Exercise-induced ventricular arrhythmias and risk of sudden cardiac death in patients with hypertrophic cardiomyopathy.

BACKGROUND: Non-sustained ventricular tachycardia (NSVT) during ambulatory electrocardiographic monitoring (typically occurring at rest or during sleep) is associated with an increased risk of sudden cardiac death in patients with hypertrophic cardiomyopathy. The prevalence and prognostic significance of ventricular arrhythmias during exercise is unknown. METHODS AND RESULTS: This was a cohort study, with prospective data collection. We studied 1380 patients, referred to a cardiomyopathy clinic in London, UK [mean age 42 years (SD 15); 62% male; mean follow-up 54 (SD 49) months]. Patients underwent two-dimensional and Doppler echocardiography, upright exercise testing, and Holter monitoring. Twenty-seven patients [mean age 40 (SD 14) years (18-64); 22 (81.5%) male] had NSVT (24) or ventricular fibrillation (VF) (3) during exercise. During exercise, 13 (54.2%) had more than one run of NSVT (maximum 5) with a mean heart rate of 221 (SD 48) b.p.m. Patients with exercise NSVT/VF had more severe hypertrophy (22.6 vs. 19.5 mm, P = 0.009) and larger left atria (47.3 vs. 43.7 mm, P = 0.03). Male gender was significantly associated with exercise NSVT/VF [22 (81.5%) vs. 832 (61.5%), P = 0.03]. Eight (29.6%) of the exercise NSVT/VF patients died or had a cardiac event (SD/ICD discharge/transplant) compared with 150 (11.1%) patients without exercise NSVT/VF, P = 0.008. Patients with NSVT/VF had a 3.73-fold increase in risk of SD/ICD discharge (HR 95% CI: 1.61-8.63, P = 0.002). Exercise NSVT alone was associated with a 2.82-fold increased risk (HR 95% CI: 1.02-7.75, P = 0.049). In multivariable analysis with other risk markers, exercise NSVT/VF (but not NSVT alone) was independently associated with an increased risk of SD/ICD [HR 3.14 (95% CI: 1.29-7.61, P = 0.01)]. CONCLUSION: Ventricular arrhythmia during symptom limited exercise is rare in patients with hypertrophic cardiomyopathy, but is associated with an increased risk of sudden cardiac death.

Biventricular response after pulmonary valve replacement for right ventricular outflow tract dysfunction: is age a predictor of outcome?

BACKGROUND: The timing of pulmonary valve replacement (PVR) for free pulmonary incompetence in patients with congenital heart disease remains a dilemma for clinicians. We wanted to assess the determinants of improvement after PVR for pulmonary regurgitation over a wide range of patient ages and to use any identified predictors to compare clinical outcomes between patient groups. METHODS AND RESULTS: Seventy-one patients (mean age 22+/-11 years; range, 8.5 to 64.9; 72% tetralogy of Fallot) underwent PVR for severe pulmonary regurgitation. New York Heart Association class improved after PVR (median of 2 to 1, P<0.0001). MRI and cardiopulmonary exercise testing were performed before and 1 year after intervention. After PVR, there was a significant reduction in right ventricular volumes (end diastolic volume 142+/-43 to 91+/-18, end systolic volume 73+/-33 to 43+/-14 mL/m(2), P<0.0001), whereas left ventricular end diastolic volume increased (66+/-12 to 73+/-13 mL/m(2), P<0.0001). Effective cardiac output significantly increased (right ventricular: 3.0+/-0.8 to 3.3+/-0.8 L/min, P=0.013 and left ventricular: 3.0+/-0.6 to 3.4+/-0.7 L/min, P<0.0001). On cardiopulmonary exercise testing, ventilatory response to carbon dioxide production at anaerobic threshold improved from 35.9+/-5.8 to 34.1+/-6.2 (P=0.008). Normalization of ventilatory response to carbon dioxide production was most likely to occur when PVR was performed at an age younger than 17.5 years (P=0.013). CONCLUSIONS: A relatively aggressive PVR policy (end diastolic volume <150 mL/m(2)) leads to normalization of right ventricular volumes, improvement in biventricular function, and submaximal exercise capacity. Normalization of ventilatory response to carbon dioxide production is most likely to occur when surgery is performed at an age

Physiological and clinical consequences of relief of right ventricular outflow tract obstruction late after repair of congenital heart defects.

