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Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations. It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies. Most patients with Danon disease will experience symptomatic heart failure. Male individuals generally present earlier than women and die of either heart failure or arrhythmia or receive a heart transplant by the third decade of life. Herein, the authors review the differential diagnosis of Danon disease, diagnostic criteria, natural history, management recommendations, and recent advances in treatment of this increasingly recognized and extremely morbid cardiomyopathy. [Display omitted] • Danon disease is a rare, X-linked genetic cardiomyopathy in which protein deficiency results in autophagy, accumulation of autophagosomes, defective mitochondria myocyte death, and adverse clinical outcomes. • Clinical features include myocardial hypertrophy, conduction abnormalities, heart failure, malignant ventricular arrhythmia, and multisystem involvement. • Understanding the pathophysiology and clinical trajectory of Danon disease may promote earlier diagnosis, risk stratification, and patient selection for medical and gene therapies that may have implications for other genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited global heart disease, with complex phenotypic and genetic expression and natural history, affecting both genders and many races and cultures. Prevalence is 1:200-1:500, largely based on the disease phenotype with imaging, inferring that 750,000 Americans may be affected by HCM. However, cross-sectional data show that only a fraction are clinically diagnosed, suggesting under-recognition, with most clinicians exposed to small segments of the broad disease spectrum. Highly effective HCM management strategies have emerged, altering clinical course and substantially lowering mortality and morbidity rates. These advances underscore the importance of reliable HCM diagnosis with echocardiography and cardiac magnetic resonance. Family screening with noninvasive imaging will identify relatives with the HCM phenotype, while genetic analysis recognizes preclinical sarcomere gene carriers without left ventricular hypertrophy, but with the potential to transmit disease. Comprehensive initial patient evaluations are important for reliable diagnosis, accurate portrayal of HCM and family history, risk stratification, and distinguishing obstructive versus nonobstructive forms. [ABSTRACT FROM AUTHOR]

Both obesity and atrial fibrillation (AF) are increasing in epidemic proportions, and both increase the prevalence of cardiovascular disease events. Obesity has adverse effects on cardiovascular hemodynamics and cardiac structure and function, and increases the prevalence of AF, partly related to electroanatomic remodeling in obese patients. However, numerous studies, including in AF, have demonstrated an obesity paradox, where overweight and obese patients with these disorders have a better prognosis than do leaner patients with the same degree of severity of cardiovascular disease/AF. In this paper, the authors discuss special issues regarding AF in obesity, as well as the evidence that despite the presence of an obesity paradox, there are benefits of weight loss, physical activity/exercise training, and increases in cardiorespiratory fitness on the prognosis of obese patients with AF. [ABSTRACT FROM AUTHOR]

Background: Preserved left ventricular (LV) ejection fraction (EF) and reduced myocardial strain are reported in patients with hypertrophic cardiomyopathy, ischemic heart disease, diabetes mellitus, and more.Objectives: The authors performed a combined mathematical and echocardiographic study to understand the inconsistencies between EF and strains.Methods: An analytical equation showing the relationship between EF and the 4 parameters, global longitudinal strain (GLS), global circumferential strain (GCS), wall thickness, and short-axis diameter, was derived from an elliptical LV model. The equation was validated by measuring the 4 parameters by echocardiography in 100 subjects with EF ranging from 16% to 72% and comparing model-predicted EF with measured EF. The effect of the different parameters on EF was explored in the model and compared with findings in the patients.Results: Calculated EF had very good agreement with measured EF (r = 0.95). The model showed that GCS contributes more than twice as much to EF than GLS. A significant reduction of GLS could be compensated by a small increase of GCS or wall thickness or reduced diameter. The model further demonstrated how EF can be maintained in ventricles with increased wall thickness or reduced diameter, despite reductions in both longitudinal and circumferential shortening. This was consistent with similar EF in 20 control subjects and 20 hypertrophic cardiomyopathy patients with increased wall thickness and reductions in both circumferential and longitudinal shortening (all p < 0.01).Conclusions: Reduced deformation despite preserved EF can be explained through geometric factors. Due to geometric confounders, strain better reflects systolic function in patients with preserved EF. [ABSTRACT FROM AUTHOR]

