Caroline Coats

Relation between serum N-terminal pro-brain natriuretic peptide and prognosis in patients with hypertrophic cardiomyopathy

AIMS To determine the relation between serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and prognosis in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS In total, 847 patients (53 ± 15 years; 67% male) with HCM (28% with left ventricular outflow tract obstruction ≥ 30 mmHg at rest) were followed for 3.5 years (IQR 2.5-4.5 years). The median NT-proBNP concentration was 78 pmol/L (range < 5-1817 pmol/L and IQR 31-183 pmol/L). Sixty-eight patients (8%) reached the primary endpoint of all-cause mortality or cardiac transplantation. NT-proBNP concentration predicted long-term survival from the primary endpoint [area under the receiver operating characteristic curve of 0.78 (95% confidence interval 0.73-0.84)]. A serum concentration of ≥ 135 pmol/L was associated with an annual event rate of 6.1% (95% CI 4.4-7.7). Three independent predictors of primary outcome were identified in a multivariable Cox model: New York Heart Association class III/IV (HR 2.10, 95% CI 1.21-3.65, P = 0.008), ejection fraction (HR 0.98, 95% CI 0.96-1.00, P = 0.035), log NT-proBNP (HR 2.04, 95% CI 1.56-2.66, P < 0.001). Log NT-proBNP was a significant predictor of heart failure (HF) and transplant-related deaths (n = 23; HR 3.03, 95% CI 1.99-4.60, P < 0.001) but not sudden death or appropriate implantable cardioverter defibrillator shock (n = 11; HR 1.54, 95% CI 0.91-2.60, P = 0.111). In patients with ejection fraction ≥ 50% (n = 673), log NT-proBNP remained an independent predictor of the primary outcome (HR 2.11, 95% CI 1.54-2.90, P < 0.001). CONCLUSION In patients with HCM, elevated NT-proBNP concentration is a strong predictor of overall prognosis, particularly HF-related death and transplantation.

Incidence and predictors of anti-bradycardia pacing in patients with Anderson-Fabry disease

BACKGROUND Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder associated with bradyarrhythmias. We sought to examine the nature of conduction system abnormalities and the indications and determinants of anti-bradycardia pacing in patients with AFD. METHODS AND RESULTS We studied 204 patients with AFD (49% male, mean age 42 years) in an observational, longitudinal, retrospective cohort study. At baseline, 5 (2.5%) patients had pacemakers for the treatment of bradycardias [4/5 (80%) for atrioventricular disease; 1/5 (20%) for sinus node disease]. PR interval <120 ms was observed in 15 (7%); PR interval >200 ms in 6 (3%); QRS interval >120 ms 18 (9%); left QRS axis deviation in 16 (8%); and right-axis deviation in 2 (1%). Age was an independent determinant of prolonged PR interval, QRS duration and left QRS axis deviation. During follow-up (189 patients; 899 patient-years), 12 (6%) had a device implanted to treat spontaneously occurring bradyarrhythmias [5/12 (42%) for atrioventricular disease; 7/12 (58%) sinus node disease] with 8% 5-year cumulative incidence. Two independent predictors of future anti-bradycardia pacing were identified in a multivariable Cox model: QRS duration [hazard ratio (HR) 1.05, 95% confidence intervals (CI) 1.02-1.09, P= 0.001; receiver operating characteristic (ROC) curve c-statistic 0.726] and PR interval duration (HR 1.03, 95% CI 1.004-1.060, P = 0.023; ROC curve c-statistic 0.548). QRS duration ≥110 ms at baseline had a sensitivity of 64%, specificity of 84%, 49% positive predictive value, and 91% negative predictive value for identifying patients likely to require anti-bradycardia pacing. CONCLUSION In patients with AFD increasing age is associated with PR and QRS interval prolongation and left QRS axis deviation. Pacing for atrioventricular and sinus node disease is common and patients with QRS≥110 ms should be closely monitored for bradyarrhythmias.

Clinical and genetic predictors of major cardiac events in patients with Anderson–Fabry Disease

Background Anderson–Fabry Disease (AFD) is an X linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Some mutations are associated with prominent and, in many cases, exclusive cardiac involvement. The primary aims of this study were to determine the incidence of major cardiac events in AFD and to identify clinical and genetic predictors of adverse outcomes. Methods and results We studied 207 patients with AFD (47% male, mean age 44 years, mean follow-up 7.1 years). Fifty-eight (28%) individuals carried mutations that have been previously associated with a cardiac predominant phenotype. Twenty-one (10%) developed severe heart failure (New York Heart Association functional class (NYHA) ≥3), 13 (6%) developed atrial fibrillation (AF), 13 (6%) received devices for the treatment of bradycardia; there were a total of 7 (3%) cardiac deaths. The incidence of the primary endpoint (a composite of new onset AF, NYHA ≥ 3 symptoms, device insertion for bradycardia and cardiac death) was 2.64 per 100 person-years (CI 1.78 to 3.77). Age (HR 1.04, CI 1.01 to 1.08, p=0.004), Mainz Severity Score Index score (HR 1.05, CI 1.01 to 1.09, p=0.012) and QRS duration (HR 1.03, CI 1.00 to 1.05, p=0.020) were significant independent predictors of the primary endpoint. The presence of a cardiac genetic variant did not predict the primary end point. Conclusions AFD is associated with a high burden of cardiac morbidity and mortality. Adverse cardiac outcomes are associated with age, global disease severity and advanced cardiac disease but not the presence of cardiac genetic variants.

