04) and LA function index (P<0.001) compared with other MVP subtypes. In multivariable linear regression adjusted for cardiovascular risk factors and MR ≥moderate, bileaflet MVP remained significantly associated with lower LA function parameters (all P<0.05). There was a significant increase in the risk of events as the LA reservoir strain and LA remodeling stage increased (P<0.001). In multivariable analysis, stage 4 of LA remodeling remained significantly associated with a higher risk of events compared with stage 1 (hazard ratio, 6.09 [95% CI, 1.69-21.9]; P=0.006). CONCLUSIONS: In a large MVP registry, bileaflet involvement is associated with reduced LA function regardless of MR severity, suggesting a primary atriopathy in this MVP subtype. Abnormal LA function, particularly when assessed through a multiparametric approach, is linked to a higher risk of cardiovascular events and may improve risk stratification in MVP, even in those without significant MR.

Mitral Annular Disjunction: An Under-Recognized Entity in Pediatrics.

Mitral annular disjunction (MAD) is a rare and under-recognized entity in the pediatric population. We present 2 cases of MAD in previously healthy pediatric patients and highlight clinical scenarios where MAD should be suspected.

Interstitial Fibrosis and Arrhythmic Mitral Valve Prolapse: Unravelling Sex-Based Differences.

Background: Interstitial fibrosis as quantified by cardiac magnetic resonance (CMR) has been demonstrated in arrhythmic mitral valve prolapse (MVP), a condition with known female predominance. However, prior studies included only MVP cases with significant mitral regurgitation (MR) or mitral annular disjunction (MAD). We sought to evaluate the association between interstitial fibrosis and complex ventricular ectopy (ComVE) in MVPs unselected for MAD or severe MR, and to investigate the contribution of sex to this association. Methods: We performed contrast CMR in consecutive individuals with MVP between 2020 and 2022. Extracellular volume fraction (ECV%), a surrogate marker for interstitial fibrosis, was quantified using T 1 mapping. Replacement fibrosis was assessed using late gadolinium enhancement (LGE). ComVE, defined as frequent premature ventricular contractions and/or non-sustained/sustained ventricular tachycardia (VT), was detected using ambulatory ECG monitoring. Results: We identified 59 MVP cases without severe MR (49% women, 80% with mild or less MR) and available ECV% measurement. Among these, 23 (39%) had ComVE, including a case of aborted ventricular fibrillation (VF) and one with sudden arrhythmic death, both females. Global ECV% was significantly greater in ComVE versus non-ComVE (31%[27-33] vs 27%[23-30], p=0.002). In MVP-ComVE, higher segmental ECV% was not limited to the inferolateral/inferior LV wall, but was also demonstrated in atypical segments including the anterior/anterolateral wall (p<0.05). The association between ComVE and ECV% was driven by female sex (32%[30-33] vs 28%[26-30], p=0.003 in females; 31%[25-33] vs 26%[23-30], p=0.22 in males). ECV% remained independently associated with an increased risk of ComVE, including VT/VF, after adjustment for cardiovascular risk factors, MAD, and LGE (p<0.01). Conclusion: In MVP without significant MR, interstitial fibrosis by CMR is associated with an increased risk of ComVE, suggesting a primary myopathic process. The stronger association between interstitial fibrosis and ComVE in females may explain why severe arrhythmic complications are more prevalent among women.

Stroke in mitral valve prolapse: risk factors and left atrial function in cryptogenic versus non-cryptogenic ischemic subtypes.

