Exercise-induced Left Ventricular Outflow Tract Research Articles

Gender-disparities in patients undergoing alcohol septal ablation for hypertrophic obstructive cardiomyopathy

Abstract Background Alcohol septal ablation (ASA) improves symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM) but gender-disparities have only rarely been investigated. Purpose To assess gender-disparities regarding outcome and procedure-related aspects in HOCM patients undergoing ASA. Methods and results 1,367 consecutive ASAs between 2002 and 2020 were retrospectively analyzed for sex-differences. Females (47.2%) had more advanced age at the timing of ASA (66.0 years [IQR 55.0–74.0] vs. 54.0 years [IQR 45.0–62.0]; p<0.0001), had more severe symptoms (NYHA class 2.8±0.6 vs. 2.5±0.8 in males; p<0.0001) and shorter distances walked in 6-min-walk-test at baseline (359.0m [IQR 272.3–442.0] vs. 464.4m [IQR 400.0–524.0] in males; p<0.0001). The baseline interventricular septal diameter (IVSD) was higher in males (21.0mm [IQR 19.0–24.0] vs. 20.0mm [IQR 18.0–23.0] in females; p<0.0001). However, the IVSD was higher in females when it was indexed to the body-surface-area (10.9 mm/m2 [IQR 9.7–12.7] vs. 10.2 mm/m2 [IQR 9.0–11.7] in males; p<0.0001). The resting and exercise-induced left ventricular outflow tract gradients (LVOTG) were lower in females when calculated 1–4 days after ASA (resting: 20.0 mmHg [IQR 12.0–37.5] vs. 22.0 mmHg [IQR 13.0–40.0] in males; p=0.0062; exercise-induced: 55.0 mmHg [IQR 30.0–109.0] vs. 71.0 mmHg [IQR 37.0–115.0] in males; p=0.0006). At 6 months follow-up females had lower exercise-induced LVOTG (34.0 mmHg [IQR 21.0–70.0] vs. 43.5 mmHg [IQR 25.0–74.8]; p=0.0072). More females had complete heart block after ASA (20.3% vs. 13.3% in men; p=0.0005) and, hence, more females (17.4%) than males (10.4%; p=0.0002) needed a pacemaker. There were no differences regarding mortality. Conclusion Female HOCM patients had more advanced age, more severe symptoms and a higher IVSD when indexed to BSA at the timing of ASA. However, early hemodynamic response was better in females, but procedure-related complete heart block was more often found in women. Gender-disparities in clinical characteristics and procedural outcome of ASA should be taken into consideration. Funding Acknowledgement Type of funding sources: None.

Gender disparities in alcohol septal ablation for hypertrophic obstructive cardiomyopathy

ObjectiveAlcohol septal ablation (ASA) improves symptoms in hypertrophic obstructive cardiomyopathy (HOCM). We conducted a large retrospective analysis investigating gender effects on outcome after ASA.Methods and results1367 ASAs between 2002 and...

Repetitive Squat-to-Stand Provocation of Dynamic Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy

Left ventricular outflow tract (LVOT) obstruction is a determinant in the management of patients with hypertrophic cardiomyopathy, including candidacy for septal reduction therapy and risk stratification for sudden cardiac death. 1 Elliott P.M. Gimeno J.R. Tomé M.T. Shah J. Ward D. Thaman R. et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J. 2006; 27: 1933-1941 Crossref PubMed Scopus (262) Google Scholar ,2 Ommen S.R. Mital S. Burke M.A. Day S.M. Deswal A. Elliott P. et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2020; 76: e159-e240 Crossref PubMed Scopus (136) Google Scholar Obstruction is defined as a maximal instantaneous gradient ≥ 30 mm Hg, and severe obstruction is defined as a maximal instantaneous gradient ≥ 50 mm Hg. 2 Ommen S.R. Mital S. Burke M.A. Day S.M. Deswal A. Elliott P. et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2020; 76: e159-e240 Crossref PubMed Scopus (136) Google Scholar Several provocative maneuvers have been used to elicit latent obstruction, including the Valsalva maneuver, amyl nitrite inhalation, and exercise on a treadmill or bike. 3 Marwick T.H. Nakatani S. Haluska B. Thomas J.D. Lever H.M. Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy. Am J Cardiol. 1995; 75: 805-809 Abstract Full Text PDF PubMed Scopus (74) Google Scholar , 4 Jensen M.K. Havndrup O. Pecini R. Dalsgaard M. Hassager C. Helqvist S. et al. Comparison of Valsalva manoeuvre and exercise in echocardiographic evaluation of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Eur J Echocardiogr. 2010; 11: 763-769 Crossref PubMed Scopus (24) Google Scholar , 5 Shah J.S. Esteban M.T.T. Thaman R. Sharma R. Mist B. Pantazis A. et al. Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy. Heart. 2008; 94: 1288-1294 Crossref PubMed Scopus (165) Google Scholar During a recent shortage of amyl nitrite, our practice implemented a repetitive squat-to-stand maneuver as an adjunct to the Valsalva maneuver when assessing for LVOT obstruction. We sought to evaluate the efficacy of this repetitive squat-to-stand maneuver in eliciting LVOT obstruction compared with the Valsalva maneuver in a retrospective study.

Value of a comprehensive exercise echocardiography assessment for patients with hypertrophic cardiomyopathy

Background: Exercise echocardiography (ExE) may assess left ventricular (LV) systolic and diastolic function, LV outflow tract (LVOT) obstruction, and mitral regurgitation (MR). We aimed to evaluate the prognostic value of these assessments during exercise in patients with hypertrophic cardiomyopathy (HCM).Methods: LV systolic function, LV-derived filling pressures, LVOT gradients, and MR were prospectively evaluated during treadmill ExE in 285 patients with HCM and preserved LV ejection fraction (EF) (≥50%). Recordings were obtained at rest and peak exercise for LV systolic function and at rest and post-exercise for LVOT gradients, MR, and ratio of early LV inflow velocity to early tissue Doppler annulus velocity (E/e´).Results: Thirty-seven patients (13%) had LVOT obstruction at rest, and 76 (27%) developed exercise-induced LVOT obstruction. New wall motion abnormalities were detected in 38 patients (13%). E/e´>14 was observed in 129 patients at rest (45%) and in 134 at post-exercise (47%). Corresponding figures for significant MR (moderate or severe) were 21 (7%) and 17 (6%). During follow-up (3.9 ± 2.5 years), 27 patients had a hard event, 39 a combined event (hard plus new atrial fibrillation or syncope), and 58 a combined event or intervention. Exercise electrocardiographic testing, exercise LVEF, and the combination of positive ExE and increased E/e´ with exercise predicted outcome. The worst event rate corresponded to patients with raised E/e’ values at post-exercise and positive ExE (annualized hard event-rate of 5.9%).Conclusions: A comprehensive assessment during ExE is feasible for patients with HCM and preserved LV systolic function, and provides significant incremental prognostic information.

Value of a comprehensive exercise echocardiography assessment for patients with hypertrophic cardiomyopathy