Background: Cardiac transthyretin amyloidosis (ATTR) is an increasingly recognized cause of heart failure. Cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a reference standard for diagnosis and characterization of cardiac amyloidosis.Objectives: The authors used CMR with extracellular volume fraction (ECV) measurement to characterize cardiac involvement in relation to outcome in ATTR.Methods: Subjects comprised 263 patients with cardiac ATTR corroborated by grade 2 to 3 99mTc-DPD (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid) cardiac uptake, 17 with suspected cardiac ATTR (grade 1 99mTc-DPD), and 12 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac light-chain (AL) amyloidosis acted as disease comparators.Results: Unlike cardiac AL amyloidosis, asymmetrical septal left ventricular hypertrophy (LVH) was present in 79% of patients with ATTR (70% sigmoid septum and 30% reverse septal contour), whereas symmetrical LVH was present in 18%, and 3% had no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical for amyloidosis (29% subendocardial, 71% transmural), including right ventricular LGE (96%). During follow-up (19 ± 14 months), 65 patients died. ECV independently correlated with mortality and remained independent after adjustment for age, N-terminal pro-B-type natriuretic peptide, ejection fraction, E/E', and left ventricular mass (hazard ratio: 1.164; 95% confidence interval: 1.066 to 1.271; p < 0.01).Conclusions: Asymmetrical hypertrophy, traditionally associated with hypertrophic cardiomyopathy, was the commonest pattern of ventricular remodeling in ATTR. LGE imaging was typical in all patients with cardiac ATTR. ECV correlated with amyloid burden and was an independent prognostic factor for survival in this cohort of patients. [ABSTRACT FROM AUTHOR]

Background: Current electrocardiographic (ECG) criteria for the diagnosis of left ventricular hypertrophy (LVH) have low sensitivity.Objectives: The goal of this study was to test a new method to improve the diagnostic performance of the electrocardiogram.Methods: The study was divided into 2 groups, a test and a validation cohort. In the test cohort, 94 patients were analyzed, including 47 with the diagnosis of hypertensive crisis and 47 with normal blood pressure at admission. Echocardiography was used to estimate the left ventricular mass index. Area under the curve (AUC) analysis was used for comparison of single and combined leads. The McNemar test was used to assess agreement among the ECG criteria against the left ventricular mass index. The proposed ECG criteria involved measuring the amplitude of the deepest S wave (SD) in any single lead and adding it to the S wave amplitude of lead V4 (SV4). Currently accepted LVH ECG criteria such as Cornell voltage and Sokolow-Lyon were used for comparison. The validation cohort consisted of 122 consecutive patients referred for an echocardiogram regardless of the admitting diagnosis.Results: The SD was the most accurate single lead measurement for the diagnosis of LVH (AUC: 0.80; p < 0.001). When both cohorts were analyzed, the SD + SV4 criteria outperformed Cornell voltage with a significantly higher sensitivity (62% [95% confidence interval [CI]: 50% to 72%] vs. 35% [95% CI: 24% to 46%]). The specificities of all the criteria were ≥90%, with no significant difference among them.Conclusions: The proposed criteria for the ECG diagnosis of LVH improved the sensitivity and overall accuracy of the test. [ABSTRACT FROM AUTHOR]

Background: Cardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function.Objectives: This study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM.Methods: In vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients.Results: In swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility ∼46°). E2A changes correlated with wall thickness changes (in vivo r2 = 0.75; in situ r2 = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was ∼17%. In healthy human control subjects, E2A increased from diastole (18°) to systole (65°; p < 0.001; E2A mobility = 45°). HCM patients showed significantly greater E2A in diastole than control subjects did (48°; p < 0.001) with impaired E2A mobility (23°; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40°; p < 0.001) with impaired E2A mobility (20°; p < 0.001).Conclusions: Myocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with altered diastolic conformation. These novel insights significantly improve understanding of contractile dysfunction at a level of noninvasive interrogation not previously available in humans. [ABSTRACT FROM AUTHOR]

Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients. [ABSTRACT FROM AUTHOR]

Background: Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement.Objectives: The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD.Methods: To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults.Results: LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes.Conclusions: Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD. [ABSTRACT FROM AUTHOR]

Background: Machine-learning models may aid cardiac phenotypic recognition by using features of cardiac tissue deformation.Objectives: This study investigated the diagnostic value of a machine-learning framework that incorporates speckle-tracking echocardiographic data for automated discrimination of hypertrophic cardiomyopathy (HCM) from physiological hypertrophy seen in athletes (ATH).Methods: Expert-annotated speckle-tracking echocardiographic datasets obtained from 77 ATH and 62 HCM patients were used for developing an automated system. An ensemble machine-learning model with 3 different machine-learning algorithms (support vector machines, random forests, and artificial neural networks) was developed and a majority voting method was used for conclusive predictions with further K-fold cross-validation.Results: Feature selection using an information gain (IG) algorithm revealed that volume was the best predictor for differentiating between HCM ands. ATH (IG = 0.24) followed by mid-left ventricular segmental (IG = 0.134) and average longitudinal strain (IG = 0.131). The ensemble machine-learning model showed increased sensitivity and specificity compared with early-to-late diastolic transmitral velocity ratio (p < 0.01), average early diastolic tissue velocity (e') (p < 0.01), and strain (p = 0.04). Because ATH were younger, adjusted analysis was undertaken in younger HCM patients and compared with ATH with left ventricular wall thickness >13 mm. In this subgroup analysis, the automated model continued to show equal sensitivity, but increased specificity relative to early-to-late diastolic transmitral velocity ratio, e', and strain.Conclusions: Our results suggested that machine-learning algorithms can assist in the discrimination of physiological versus pathological patterns of hypertrophic remodeling. This effort represents a step toward the development of a real-time, machine-learning-based system for automated interpretation of echocardiographic images, which may help novice readers with limited experience. [ABSTRACT FROM AUTHOR]

Background: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death.Objectives: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass.Methods: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment.Results: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo.Conclusions: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%.Objectives: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients.Methods: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations.Results: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively.Conclusions: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated. [ABSTRACT FROM AUTHOR]

About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF). Although the etiology of HFpEF is most commonly related to long-standing hypertension and atherosclerosis, a significant number of suspected HFpEF patients have a restrictive cardiomyopathy or chronic pericardial disease. Recognizing these syndromes is important because early diagnosis may lead to instituting specific therapy that may prolong survival, improve quality of life, and/or recognize and treat an underlying systemic disorder. Advances in diagnostic imaging, biomarkers, and genetic testing today allow identification of the specific etiology in most cases. Novel pharmacological, immunologic, and surgical therapies are leading to improved quality of life and survival. [ABSTRACT FROM AUTHOR]

Background: Left ventricular outflow tract gradients are absent in an important proportion of patients with hypertrophic cardiomyopathy (HCM). However, the natural course of this important patient subgroup remains largely unresolved.Objectives: The authors systematically employed exercise (stress) echocardiography to define those patients without obstruction to left ventricular outflow at rest and/or under physiological exercise and to examine their natural history and clinical course to create a more robust understanding of this complex disease.Methods: We prospectively studied 573 consecutive HCM patients in 3 centers (44 ± 17 years; 66% male) with New York Heart Association functional class I/II symptoms at study entry, including 249 in whom left ventricular outflow tract obstruction was absent both at rest and following physiological exercise (<30 mm Hg; nonobstructive HCM) and retrospectively assembled clinical follow-up data.Results: Over a median follow-up of 6.5 years, 225 of 249 nonobstructive patients (90%) remained in classes I/II, whereas 24 (10%) developed progressive heart failure to New York Heart Association functional classes III/IV. Nonobstructive HCM patients were less likely to experience advanced limiting class III/IV symptoms than the 324 patients with outflow obstruction (1.6%/year vs. 7.4%/year rest obstruction vs. 3.2%/year provocable obstruction; p < 0.001). However, 7 nonobstructive patients (2.8%) did require heart transplantation for progression to end stage versus none of the obstructive patients. HCM-related mortality among nonobstructive patients was low (n = 8; 0.5%/year), with 5- and 10-year survival rates of 99% and 97%, respectively, which is not different from expected all-cause mortality in an age- and sex-matched U.S. population (p = 0.15).Conclusions: HCM patients with nonobstructive disease appear to experience a relatively benign clinical course, associated with a low risk for advanced heart failure symptoms, other disease complications, and HCM-related mortality, and largely without the requirement for major treatment interventions. A small minority of nonobstructive HCM patients progress to heart transplant. [ABSTRACT FROM AUTHOR]