BACKGROUND: Right ventricular outflow tract obstruction (RVOTO) is a common problem after repair of congenital heart disease. Percutaneous pulmonary valve implantation (PPVI) can treat this condition without consequent pulmonary regurgitation or cardiopulmonary bypass. Our aim was to investigate the clinical and physiological response to relieving RVOTO. METHODS AND RESULTS: We studied 18 patients who underwent PPVI for RVOTO (72% male, median age 20 years) from a total of 93 who had this procedure for various indications. All had a right ventricular outflow tract (RVOT) gradient >50 mm Hg on echocardiography without important pulmonary regurgitation (less than mild or regurgitant fraction <10% on magnetic resonance imaging [MRI]). Cardiopulmonary exercise testing, tissue Doppler echocardiography, and MRI were performed before and within 50 days of PPVI. PPVI reduced RVOT gradient (51.4 to 21.7 mm Hg, P<0.001) and right ventricular systolic pressure (72.8 to 47.3 mm Hg, P<0.001) at catheterization. Symptoms and aerobic (25.7 to 28.9 mL.kg(-1).min(-1), P=0.002) and anaerobic (14.4 to 16.2 mL.kg(-1).min(-1), P=0.002) exercise capacity improved. Myocardial systolic velocity improved acutely (tricuspid 4.8 to 5.3 cm/s, P=0.05; mitral 4.7 to 5.5 cm/s, P=0.01), whereas isovolumic acceleration was unchanged. The tricuspid annular velocity was not maintained on intermediate follow-up. Right ventricular end-diastolic volume (99.9 to 89.7 mL/m2, P<0.001) fell, whereas effective stroke volume (43.7 to 48.3 mL/m2, P=0.06) and ejection fraction (48.0% to 56.8%, P=0.01) increased. Left ventricular end-diastolic volume (72.5 to 77.4 mL/m2, P=0.145), stroke volume (45.3 to 50.6 mL/m2, P=0.02), and ejection fraction (62.6% to 65.8%, P=0.03) increased. CONCLUSIONS: PPVI relieves RVOTO, which leads to an early improvement in biventricular performance. Furthermore, it reduces symptoms and improves exercise tolerance. These findings have important implications for the management of this increasingly common condition.

Reversal of inappropriate peripheral vascular responses in hypertrophic cardiomyopathy.

OBJECTIVES: We assessed the frequency of abnormal forearm vasodilator responses during lower body negative pressure (LBNP) in 21 non-obstructive hypertrophic cardiomyopathy (HCM) patients (31 +/- 8 [20 to 43] years) with abnormal blood pressure response (ABPR) to exercise and the effects of three drugs used to treat vasovagal syncope (propranolol, clonidine, and paroxetine) in a double-blind crossover study. BACKGROUND: Some HCM patients have an ABPR to exercise, which may be due to paradoxical peripheral vasodilatation. A similar proportion has paradoxical forearm vasodilatation during central volume unloading using LBNP. These abnormal reflexes may be caused by left ventricular mechanoreceptor activation. Similar mechanisms may also contribute to some cases of vasovagal syncope. METHODS: Blood pressure changes were assessed during exercise, and forearm vascular responses and baroreceptor sensitivity were assessed during LBNP using plethysmography. RESULTS: Nine (43%) patients (group A) had paradoxical vasodilator responses (forearm vascular resistance [FVR] fell by 7.5 +/- 4.6 U), and 12 (57%) patients (group B) had normal vasoconstrictor responses during LBNP (FVR increased by 7.7 +/- 4.9 U). Paroxetine augmented systolic blood pressure (SBP) during exercise in group A (21 +/- 6 mm Hg vs. 14 +/- 11 mm Hg at baseline, p = 0.02); no effect was detected in group B. Paroxetine reversed paradoxical vascular responses during LBNP in seven (78%) patients from group A. Propranolol and clonidine had no significant effect on SBP during exercise but reversed paradoxical vascular responses in some patients from group A (n = 5 and n = 3). CONCLUSIONS: Paradoxical vasodilatation during LBNP occurs in 40% of patients with ABPR during exercise and is reversed by propranolol, clonidine, and paroxetine. Paroxetine also improved SBP response to exercise.

Usefulness of N-terminal pro-B-type natriuretic peptide levels to predict exercise capacity in hypertrophic cardiomyopathy.