Abstract Background Exercise echocardiography (ExE) may assess left ventricular (LV) systolic and diastolic function, LV outflow tract (LVOT) obstruction and mitral regurgitation (MR). We aimed to assess the feasibility and prognostic value of the assessment of all these issues during exercise in patients with hypertrophic cardiomyopathy (HCM). Methods LV systolic and diastolic function, LVOT gradients, and MR were evaluated during ExE in 285 patients with HCM (age 60±14 years, 168 men) and preserved LVEF (≥50%). Recordings were obtained at rest and peak exercise for regional/global LV systolic function and at rest and within 1.5 min after exercise for the rest of assessments: LVOT gradients, MR and ratio of early LV inflow velocity to early tissue Doppler septal annulus velocity (E/e'). Results Feasibility was 100%, 97%, 98% and 98% for LV systolic function, E/e', LVOT gradients, and MR assessments at exercise, respectively. Thirty-seven patients (13%) had LVOT obstruction at rest, and 76 (27%) developed exercise-induced LVOT obstruction. Mean resting LVEF was 63±3%. New wall motion abnormalities (WMAs) were detected in 38 patients (13%). E/e'>15 was observed in 108 patients at rest (38%) and in 119 at exercise (42%). Corresponding figures for significant MR (moderate or severe) were 20 (7%) and 17 (6%). During follow-up of 3.9±2.5 years, 21 patients had a hard event (cardiac death or transplantation, appropriate discharge of a defibrillator, stroke, myocardial infarction, hospitalization for heart failure), 33 a combined event (hard plus new atrial fibrillation or syncope), and 53 a combined event plus any interventionism. After adjustment, LV wall thickness, resting LVEF, maximal workload in Metabolic Equivalents (METs), and E/e' post-exercise resulted independent predictors of hard events (HR=1.45, 95% CI: 1.21–1.74, p<0.001; HR=0.80, CI: 0.71–0.89, p<0.001; HR=0.73, 95% CI: 0.62–0.86, p<0.001; HR=1.08, 95% CI: 1.02–1.14, p<0.009, respectively). Independent predictors of combined events included also LV wall thickness, resting LVEF, and METs, along with therapy with beta-blockers at the time of ExE (HR=1.29, 95% CI: 1.12–1.50, p=0.001; HR=0.89, CI: 0.81–0.97, p=0.012; HR=0.83, 95% CI: 0.74–0.93, p=0.001; HR=2.51, 95% CI: 1.20–5.25, p=0.015), whereas the model for combined events+any interventionism consisted of beta-blockers, LV wall thickness, LA dimension, METs and new WMAs. (HR=2.15, 95% CI: 1.20–3.86, p=0.01; HR=1.17, 95% CI: 1.03–1.32, p=0.02; HR=1.07, CI: 1.02–1.11, p=0.005; HR=0.90, 95% CI: 0.82–0.98, p=0.01; HR=2.33, 95% CI: 1.17–4.63, p=0.016) Conclusions A comprehensive assessment during ExE is feasible for patients with HCM and provides significant incremental prognostic information Funding Acknowledgement Type of funding source: None

Prognostic role of stress echocardiography in hypertrophic cardiomyopathy: The International Stress Echo Registry

BackgroundStress echo (SE) may have a role in the outcome in patients with hypertrophic cardiomyopathy (HCM). ObjectivesThe aim was to assess the prognostic value of SE in a retrospective multicenter study in HCM. MethodsWe enrolled 706 HCM patients. The employed stress was exercise (n=608) and/or vasodilator (n=146, dipyridamole in 98 and adenosine in 48). We defined SE positivity according to clinical/hemodynamic criteria including: symptoms (all stress modalities), exercise-induced hypotension (failure to increase or fall >20mmHg, exercise) and exercise-induced left ventricular outflow tract obstruction (left ventricular outflow tract obstruction >50mmHg); and ischemic criteria, such as new wall motion abnormalities (new wall motion abnormality) and/or reduction of coronary flow reserve velocity (CFVR≤2.0) on left anterior descending coronary artery with vasodilator stress assessed in 116 patients. All patients completed the clinical follow-up. ResultsPositive SE showed more frequently CFVR reduction, exercise-induced hypotension, left ventricular outflow tract obstruction, and symptoms (38, 23, 20 and 15% respectively), but new wall motion abnormality only in 6%. During a median follow-up of 49months 180 events were observed, including 40 deaths. Clinical/hemodynamic criteria did not predict outcome (X2 0.599, p=0.598), whereas ischemia-related SE criteria (X2: 111.120, p<0.0001) was significantly related to outcome. Similarly, mortality was predicted with SE ischemic-criteria (X2 16.645, p<0.0001). ConclusionsSE has an important prognostic significance in HCM patients, with ischemia-related end-points showing greater predictive accuracy than hemodynamic endpoints. New wall motion abnormalities and impairment of CFVR should be specifically included in SE protocols for HCM.