Background: Although a common symptom in patients with severe aortic stenosis (AS) without obstructive coronary artery disease (CAD), little is known about the pathogenesis of exertional angina.Objectives: This study sought to prove that microvascular dysfunction is responsible for chest pain in patients with severe AS and normal epicardial coronary arteries using adenosine-stress cardiac magnetic resonance (CMR) imaging.Methods: Between June 2012 and April 2015, 117 patients with severe AS without obstructive CAD and 20 normal controls were enrolled prospectively. After exclusions, study patients were divided into 2 groups according to presence of exertional chest pain: an angina group (n = 43) and an asymptomatic group (n = 41), and the semiquantitative myocardial perfusion reserve index (MPRI) was calculated.Results: MPRI values were significantly lower in severe AS patients than in normal controls (0.90 ± 0.31 vs. 1.25 ± 0.21; p < 0.001), and were much lower in the angina group than the asymptomatic group (0.74 ± 0.25 vs. 1.08 ± 0.28; p < 0.001). In logistic regression analysis, the only independent predictor for angina was MPRI (odds ratio: 0.003; p < 0.001). Univariate associations with MPRI were identified for diastolic blood pressure, E/e' ratio, left ventricular volume and ejection fraction, cardiac index, presence of late gadolinium enhancement, and left ventricular mass index (LVMI). In multivariate analysis, LVMI was the strongest contributing factor to MPRI (standardization coefficient: -0.428; p < 0.001).Conclusions: Our results suggest that, in patients with severe AS without obstructive CAD, angina is related to impaired coronary microvascular function along with LV hypertrophy detectable by semiquantitative MPRI using adenosine-stress CMR.Clinical Trial Registration: NCT02575768. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease among hemodialysis (HD) patients is linked to poor outcomes. The Acute Dialysis Quality Initiative Workgroup proposed echocardiographic (ECHO) criteria for structural heart disease (SHD) in dialysis patients. The association of SHD with important patient outcomes is not well defined.Objectives: This study sought to determine prevalence of ECHO-determined SHD and its association with survival among incident HD patients.Methods: We analyzed patients who began chronic HD from 2001 to 2013 who underwent ECHO ≤1 month prior to or ≤3 months following initiation of HD (n = 654).Results: Mean patient age was 66 ± 16 years, and 60% of patients were male. ECHO findings that met 1 or more and ≥3 of the new criteria were discovered in 87% and 54% of patients, respectively. Over a median of 2.4 years, 415 patients died: 108 (26%) died within 6 months. Five-year mortality was 62%. Age- and sex-adjusted structural heart disease variables associated with death were left ventricular ejection fraction (LVEF) ≤45% (hazard ratio [HR]: 1.48; confidence interval [CI]: 1.20 to 1.83) and right ventricular (RV) systolic dysfunction (HR: 1.68; CI: 1.35 to 2.07). An additive of higher death risk included LVEF ≤45% and RV systolic dysfunction rather than neither (HR: 2.04; CI: 1.57 to 2.67; p = 0.53 for test for interaction). Following adjustment for age, sex, race, diabetic kidney disease, and dialysis access, RV dysfunction was independently associated with death (HR: 1.66; CI 1.34 to 2.06; p < 0.001).Conclusions: SHD was common in our HD study population, and RV systolic dysfunction independently predicted mortality. [ABSTRACT FROM AUTHOR]