Background and purpose: Mitral valve prolapse (MVP) has been associated with an increased risk of ischemic stroke. Older age, thicker mitral leaflets, and significant mitral regurgitation (MR) leading to atrial fibrillation have been traditionally considered risk factors for ischemic stroke in MVP. However, specific risk factors for MVP-stroke subtypes are not well defined. The aim of this study is to evaluate clinical and echocardiographic parameters, including left atrial (LA) function, in MVP with cryptogenic (C) vs. non-cryptogenic (NC) stroke. Methods: In this case-control matched study, MVPs were identified in consecutive echocardiograms obtained after a stroke from January 2013 to December2016 at the University of California, San Francisco. MVP was defined as leaflet displacement ≥2 mm in the parasternal long-axis view at end-systole. Age/gender matched MVPs without stroke and healthy controls without MVP were also identified. We analyzed LA end-systolic/diastolic volume index, emptying fraction (LAEF), function index (LAFI), and global longitudinal strain in all MVPs and controls. We also measured left ventricular (LV) volume indexes, mass index, ejection fraction (EF), degree of MR and leaflet thickness. Results: We identified a total of 30 MVPs (age 70 ± 12, 50% females) with stroke (11 with C- and 19 with NC-stroke), 20 age/gender matched MVPs without a stroke and 16 controls. MVPs without stroke had lower BMI, less hypertension but more MR (≥moderate in 45% vs. 17%), more abnormal LA function (lower LAEF, LAFI) and larger LV volumes/mass (all p < 0.05) when compared to MVPs with stroke. Leaflet thickness was overall mild (<3 mm) and similar in the 2 groups. Within the MVP stroke group, NC-stroke had higher BMI, more hypertension and more atrial fibrillation compared to C-stroke. In the variables tested, patients with C-stroke did not differ from controls. Conclusions: MVP-related MR may be protective against stroke despite abnormal LA function. Risk of NC-stroke in MVP is related to common stroke risk factors rather than mitral valve leaflet thickness. The etiology of C-stroke in MVP warrants further studies.

Mechanical Dispersion Discriminates between Arrhythmic and Non-Arrhythmic Sudden Death: From the POST SCD Study.

Background: Global longitudinal strain (GLS) and mechanical dispersion (MD) by speckle-tracking echocardiography can predict sudden cardiac death (SCD) beyond left ventricular ejection fraction (LVEF) alone. However, prior studies have presumed cardiac cause from EMS records or death certificates rather than gold-standard autopsies. Objectives: We sought to investigate whether abnormal GLS and MD, reflective of underlying myocardial fibrosis, are associated with autopsy-defined sudden arrhythmic death (SAD) in a comprehensive postmortem study. Methods: We identified and autopsied all World Health Organization-defined (presumed) SCDs ages 18-90 via active surveillance of out of hospital deaths in the ongoing San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study to refine presumed SCDs to true cardiac causes. We retrieved all available pre-mortem echocardiograms and assessed LVEF, LV-GLS, and MD. The extent of LV myocardial fibrosis was assessed and quantified histologically. Results: Of 652 autopsied subjects, 65 (10%) had echocardiograms available for primary review, obtained at a mean 1.5 years before SCD. Of these, 37 (56%) were SADs and 29 (44%) were non-SADs; fibrosis was quantified in 38 (58%). SADs were predominantly male, but had similar age, race, baseline comorbidities, and LVEF compared to non-SADs (all p>0.05). SADs had significantly reduced LV-GLS (median: -11.4% versus -18.5%, p=0.008) and increased MD (median: 14.8 ms versus 9.4 ms, p=0.006) compared to non-SADs. MD was associated with total LV fibrosis by linear regression in SADs (r=0.58, p=0.002). Conclusion: In this countywide postmortem study of all sudden deaths, autopsy-confirmed arrhythmic deaths had significantly lower LV-GLS and increased MD than non-arrhythmic sudden deaths. Increased MD correlated with higher histologic levels of LV fibrosis in SADs. These findings suggest that increased MD, which is a surrogate for the extent of myocardial fibrosis, may improve risk stratification and specification for SAD beyond LVEF. PERSPECTIVES: Competency in medical knowledge: Mechanical dispersion derived from speckle tracking echocardiography provides better discrimination between autopsy-defined arrhythmic vs non-arrhythmic sudden death than LVEF or LV-GLS. Histological ventricular fibrosis correlates with increased mechanical dispersion in SAD.Translational outlook: Speckle tracking echocardiography parameters, in particular mechanical dispersion, may be considered as a non-invasive surrogate marker for myocardial fibrosis and risk stratification in SCD.

Identifying Mitral Valve Prolapse at Risk for Arrhythmias and Fibrosis From Electrocardiograms Using Deep Learning.