Elevated Left Ventricular Outflow Tract Velocities on Exercise Stress Echocardiography May Be a Normal Physiologic Response in Healthy Youth

Children with heart disease are at risk for sudden death during exercise, yet decisions regarding sports participation are often based on resting data. Acceleration across the left ventricular outflow tract (LVOT) assessed on stress echocardiography may suggest a diagnosis of hypertrophic cardiomyopathy in patients in whom it is not otherwise obvious. However, the range of peak velocities across the LVOT in healthy youth is unknown. The aim of this study was to describe LVOT velocities with maximal exercise in this age group. Subjects up to 18 years old were prospectively enrolled if they had normal results on resting echocardiography and were undergoing exercise testing for other reasons. Subjects with significant comorbidities, suspected cardiomyopathy, or family histories of cardiomyopathy were excluded. Peak LVOT velocities were measured in the upright position using continuous-wave Doppler immediately after maximal exercise. Fifty subjects (mean age, 13.8 ± 2.8 years) were included. Twenty-eight (56%) were male, and 40 (80%) were Caucasian. The median peak LVOT velocity measured immediately after exercise was 2.5m/sec (range, 1.3-5.9 m/sec). Sixteen subjects (32%) developed peak LVOT velocities of ≥3 m/sec. Twelve of the 16 (75%) with elevated velocities had a dynamic outflow tract Doppler pattern, of whom eight had evidence of intracavitary narrowing on two-dimensional echocardiography. The development of significant exercise-induced LVOT velocities may be a normal physiologic finding in healthy youth. The measurement of LVOT velocities alone with maximal exercise may not help distinguish patients with hypertrophic cardiomyopathy from healthy children.

Symptomatic Exercise-Induced Left Ventricular Outflow Tract Obstruction without Left Ventricular Hypertrophy

Left ventricular (LV) outflow tract obstruction (LVOTO) is most commonly seen in patients with hypertrophic cardiomyopathy. Postexercise dynamic LVOTO (DLVOTO) has been infrequently identified in symptomatic patients without LV hypertrophy, and its pathophysiology is not well established. The aim of this study was to identify echocardiographic abnormalities that might explain the dynamic development of systolic anterior motion, mitral-septal contact, and LVOTO in these patients. Patients with DLVOTO and normal wall thickness were compared with 20 age-matched and gender-matched controls with normal stress echocardiographic findings. Two other groups were also compared: patients with DLVOTO and mild segmental hypertrophy (segmental wall thickness ≤15 mm) and patients with normal left ventricles but DLVOTO after dobutamine stress. Six symptomatic patients were identified (mean age, 48 ± 9 years; range, 37-60 years; five men) with normal wall thickness who developed DLVOTO after exercise during a 6-year period. Five had been hospitalized for cardiac symptoms. The mean postexercise LV outflow tract gradient caused by systolic anterior motion mitral-septal contact was 107 ± 55 mm Hg (range, 64-200 mm Hg). All patients had echocardiographic LV wall thicknesses in the normal range (≤12 mm). Structural abnormalities of the mitral valve were identified in all six patients. These were elongated posterior leaflets (2.0 vs 1.5 cm, P < .0005), elongated anterior leaflets (3.2 vs 2.6 cm, P= .015), increased protrusion height of the mitral valve beyond the mitral annular plane (2.6 vs 0.6 cm, P < .00001), and residual protruding portions of the mitral valve leaflets (0.85 vs 0.24 cm, P < .005). There was anterior positioning of the papillary muscles in the LV cavity, with a greater distance from the plane of the papillary muscles to the posterior wall (1.8 vs 1.3 cm, P= .03). In two patients, potentially provoking medications were stopped; two patients received β-blockers, with reductions of angina. Medium-term prognosis was good; no patient had died after 3.5 years. The mitral valve abnormalities in the 10 patients with DLVOTO and mild segmental hypertrophy were qualitatively and quantitatively very similar to those in patients with DLVOTO without hypertrophy. In contrast, the valves of patients with dobutamine stress DLVOTO were not elongated, but 50% had residual mitral leaflets that protruded past the coaptation point by ≥5 mm. DLVOTO after exercise can occur in the absence of LV hypertrophy and may be associated with high gradients and cardiac symptoms. Elongated, redundant mitral valve leaflets with anterior position of the papillary muscles appear to cause the postexercise obstruction.