Background: Cardiomyopathies are usually inherited and predominantly affect adults, but they can also present in childhood. Although our understanding of the molecular basis of pediatric cardiomyopathy has improved, the underlying mechanism remains elusive in a substantial proportion of cases.Objectives: This study aimed to identify new genes involved in pediatric cardiomyopathy.Methods: The authors performed homozygosity mapping and whole-exome sequencing in 2 consanguineous families with idiopathic pediatric cardiomyopathy. Sixty unrelated patients with pediatric cardiomyopathy were subsequently screened for mutations in a candidate gene. First-degree relatives were submitted to cardiac screening and cascade genetic testing. Myocardial samples from 2 patients were processed for histological and immunohistochemical studies.Results: We identified 5 patients from 3 unrelated families with pediatric cardiomyopathy caused by homozygous truncating mutations in ALPK3, a gene encoding a nuclear kinase that plays an essential role in early differentiation of cardiomyocytes. All patients with biallelic mutations presented with severe hypertrophic and/or dilated cardiomyopathy in utero, at birth, or in early childhood. Three patients died from heart failure within the first week of life. Moreover, 2 of 10 (20%) heterozygous family members showed hypertrophic cardiomyopathy with an atypical distribution of hypertrophy. Deficiency of alpha-kinase 3 has previously been associated with features of both hypertrophic and dilated cardiomyopathy in mice. Consistent with studies in knockout mice, we provide microscopic evidence for intercalated disc remodeling.Conclusions: Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies. [ABSTRACT FROM AUTHOR]

Background: Relative wall thickness (RWT), defined as 2 times posterior wall thickness divided by the left ventricular (LV) diastolic diameter, is a measure of LV geometry and may be a marker for adverse events in patients with LV dysfunction.Objectives: The aim of this study was to investigate the relationship between RWT and the risk for ventricular tachyarrhythmia (VA) in patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) study.Methods: The study population comprised 1,260 patients with mild heart failure and left bundle branch block.Results: In a multivariable model, RWT was the most powerful echocardiographic measure for estimating the risk of VAs compared with commonly used echocardiographic variables. Patients with low RWT (<0.24) had 83% (p < 0.001) increased risk for VA and 68% (p < 0.001) increase in VA risk or death (VA/death) compared with patients with higher RWT values. Each 0.01-unit decrease in RWT was associated with 12% (p < 0.001) and 10% (p < 0.001) increases in the risk of VA and VA/death, respectively. Treatment with cardiac resynchronization therapy with defibrillator (CRT-D; CRT with implantable cardioverter-defibrillator) was associated with a greater increase in RWT compared with implantable cardioverter-defibrillator at 12 months (4.6 ± 6.8% vs. 1.5 ± 2.7%; p < 0.001), and every 10% increase in RWT in CRT-D patients was associated with 34% (p = 0.027) and 36% (p = 0.009) reductions in the risk of subsequent VA and VA/death, respectively.Conclusions: In patients with mild heart failure and left bundle branch block, decreased RWT was associated with an increase in the risk of VA and VA/death. CRT-D therapy was associated with a favorable increase in RWT and reduction in risk of VA and VA/death. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). [ABSTRACT FROM AUTHOR]

