Abstract Background Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural ...history studies of LMNA -associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain. Objectives This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype. Methods The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined. Results The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death. Conclusions LMNA -related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.
Abstract Background Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is ...not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed ( MYH7 , TNNT2 , TNNI3 , TPM1 , MYBPC3 , ACTC , LMNA , PLN , TAZ , and LDB3 ), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7 , LMNA , or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.
In hypertrophic cardiomyopathy (HC), electrocardiographic (ECG) changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when left ventricular (LV) ...wall thickness is still normal. However, the ECG features of mutation carriers have not been fully characterized. Therefore, we systematically analyzed ECGs in a genotyped HC population to characterize ECG findings in mutation carriers (G+) with and without echocardiographic LV hypertrophy (LVH), and to evaluate the accuracy of ECG findings to differentiate at-risk mutation carriers from genetically unaffected relatives during family screening. The ECG and echocardiographic findings were analyzed from 213 genotyped subjects (76 G+/LVH−, 57 G+/LVH+ overt HC, 80 genetically unaffected controls). Cardiac magnetic resonance imaging was available on a subset. Q waves and repolarization abnormalities (QST) were highly specific (98% specificity) markers for LVH− mutation carriers, present in 25% of G+/LVH− subjects, and 3% of controls (p <0.001). QST ECG abnormalities remained independently predictive of carrying a sarcomere mutation after adjusting for age and impaired relaxation, another distinguishing feature of G+/LVH− subjects (odds ratio 8.4, p = 0.007). Myocardial scar or perfusion abnormalities were not detected on cardiac magnetic resonance imaging in G+/LVH− subjects, irrespective of the ECG features. In overt HC, 75% had Q waves and/or repolarization changes, but <25% demonstrated common isolated voltage criteria for LVH. In conclusion, Q waves and repolarization abnormalities are the most discriminating ECG features of sarcomere mutation carriers with and without LVH. However, owing to the limited sensitivity of ECG and echocardiographic screening, genetic testing is required to definitively identify at-risk family members.
The relative contribution of heart failure (HF) compared with other medical and nonmedical factors on diminished quality of life (QOL) across subtypes with reduced, better, and preserved left ...ventricular ejection fraction (LVEF) in a large ambulatory HF population was evaluated.
Dominant factors influencing limited QOL in patients with HF have not been investigated.
Before routine HF clinic visits, 726 patients with ambulatory HF (mean age 56 ± 15 years, 37% women) completed a 1-page questionnaire that assessed QOL and relative contributions of HF compared with other medical and nonmedical factors to their QOL limitations. Visual analogue scales were used to assess overall QOL, breathing, and energy level. Results were compared across reduced (57%), preserved (16%) and better (improvement in LVEF ≥50%) (19%) subtypes.
Just under one-half of patients (48%) rated QOL as limited dominantly by HF, 19% rated HF and medical problems as equally limiting, 18% cited medical problems as dominant, and 15% cited nonmedical factors. Patients with HF with better LVEF had the highest overall QOL score and less dyspnea burden than those with HF with preserved EF. Independent correlates of HF-dominated diminished QOL were prior cardiac surgery, worse New York Heart Association functional class, renin-angiotensin-aldosterone antagonism, use of diuretic agents, lower body mass index, lower LVEF, and lack of arthritis or history of cancer.
Fewer than one-half of patients with ambulatory HF rated HF as the greatest limitation to their QOL, suggesting that this important outcome will be difficult to affect by HF-targeted therapies alone, particularly in those with higher LVEFs and comorbidities. Patients with HF with better LVEF represent a distinct subtype with better overall QOL.
Abstract Background Patients perceive different symptoms of heart failure decompensation. It is not known whether the nature of the worst symptom relates to hemodynamic profile, response to therapy, ...or improvement in clinical trials. Methods and Results Patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial were hospitalized with advanced heart failure, ejection fraction ≤30%, and at least 1 sign and 1 symptom of elevated filling pressures. Visual analog scales (VAS) for symptoms were completed by 371 patients, who selected their worst symptom as difficulty breathing, fatigue, abdominal discomfort, or body swelling and also scored breathing and global condition at baseline and discharge. The dominant symptom identified was difficulty breathing by 193 (52%) patients, fatigue by 118 (32%), and abdominal discomfort and swelling each by 30 (8%) patients, combined as right-sided congestion for analysis. Clinical and hemodynamic assessments were not different between groups except that right-sided congestion was associated with more hepatomegaly, ascites, third heart sounds, and jugular venous distention. This group also had greater reduction in jugular venous distention and trend toward higher blood urea nitrogen after therapy. By discharge, average improvements in worst symptom and global score were 28 points and 24 points. For those with ≥10 points in improvement in worst symptom, 84% also improved global assessment ≥10 points. Initial fatigue was associated with less improvement ( P = .002) during and after hospitalization, but improvements in symptom scores were sustained when re-measured during 6 months after discharge. Conclusion In most patients hospitalized with clinical congestion, therapy will improve symptoms regardless of the worst symptom perceived, with more evidence of baseline fluid retention and reduction during therapy for worst symptoms of abdominal discomfort or edema. Improvement in trials should be similar when tracking worst symptom, dyspnea, or global assessment.
We present the course of 4 pregnancies in 3 women with desmoplakin cardiomyopathy, with a focus on changes in left ventricular ejection fraction and N-terminal pro–B-type natriuretic peptide levels ...from the prepregnancy period through the postpartum period, as well as maternal cardiac, obstetric, and neonatal outcomes. (Level of Difficulty: Advanced.)
Display omitted
Three-dimensional, volume-rendered images with multiobject segmentation of the TAH and surrounding structures from a pulmonary embolism protocol computed tomography angiography negative for pulmonary ...embolism showed no evidence of pulmonary vein (red) compression by the anastomotic ring (yellow) as a cause of hypoxemia (B, Online Video 1).
The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers.
HCM is caused by sarcomere ...mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence.
In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement.
Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end-diastolic diameter improved toward normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. –0.5; p < 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (–0.02 vs. +0.15; p = 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group.
Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982).
PDF