β Blockers for Prevention of Exercise-Induced Left Ventricular Outflow Tract Obstruction in Patients With Hypertrophic Cardiomyopathy

Whether treatment with β blockers (BBs) is of benefit to patients with hypertrophic cardiomyopathy (HC) and provocable outflow obstruction (with none or with only mild heart failure symptoms) is largely unresolved. Thus, we prospectively studied 27 patients with HC (age 36 ± 15 years; 81% men) with New York Heart Association class I or II, without obstruction at rest, but with exercise-induced left ventricular outflow tract (LVOT) gradient of ≥ 30 mm Hg. Patients underwent exercise echocardiography at baseline and after treatment with nadolol (n = 18; 40 to 80 mg/day) or bisoprolol (n = 9; 5 to 10 mg/day), according to a prespecified protocol. Without the BBs, the postexercise LVOT gradient was 87 ± 29 mm Hg and >50 mm Hg in 25 patients (93%). After a 12 ± 4-month period of BB treatment, the postexercise LVOT gradient had decreased to 36 ± 22 mm Hg (p <0.001) and was virtually abolished (to 0 or <30 mm Hg) in 14 patients (52%), substantially blunted (≥ 20 mm Hg reduction) in 9 (33%), and unchanged in only 4 (15%). Severe postexercise obstruction (range 58 to 80 mm Hg) persisted in 6 patients (22% compared to 93% without BBs; p <0.001). Nonresponders (residual postexercise gradient of ≥ 30 mm Hg with BBs) were characterized by an increased body mass index (hazard ratio 2.03/1 kg/m(2), 95% confidence interval 1.2 to 3.4; p <0.05). In conclusion, in patients with HC with mild or no symptoms, treatment with BBs can prevent the development of LVOT obstruction triggered by physiologic exercise. These findings provide a rationale for the novel strategy of early prophylactic pharmacologic treatment with standard, well-tolerated doses of BBs in physically active patients with provocable gradients, aimed at effective prevention of the hemodynamic burden associated with dynamic obstruction.

Cardiomyopathy of Friedreich’s Ataxia (FRDA)

We read the review article on the cardiomyopathy of Friedreich’s ataxia (FRDA) by Drs Bourke and Keane with great interest [1]. It nicely summarizes some of the historical findings related to the cardiomyopathy associated with this disease and appropriately emphasizes a multidisciplinary approach to the treatment of FRDA. However, we believe the authors have made a fundamental error in drawing an analogy between the cardiomyopathy of FRDA and that of hypertrophic cardiomyopathy (HCM) [2]. This distinction is very important because the therapeutic recommendations for FA cardiomyopathy contained within the article by Bourke and Keane are based on the assumption of a similarity with HCM. In HCM the basic defect is in the sarcomere, which is the minimal contractile unit of the cardiomyocyte. There is a disorganized expansion of nonfunctional contractile fibers within the cardiomyocyte which leads to hypertrophy [2]. Approximately 30% of subjects with HCM have a resting left ventricular outflow tract (LVOT) pressure gradient [2], but 70% have either a resting or provokable LVOT pressure gradient due to systolic anterior motion of an abnormal anterior mitral leaflet in conjunction with asymmetric septal hypertrophy and vigorous left ventricular contraction [3]. Numerous nonrandomized clinical trials support recommendations for the use of negatively inotropic medications in symptomatic patients with the obstructive form of HCM [2]. Nevertheless, it is recognized that response to treatment in obstructive HCM is variable and that patients who do not respond to one drug may need to be changed to another [2]. The evidence for drug treatment in nonobstructive HCM is even less clear. In contrast with HCM, the basic defect in FRDA is in the mitochondrion and results from a primary deficiency of frataxin. There is both basic and clinical evidence showing uncontrolled proliferation of dysfunctional mitochondria and loss of sarcomeres in the cardiomyocyte [4–6]. Loss of sarcomeres leads to decreased contractile performance and there is an accompanying increase in fibrosis. Asymmetric septal hypertrophy is much less common in FRDA than in HCM and anatomical abnormalities of the mitral valve have not been described in FRDA [7, 8]. In the published literature, and our combined clinical experience of more than 140 subjects with FRDA, resting LVOT obstruction is rare even in those patients with marked hypertrophy. So even if negatively inotropic drugs could be assumed to be beneficial in FRDA patients with LVOT obstruction, such treatment would rarely be indicated. We are not aware of any data regarding provokable LVOT obstruction in FRDA, however, exercise-induced LVOT gradients would not only be difficult to evaluate in this population, given the frequent difficulties with walking, but may also be less clinically relevant for the same reason. In the most common cardiac scenario in FRDA of an asymptomatic subject with a small left ventricle and increased relative wall thickness [8], there is currently no evidence to support the use of any drug treatment. On the other hand, FRDA patients can develop a dilated left ventricle with reduced ejection fraction and this is a progressive condition which leads to heart failure and death. R. M. Payne (&) Indiana University School of Medicine, 1044 W Walnut, R4-302, Indianapolis, IN 46202, USA e-mail: rpayne@iupui.edu