Most patients with hypertrophic cardiomyopathy (HC) have reduced maximal oxygen consumption (VO2max) during exercise. The degree of impairment is poorly predicted by the magnitude of hypertrophy, left ventricular (LV) outflow tract obstruction, and other conventional markers of disease severity. The aim of this study was to determine the usefulness of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) as a marker of exercise performance in HC. Plasma NT-pro-BNP was measured in 171 consecutive patients (mean age 46 +/- 18 years) who underwent echocardiography and cardiopulmonary exercise testing. The mean log NT-pro-BNP was 2.79 +/- 0.5; log NT-pro-BNP levels were higher in women patients (p = 0.001) and patients with chest pain (p = 0.010), in New York Heart Association class > or = II (p = 0.009), with atrial fibrillation (p < 0.001), with systolic impairment (p = 0.025), and with LV outflow tract obstructions (p < 0.0001). NT-pro-BNP levels were also correlated with maximal wall thickness (r = 0.335, p < 0.0001), left atrial size (r = 0.206, p = 0.007), and the mitral Doppler E/A ratio (r = 0.197, p = 0.012). The mean percent VO2max achieved was 73.8 +/- 22.6%; percent VO2max was smaller in patients with systolic impairment (p = 0.044) and LV outflow tract obstructions (p = 0.025). There were inverse correlations between percent VO2max and NT-pro-BNP (r = -0.352, p = 0.001), LV end-systolic cavity size (r = -0.182, p = 0.031), and left atrial size (r = -0.251, p = 0.003). On multivariate analysis, only NT-pro-BNP was correlated with percent VO2max. A NT-pro-BNP level of 316 ng/L had 78% sensitivity and 44% specificity (area under the curve 0.616) for predicting percent VO2max < 80%. In conclusion, NT-pro-BNP levels correlate with peak oxygen consumption in HC and are more predictive of functional impairment than other conventional markers of disease severity.

Progressive left ventricular remodeling in patients with hypertrophic cardiomyopathy and severe left ventricular hypertrophy.

OBJECTIVES: The aim of this study was to determine the natural history of patients with hypertrophic cardiomyopathy (HCM) and severe left ventricular hypertrophy (LVH) (i.e., maximal left ventricular wall thickness [MLVWT] >/=30 mm) and whether changes in cardiac morphology influence the course of the disease. BACKGROUND: Severe LVH is common in young and rare among elderly patients with HCM. This has been explained by a high incidence of sudden death. We hypothesized that this age-related difference might be explained by left ventricular wall thinning. METHODS: A total of 106 (age 33 +/- 15 years; 71 males) consecutive patients with severe LVH underwent history taking, examination, electrocardiography, echocardiography, cardiopulmonary exercise testing, and Holter analysis. Survival data were collected at subsequent clinic visits or by communication with patients and their general practioners. In order to assess morphologic and functional changes, 71 (67.0%) patients (mean age 31 +/- 15 years; 47 males) followed at our institution underwent serial (>/=1 year) assessment. RESULTS: Of the 106 patients, the majority (78 [71.6%]) were <40 years of age. During follow-up (92 +/- 50 months [range 1 to 169]), 18 (17.0%) patients died or underwent heart transplantation (13 sudden cardiac deaths, 2 heart failure deaths, 1 heart transplantation, 1 stroke, 1 postoperative death). Five-year survival from sudden death was 90.1% (95% confidence interval [CI] 84.0% to 96.3%), and that from heart failure death or transplantation was 97.7% (95% CI 94.5 to 100). In patients serially evaluated over 85 +/- 51 months, there was an overall reduction in MLVWT of 0.6 mm/year (95% CI 0.31 to 0.81, p = 0.00004). Wall thinning >/=5 mm was observed in 41 patients (57.7%; age 35 +/- 13 years; 28 males). On multivariate analysis, the follow-up duration only predicted wall thinning (0.6 mm/year, 95% CI 0.38 to 0.85, p < 0.00001). CONCLUSIONS: Left ventricular remodeling is common in patients with severe LVH and contributes to the low prevalence of severe LVH seen in middle age and beyond.

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.

Cardiac output response and peripheral oxygen extraction during exercise among symptomatic hypertrophic cardiomyopathy patients with and without left ventricular outflow tract obstruction.