Arrhythmogenic Left Ventricular Cardiomyopathy

A 53-year-old white man was identified through family screening as having arrhythmogenic right ventricular cardiomyopathy caused by a frameshift mutation in the desmoplakin gene (DSP S1015fsX1017). Direct questioning revealed a previously undisclosed history of palpitations. The electrocardiogram (ECG) showed anterolateral T-wave inversion (Figure 1). Holter monitoring detected an asymptomatic 11-beat run of nonsustained ventricular tachycardia, 2 triplets, 11 couplets, and 1754 multifocal ventricular ectopics. These ectopics were of left ventricular (LV) origin when captured on 12-lead ECG. There were no late potentials on signal-averaged ECG. Figure 1. ECG …

Cardiopulmonary Exercise Testing and Prognosis in Hypertrophic Cardiomyopathy

Background—Exercise testing is performed in patients with hypertrophic cardiomyopathy to evaluate blood pressure response, a risk factor for sudden cardiac death. The prognostic role of exercise gas exchange variables is unknown. Methods and Results—Between 1998 and 2010, 1898 patients (age 47±15 years, range 16–86 years; 67% male) with hypertrophic cardiomyopathy underwent cardiopulmonary exercise testing. A total of 178 (9.4%) patients reached the primary end point of all-cause mortality or heart transplant (death/transplant) during a median follow-up of 5.6 years (interquartile range 2.6–8.9), giving an annual event rate of 1.6% per person year. Peak oxygen consumption (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.77–0.88, P<0.001), ventilatory efficiency (adjusted HR 1.10, 95% CI 1.00–1.22, P=0.049), and ventilatory anaerobic threshold (adjusted HR 0.82, 95% CI 0.70–0.96, P=0.016) were predictors of the primary outcome after correction for age, sex, left atrial size, nonsustained ventricular tachycardia, and ejection fraction. The overall adjusted death/transplant estimates for patients in the lowest quartile with peak oxygen consumption ⩽15.3 mL/kg/min were 14% at 5 years and 31% at 10 years. Peak oxygen consumption (HR 0.81, 95% CI 0.77–0.86, P<0.01) and ventilation to carbon dioxide production (HR 1.10, 95% CI 1.08–1.13, P<0.001) were predictors of death because of heart failure or transplantation but not sudden cardiac death or implantable cardioverter defibrillator shocks. Conclusions—Cardiopulmonary exercise testing provides prognostic information in patients with hypertrophic cardiomyopathy. Submaximal exercise parameters, such as ventilatory efficiency and anaerobic threshold, measured alone or in combination with peak oxygen consumption, predict death from heart failure.

Hypertrophic Cardiomyopathy: Lessons from History

The modern description of hypertrophic cardiomyopathy is credited to the London pathologist, Robert Donald Teare who likened the disease to “a tumour of the heart” and published his observations in the British Heart Journal 50 years ago. Teare recognised asymmetrical hypertrophy and myocyte disarray as a familial condition associated with premature and sudden death in young people. He rightly deserves the accolade for bringing a poorly understood, but well recognised phenomenon into the public domain. Thick and heavy hearts had been of interest and investigation to physicians and pathologists for many centuries. This article reviews the early history of hypertrophic cardiomyopathy and reflects on several centuries of progress in our understanding of the condition.

Exercise-Induced Left Ventricular Outflow Tract Obstruction in Symptomatic Patients With Anderson-Fabry Disease

To the Editor: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations in the gene encoding alpha-galactosidase A. The resultant deficiency in alpha-galactosidase A leads to progressive intracellular accumulation of neutral glycosphingolipids throughout the body,

Genetic biomarkers in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a common inherited heart muscle disorder associated with sudden cardiac death, arrhythmias and heart failure. Genetic mutations can be identified in approximately 60% of patients; these are commonest in genes that encode proteins of the cardiac sarcomere. Similar to other Mendelian diseases these mutations are characterized by incomplete penetrance and variable clinical expression. Our knowledge of this genetic diversity is rapidly evolving as high-throughput DNA sequencing technology is now used to characterize an individual patients disease. In addition, the genomic basis of several multisystem diseases associated with a hypertrophic cardiomyopathy phenotype has been elucidated. Genetic biomarkers can be helpful in making an accurate diagnosis and in identifying relatives at risk of developing the condition. In the clinical setting, genetic testing and genetic screening should be used pragmatically with appropriate counseling. Here we review the current role of genetic biomarkers in hypertrophic cardiomyopathy, highlight recent progress in the field and discuss future challenges.

Pregnancy and its management in women with GSD type III - a single centre experience

We present a review of our experience and pregnancy outcome in patients with GSD III managed by our centre. Between 1997 and 2010 there were 15 pregnancies in seven women with GSD III. Four women had GSD IIIb (nine pregnancies) and three GSD IIIa (six pregnancies). There was a successful outcome in all 15 pregnancies with delivery of 15 liveborn infants. Four infants were of low birthweight (<2nd centile) but all have developed normally apart from one with behavioural/psychiatric problems. Three women had pre-existing cardiomyopathy prior to pregnancy. One of these women had deterioration of her cardiomyopathy during pregnancy and again in the post-partum period. Women with GSD III do not seem to have any issues with fertility. Overall the outcome of pregnancy for both mother and child is good. Care needs to be taken to avoid maternal hypoglycemia which may be associated with intrauterine growth restriction and low birth weight. Cardiac function should be monitored carefully particularly in those with pre-existing cardiomyopathy.

Current applications of biomarkers in cardiomyopathies.

Cardiomyopathies are an important cause of sudden cardiac death in young people and are responsible for arrhythmias and premature heart failure in all age groups. Although many cardiomyopathies are inherited, biochemical markers are a fundamental part of the diagnostic work-up and are useful in the prognostic assessment of disease. In this article, the authors review the rationale and evidence for important biomarkers according to their role in patient management. Emerging biomarkers are briefly reviewed, alongside modern scientific approaches to biomarker discovery.