Prognostic Value of Exercise Echocardiography in Patients with Hypertrophic Cardiomyopathy

Although exercise echocardiography may assess left ventricular (LV) function and LV outflow tract (LVOT) gradients during exercise in patients with hypertrophic cardiomyopathy (HCM), its value for predicting outcomes has not been studied. The aim of this study was to determine whether exercise echocardiography predicts outcomes in patients with HCM. LV function and LVOT gradients were evaluated during exercise echocardiography in 239 patients with HCM. Sixty patients (25.1%) had LVOT obstruction at rest, and 43 (18%) developed exercise-induced LVOT obstruction. The mean resting LV ejection fraction was 69 ± 9%, and the mean resting wall motion score index was 1.00 ± 0.06. Wall motion abnormalities during exercise were seen in 19 patients (7.9%). During follow-up of 4.1 ± 2.6 years, 19 patients had hard events (cardiac death, cardiac transplantation, appropriate discharge of a defibrillator, stroke, myocardial infarction, or hospitalization for heart failure), and 41 patients had composite end points of hard or soft events (including atrial fibrillation and syncope). Exercise wall motion abnormalities occurred in 31.5% of patients with hard events compared with 5.9% of patients without hard events (P < .001). After adjustment, LV wall thickness (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.05-1.21; P = .002), resting wall motion score index (HR, 21.59; 95% CI, 2.38-196.1, P = .006), and metabolic equivalents (HR, 0.74; 95% CI, 0.63-0.88; P = .001) remained independent predictors of hard events. Change in wall motion score index was also independently associated with hard events (HR, 52.30; 95% CI, 3.81-718.5; P = .003) and with the composite end point (HR, 39.51; 95% CI, 3.79-412.4; P = .002). LVOT obstruction was not associated with either end point. Assessment of exercise capacity and LV systolic function during exercise echocardiography may have a role in risk stratification of patients with HCM.

Imaging Phenotype Versus Genotype in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common monogenetic cardiac disease with a prevalence of 0.2%1 that usually is inherited as an autosomal dominant trait with variable penetrance and expression. Clinically, HCM is defined by the presence of left ventricular (LV) hypertrophy (LVH) unexplained by abnormal loading conditions.1 The natural history varies from an asymptomatic course to drug-refractory angina/dyspnea, sudden cardiac death (SCD), and end-stage heart failure. The incidence of HCM-related SCD is approximately 1% to 2% in children and adolescents and 0.5% to 1% in adults.2,3 In this review, we examine the impact of advanced diagnostic imaging technologies on HCM, with particular emphasis on the detection of particular genetic subtypes. In ≈60% of cases, HCM is inherited as an autosomal dominant trait caused by mutations in genes coding for cardiac sarcomere proteins (Figure 1).4–7 Mutations in genes encoding Z-disc proteins and proteins involved in calcium regulation account for <5% of cases. The absence of sarcomeric gene mutations can be explained by limitations of current mutation detection techniques or mutations in as yet unidentified genes, but in some cases, hypertrophy is caused by other diseases that mimic the phenotype of sarcomeric protein disease. Table 1 lists genetic disorders associated with HCM. Figure 1. A schematic illustration of a cardiac sarcomere. View this table: Table 1. Currently Known Genes Implicated in HCM More than 600 different sarcomeric gene mutations are reported in patients with HCM.8–16 The majority are missense mutations, but nonsense, frameshift, and in-frame insertion/deletion mutations also occur. Most mutations are characterized by incomplete penetrance and variable clinical expression likely due to locus heterogeneity and the effect of mutations at different locations within the same gene. Most mutations probably have a dominant negative effect on sarcomere function, but in some cases, haploinsufficiency (ie, only a single functional …