OBJECTIVE: Reduction of left ventricular outflow tract obstruction (LVOTO) often improves symptoms in hypertrophic cardiomyopathy (HCM), but the correlation between exercise performance and measured LVOT gradients is weak. We investigated the relationship between LVOTO and cardiorespiratory responses during exercise. METHODS: The study cohort included 70 patients with HCM (32 with LVOTO, 55 male, age 47±13) attending a dedicated cardiomyopathy clinic and 28 normal volunteers. All underwent cardiopulmonary exercise testing with simultaneous non-invasive haemodynamic assessment using finger plethysmography. Main outcome measures were peak oxygen consumption, cardiac index and arteriovenous oxygen difference. RESULTS: When compared with controls, patients had reduced peak exercise oxygen consumption (22.4±6.1 vs 34.7±7.7 mL/kg/min, p<0.0001) and cardiac index (5.5±1.9 vs 9.4±2.9 L/min/m(2), p<0.0001). At all workloads, stroke volume index (SVI) was lower and arteriovenous oxygen difference greater in patients. During all stages of exercise, LVOTO in patients was associated with failure to augment SVI and higher oxygen consumption; cardiac reserve (4.4±2.7 vs 6.3±3.6 L/min, p=0.025) and peak mean arterial pressure (104±16 vs 112±16 mm Hg, p=0.033) were lower. Multivariable predictors of cardiac output response were age (ß: -0.11; CI -0.162 to -0.057; p<0.0001), peak LVOT gradient (ß: -0.018; CI -0.034 to -0.002; p=0.031) and gender (ß: -2.286; CI -0.162 to -0.577; p=0.01). Within the obstructive cohort, different patterns of SV response were elicited in patients with similar clinical features. CONCLUSIONS: Cardiac reserve is reduced in HCM because of failure of SV augmentation. LVOTO exacerbates this abnormal response, but haemodynamic responses vary significantly. Non-invasive exercise haemodynamic assessment may improve understanding of symptoms and help tailor therapy.

Heart rate recovery in patients with hypertrophic cardiomyopathy.

Recovery in heart rate (HR) after exercise is a measure of autonomic function and a prognostic indicator in cardiovascular disease. The aim of this study was to characterize heart rate recovery (HRR) and to determine its relation to cardiac function and morphology in patients with hypertrophic cardiomyopathy (HC). We studied 18 healthy volunteers and 41 individuals with HC. All patients underwent clinical assessment and transthoracic echocardiography. Continuous beat-by-beat assessment of HR was obtained during and after cardiopulmonary exercise testing using finger plethysmography. HRR and power spectral densities were calculated on 3 minutes of continuous RR recordings. Absolute HRR was lower in patients than that in controls at 1, 2, and 3 minutes (25.7 ± 8.4 vs 35.3 ± 11.0 beats/min, p <0.001; 36.8 ± 9.4 vs 53.6 ± 13.2 beats/min, p <0.001; 41.2 ± 12.2 vs 62.1 ± 14.5 beats/min, p <0.001, respectively). HRR remained lower in patients at 2 and 3 minutes after normalization to peak HR. After normalization to the difference in HR between peak exercise and rest, HRR was significantly impaired in individuals with obstructive HC at 3 minutes compared with controls. HR at 3 minutes correlated with peak left ventricular outflow tract gradient (B 0.154 beats/min/mm Hg, confidence interval 0.010 to 0.299, p = 0.037) and remained a significant predictor of HRR after multivariable analysis. Spectral analysis showed a trend toward an increased low-frequency to high-frequency ratio in patients (p = 0.08) suggesting sympathetic predominance. In conclusion, HRR is impaired in HC and correlates with the severity of left ventricular outflow tract gradient. Prospective studies of the prognostic implications of impaired HRR in HC are warranted.

Non-invasive assessment of cardiac output at rest and during exercise by finger plethysmography.

AIMS: We sought to determine the accuracy of finger plethysmography using pulse waveform analysis with brachial calibration for measurement of cardiac output during submaximal exercise by comparing it against an acetylene (C2H2) uptake technique. METHODS: The study included 24 healthy volunteers (12 males, age 35 ± 8 years). Testing was performed on an upright cycle ergometer using an incremental protocol. Cardiac output measurements were performed at rest and during sub-maximal exercise using a single breath C2H2 uptake technique and continuously using finger plethysmography with brachial calibration. RESULTS: Valid results at rest and during sub-maximal exercise were achieved in 20 of 24 participants. Cardiac output at rest was 5.3 ± 1.1 and 5.2 ± 1.2 l min(-1) for finger plethysmography and C2H2, respectively, P = 0.712. Mean difference between techniques was -0.1 ± 0.5 l min(-1). Cardiac output during submaximal exercise was 10.2 ± 2.3 and 10.3 ± 2.1 l min(-1) for finger plethysmography and C2H2, respectively, P = 0.898. Mean difference between techniques was 0.1 ± 1.5 l min(-1). The overall correlation between finger plethysmography and C2H2 data obtained during rest and exercise was r(2) = 0.872, P<0.0001. Mean rise in cardiac output during exercise was 4.9 ± 1.5 (finger plethysmography) and 5.1 ± 1.5 l min(-1) (C2H2), P = 0.64. CONCLUSION: Finger plethysmography determined cardiac output values both at rest and during sub-maximal exercise are comparable with those obtained using a single breath C2H2 uptake technique.