Background Physiological cardiac adaptation to regular exercise, including biventricular dilation and T-wave inversion (TWI), may create diagnostic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC). Objectives The goal of this study was to assess the accuracy of diagnostic criteria for ARVC when applied to athletes exhibiting electrocardiographic TWI and to identify discriminators between physiology and disease. Methods The study population consisted of athletes with TWI (n = 45), athletes without TWI (n = 35), and ARVC patients (n = 35). Subjects underwent electrocardiography (ECG), signal-averaged electrocardiography (SAECG), echocardiography, cardiac magnetic resonance imaging (CMRI), Holter monitoring, and exercise testing. Results There were no electrical, structural, or functional cardiac differences between athletes exhibiting TWI and athletes without TWI. When athletes were compared with ARVC patients, markers of physiological remodeling included early repolarization, biphasic TWI, voltage criteria for right ventricular (RV) or left ventricular hypertrophy, and symmetrical cardiac enlargement. Indicators of RV pathology included the following: syncope; Q waves or precordial QRS amplitudes <1.8 mV; 3 abnormal SAECG parameters; delayed gadolinium enhancement, RV ejection fraction ≤45%, or wall motion abnormalities at CMRI; >1,000 ventricular extrasystoles (or >500 non-RV outflow tract) per 24 h; and symptoms, ventricular tachyarrhythmias, or attenuated blood pressure response during exercise. Nonspecific parameters included the following: prolonged QRS terminal activation; ≤2 abnormal SAECG parameters; RV dilation without wall motion abnormalities; RV outflow tract ectopy; and exercise-induced T-wave pseudonormalization. Conclusions TWI and balanced biventricular dilation are likely to represent benign manifestations of training in asymptomatic athletes without relevant family history. Diagnostic criteria for ARVC are nonspecific in such individuals. Comprehensive testing using widely available techniques can effectively differentiate borderline cases. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to examine the association between left ventricular hypertrophy (LVH), defined by cardiac magnetic resonance (CMR) and electrocardiography (ECG), with incident atrial fibrillation (AF). Background: Previous studies of the association between AF and LVH were based primarily on echocardiographic measures of LVH. Methods: The MESA (Multi-Ethnic Study of Atherosclerosis) enrolled 4,942 participants free of clinically recognized cardiovascular disease. Incident AF was based on MESA-ascertained hospital-discharge International Classification of Diseases codes and Centers for Medicare and Medicaid Services inpatient hospital claims. CMR-LVH was defined as left ventricular mass ≥95th percentile of the MESA population distribution. Eleven ECG-LVH criteria were assessed. The association of LVH with incident AF was evaluated using multivariable Cox proportional hazards models adjusted for CVD risk factors. Results: During a median follow-up of 6.9 years, 214 incident AF events were documented. Participants with AF were more likely to be older, hypertensive, and overweight. The risk of AF was greater in participants with CMR-derived LVH (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.15 to 3.62). AF was associated with ECG-derived LVH measure of Sokolow-Lyon voltage product after adjusting for CMR-LVH (HR: 1.83, 95% CI: 1.06 to 3.14, p = 0.02). The associations with AF for CMR-LVH and Sokolow-Lyon voltage product were attenuated when adjusted for CMR left atrial volumes. Conclusions: In a multiethnic cohort of participants without clinically detected cardiovascular disease, both CMR and ECG-derived LVH were associated with incident AF. ECG-LVH showed prognostic significance independent of CMR-LVH. The association was attenuated when adjusted for CMR left atrial volumes. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the incidence and patterns of late gadolinium enhancement (LGE) in different forms of left ventricular hypertrophy (LVH) and to determine their relation to severity of left ventricular (LV) remodeling. Background: Left ventricular hypertrophy is an independent predictor of cardiac mortality. The relationship between LVH and myocardial fibrosis as defined by LGE cardiovascular magnetic resonance (CMR) is not well understood. Methods: A total of 440 patients with aortic stenosis (AS), arterial hypertension (AH), or hypertrophic cardiomyopathy (HCM) fulfilling echo criteria of LVH underwent CMR with assessment of LV size, weight, function, and LGE. Patients with increased left ventricular mass index (LVMI) resulting in global LVH in CMR were included in the study. Results: Criteria were fulfilled by 83 patients (56 men, age 57 ± 14 years; AS, n = 21; AH, n = 26; HCM, n = 36). Late gadolinium enhancement was present in all forms of LVH (AS: 62%, AH: 50%; HCM: 72%, p = NS) and was correlated with LVMI (r = 0.237, p = 0.045). There was no significant relationship between morphological obstruction and LGE. The AS subjects with LGE showed higher LV end-diastolic volumes than those without (1.0 ± 0.2 ml/cm vs. 0.8 ± 0.2 ml/cm, p < 0.015). Typical patterns of LGE were observed in HCM but not in AS and AH. Conclusions: Fibrosis as detected by CMR is a frequent feature of LVH, regardless of its cause, and depends on the severity of LV remodeling. As LGE emerges as a useful tool for risk stratification also in nonischemic heart diseases, our findings have the potential to individualize treatment strategies. [Copyright &y& Elsevier]