Timing and Significance of Exercise-Induced Left Ventricular Outflow Tract Pressure Gradients in Hypertrophic Cardiomyopathy

The relation of exercise-induced left ventricular (LV) outflow tract obstruction to functional capacity in hypertrophic cardiomyopathy (HC) is incompletely defined. Thus, we assessed the patterns of onset of physiologically provoked LV outflow gradients and exercise performance in 74 consecutive patients with HC (age 45 ± 16 years; 74% men) without LV outflow obstruction at rest. The subaortic gradients were measured serially using echocardiography in these 74 patients during maximum, symptom-limited, upright bicycle exercise testing. The time course of the provoked gradients and the relation to exercise performance were assessed. Of the 74 patients, 30 (41%) developed a dynamic LV outflow gradient of ≥30 mm Hg (mean 78 ± 37 mm Hg) during upright exercise testing that correlated highly with the gradients measured with the patients supine during the immediate recovery period (R² = 0.97). The 16 patients in whom outflow obstruction developed rapidly at low exercise levels (≤5 METs) had a significantly reduced exercise capacity (6.1 ± 1.3 vs 8.0 ± 1.6 METs; p <0.01) compared to the other 14 patients in whom obstruction appeared later at greater exercise levels of >5 METs. The timing of the gradient onset was not predictable from the baseline clinical and echocardiographic features, peak exercise LV outflow tract gradient, or symptoms. In conclusion, in patients with HC without outflow obstruction at rest, the earlier onset of LV outflow tract gradients during physiologic exercise was associated with impaired exercise performance. These findings have provided insights into the determinants of functional impairment in HC and support the potential value of exercise echocardiography in the clinical assessment of patients with HC.

Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy

Background:Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical...

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is a fascinating disease entity in which hypertrophy of the myocardium occurs, primarily as a result of mutations of genes encoding the cardiac sarcomere.1–3 Our knowledge of patients with this unique disease of the heart muscle has advanced significantly. Once thought to be a rare malignant disease with a high risk of sudden death, population studies have revealed hypertrophic cardiomyopathy to be a more common disease with a benign outlook in the majority of affected patients.4 Hypertrophic cardiomyopathy is now recognized to comprise a wide spectrum of disease processes, with varying genetics, anatomy, clinical presentation, and prognosis. The dynamic left ventricular outflow tract obstruction that was initially the hallmark of hypertrophic cardiomyopathy continues to be a source of controversy. Article p 2232 The pathophysiology of hypertrophic cardiomyopathy is complex and still not completely understood. The first description of hypertrophic cardiomyopathy came in 1957 when Sir Russell Brock5 found a functional subvalvular obstruction in patients undergoing aortic valvotomy for clinically suspected valvular aortic stenosis. In 1958, Teare6 described the cardiac anatomy of 8 young patients who died suddenly with severe asymmetric left ventricular hypertrophy with bizarre muscle bundle orientation. In the 1960s, Braunwald et al7 defined a specific disease process in which asymmetric septal hypertrophy, myofibril disarray, and dynamic outflow tract obstruction were found. Thus, the early focus of hypertrophic cardiomyopathy was on this dynamic obstruction; the response of the obstruction to changes in preload, afterload, and contractility formed the basis for diagnosis. With the advent of echocardiography, which allowed direct visualization of the hypertrophied myocardium, it became apparent that obstruction was not necessary for the diagnosis of hypertrophic cardiomyopathy. The entire relationship of obstruction to hypertrophic cardiomyopathy was subsequently questioned. Some thought that hypertrophic cardiomyopathy was primarily a disease of diastole, with obstruction …