BACKGROUND: Mitral valve prolapse (MVP) is a common valvulopathy, with a subset developing sudden cardiac death or cardiac arrest. Complex ventricular ectopy (ComVE) is a marker of arrhythmic risk associated with myocardial fibrosis and increased mortality in MVP. OBJECTIVES: The authors sought to evaluate whether electrocardiogram (ECG)-based machine learning can identify MVP at risk for ComVE, death and/or myocardial fibrosis on cardiac magnetic resonance (CMR) imaging. METHODS: A deep convolutional neural network (CNN) was trained to detect ComVE using 6,916 12-lead ECGs from 569 MVP patients from the University of California-San Francisco between 2012 and 2020. A separate CNN was trained to detect late gadolinium enhancement (LGE) using 1,369 ECGs from 87 MVP patients with contrast CMR. RESULTS: The prevalence of ComVE was 28% (160/569). The area under the receiver operating characteristic curve (AUC) of the CNN to detect ComVE was 0.80 (95% CI: 0.77-0.83) and remained high after excluding patients with moderate-severe mitral regurgitation [0.80 (95% CI: 0.77-0.83)] or bileaflet MVP [0.81 (95% CI: 0.76-0.85)]. AUC to detect all-cause mortality was 0.82 (95% CI: 0.77-0.87). ECG segments relevant to ComVE prediction were related to ventricular depolarization/repolarization (early-mid ST-segment and QRS from V1, V3, and III). LGE in the papillary muscles or basal inferolateral wall was present in 24% patients with available CMR; AUC for detection of LGE was 0.75 (95% CI: 0.68-0.82). CONCLUSIONS: CNN-analyzed 12-lead ECGs can detect MVP at risk for ventricular arrhythmias, death and/or fibrosis and can identify novel ECG correlates of arrhythmic risk. ECG-based CNNs may help select those MVP patients requiring closer follow-up and/or a CMR.

Abnormal Mechanics Relate to Myocardial Fibrosis and Ventricular Arrhythmias in Patients With Mitral Valve Prolapse.

BACKGROUND: The relation between ventricular arrhythmia and fibrosis in mitral valve prolapse (MVP) is reported, but underlying valve-induced mechanisms remain unknown. We evaluated the association between abnormal MVP-related mechanics and myocardial fibrosis, and their association with arrhythmia. METHODS: We studied 113 patients with MVP with both echocardiogram and gadolinium cardiac magnetic resonance imaging for myocardial fibrosis. Two-dimensional and speckle-tracking echocardiography evaluated mitral regurgitation, superior leaflet and papillary muscle displacement with associated exaggerated basal myocardial systolic curling, and myocardial longitudinal strain. Follow-up assessed arrhythmic events (nonsustained or sustained ventricular tachycardia or ventricular fibrillation). RESULTS: Myocardial fibrosis was observed in 43 patients with MVP, predominantly in the basal-midventricular inferior-lateral wall and papillary muscles. Patients with MVP with fibrosis had greater mitral regurgitation, prolapse, and superior papillary muscle displacement with basal curling and more impaired inferior-posterior basal strain than those without fibrosis (P<0.001). An abnormal strain pattern with distinct peaks pre-end-systole and post-end-systole in inferior-lateral wall was frequent in patients with fibrosis (81 versus 26%, P<0.001) but absent in patients without MVP with basal inferior-lateral wall fibrosis (n=20). During median follow-up of 1008 days, 36 of 87 patients with MVP with >6-month follow-up developed ventricular arrhythmias associated (univariable) with fibrosis, greater prolapse, mitral annular disjunction, and double-peak strain. In multivariable analysis, double-peak strain showed incremental risk of arrhythmia over fibrosis. CONCLUSIONS: Basal inferior-posterior myocardial fibrosis in MVP is associated with abnormal MVP-related myocardial mechanics, which are potentially associated with ventricular arrhythmia. These associations suggest pathophysiological links between MVP-related mechanical abnormalities and myocardial fibrosis, which also may relate to ventricular arrhythmia and offer potential imaging markers of increased arrhythmic risk.