Effect of altering pathologic right ventricular loading conditions by percutaneous pulmonary valve implantation on exercise capacity.

The data describing the change in exercise capacity after surgical or interventional management of the patient with right ventricular (RV) outflow tract (OT) dysfunction are conflicting. The pathophysiologic consequences of RVOT interventions and the subsequent change in exercise performance are still poorly understood. We sought to assess the effect of percutaneous pulmonary valve implantation (PPVI) on exercise capacity in (1) patients with predominantly pulmonary stenosis (PS) and (2) in patients with predominantly pulmonary regurgitation (PR). A total of 63 patients with either predominantly PS (n = 37) or PR (n = 26) underwent PPVI. Cardiopulmonary exercise testing and magnetic resonance imaging were performed before and within 1 month after PPVI. On magnetic resonance imaging, the at rest effective biventricular stroke volumes improved in both groups after PPVI (p <0.001), but the ejection fraction improved only in the PS group. In the PS group, exercise capacity (peak oxygen uptake, p <0.001), ventilatory efficiency (p <0.001), and peak oxygen pulse (p <0.001) improved after PPVI. In the PR group, none of these parameters changed after PPVI (p = 0.6, p = 0.12, and p = 0.9, respectively). On multivariate analysis, the reduction in RVOT gradient was the only predictor of improved peak oxygen uptake when assessed in the whole patient group (r(part) = -0.59; p <0.001) or in the PS (r(part) = -0.45; p = 0.002) or PR groups alone (r(part) = -0.45; p = 0.02). In conclusion, acutely after PPVI, exercise capacity improves with the relief of stenosis but not regurgitation. A reduction in the RVOT gradient, even small gradients, was the only independent predictor of improved peak oxygen uptake in both patient groups, irrespective of improved pulmonary valve competence.

Physiological consequences of percutaneous pulmonary valve implantation: the different behaviour of volume- and pressure-overloaded ventricles.

AIMS: To investigate the early clinical and physiological consequences of relieving chronic right ventricular (RV) volume overload with percutaneous pulmonary valve implantation (PPVI). METHODS AND RESULTS: We selected 17 patients (age 21.2 +/- 8.7 years), from a total of 125 who underwent PPVI, because they had important pulmonary regurgitation (PR) [regurgitant fraction > 25% on magnetic resonance (MR)] and an echocardiographic gradient < 50 mmHg across the RV outflow tract. Cardiopulmonary exercise testing, tissue Doppler and MR were performed before and within 3 months of PPVI. Following PPVI, PR (40.7 +/- 7.3 to 4.1 +/- 6.1%, P < 0.001) and RV end-diastolic volume fell (115.4 +/- 33.1 to 98.9 +/- 32.0 mL/m(2), P = 0.001); effective RV stroke volume increased (34.3 +/- 7.8 to 44.4 +/- 9.3 mL/m(2), P < 0.001). Left ventricular end-diastolic volume (66.6 +/- 18.0 to 73.4 +/- 16.5 mL/m(2), P = 0.014), stroke volume (38.4 +/- 11.1 to 46.4 +/- 10.2 mL/m(2), P = 0.001) and ejection fraction (57.8 +/- 8.1 to 63.5 +/- 5.2 mL/m(2), P = 0.001) increased. Pulmonary artery diastolic pressure (8.9 +/- 4.5 to 12.5 +/- 5.2 mmHg, P = 0.041) and mitral E/Ea increased (from 9.0 +/- 2.0 to 11.6 +/- 3.1, P = 0.003). Patients felt better, but standard measures of exercise capacity were unchanged. CONCLUSION: PPVI relieves PR and restores compensatory cardiac performance. The lack of improvement in exercise parameters suggests that, in contrast to pressure overload, the contractile reserve of chronically volume-overloaded myocardium is limited.