Energy Impairment With Exercise in Hypertrophic Cardiomyopathy
Energy Impairment With Exercise in Hypertrophic Cardiomyopathy
Aims. Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in the young, with an excess of exercise-related deaths. The HCM sarcomere mutations increase the energy cost of contraction and impaired resting cardiac energetics has been documented by measurement of phosphocreatine/ATP (PCr/ATP) using Phosphorus MR Spectroscopy (P MRS). We hypothesized that cardiac energetics are further impaired acutely during exercise in HCM and that this would have important functional consequences.
Methods and Results. P MRS was performed in 35 HCM patients and 20 age- and gender-matched normal volunteers at rest and during leg exercise with 2.5 kg ankle weights. Peak left-ventricular filling rates (PFRs) and myocardial perfusion reserve (MPRI) were calculated during adenosine stress. Resting PCr/ATP was significantly reduced in HCM (HCM: 1.71 ± 0.35, normal 2.14 ± 0.35 P < 0.0001). During exercise, there was a further reduction in PCr/ATP in HCM (1.56 ± 0.29, P = 0.02 compared with rest) but not in normals (2.16 ± 0.26, P = 0.98 compared with rest). There was no correlation between PCr/ATP reduction and cardiac mass, wall thickness, MPRI, or late-gadolinium enhancement. PFR and PCr/ATP were significantly correlated at rest (r = 0.48, P = 0.02) and stress (r = 0.53, P = 0.01).
Conclusion. During exercise, the pre-existing energetic deficit in HCM is further exacerbated independent of hypertrophy, perfusion reserve, or degree of fibrosis. This is in keeping with the change at the myofilament level. We offer a potential explanation for exercise-related diastolic dysfunction in HCM.
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is the commonest cause of sudden cardiac death in the young, including competitive athletes. Despite being a common genetic cardiomyopathy, determining disease progression and risk stratification remains a clinical dilemma. With the availability of therapeutic measures that prevent sudden death (i.e. implantable cardioverter defibrillators), the identification of high-risk patients is now of even greater importance. Abnormal myocardial energy utilization has been implicated in playing a crucial role in the pathophysiology of HCM.
Original predictions based on data from in vitro studies of recombinant proteins, supported by evidence from animal models and patients, including HCM phenocopies (i.e. an HCM-like phenotype) strongly support the energy depletion hypothesis as a unifying mechanism causing disease in HCM.
Cardiac P MRS is the only technique that allows non-invasive measurement of cardiac high-energy phosphate metabolism in vivo. Impaired energetics (decreased PCr/ATP-ratios) have been documented in genetically modified animal models of HCM; in both symptomatic and asymptomatic patients with clinical features of HCM; and in genotyped HCM patients without overt hypertrophy (mutation carriers). In support of a potentially reversible abnormality in energy metabolism in HCM, Abozguia et al. demonstrated that the metabolic modulator, perhexiline, improves cardiac energetics and diastolic dysfunction in HCM.
While all previous studies of cardiac energetics in HCM have been conducted at rest, an energetic deficit would be expected to worsen, or only become unmasked, when cardiac workload is increased, e.g. during exercise. Furthermore, it is conceivable that the high incidence of exercise-related death in HCM may be explained by a possible further acute impairment of myocardial energetic resulting in ion-pump dysfunction, calcium overload, and ventricular arrhythmias. However, cardiac energetics during exercise conditions have not been previously examined in patients with HCM. The measurement of P MRS during exercise is technically challenging due to increased susceptibility for contamination from surrounding structures coupled with an acceptable scan time needed to acquire sufficient data while exercising. We developed a P MRS acquisition which was short enough to facilitate scanning during exercise and which effectively addresses issues of contamination and signal distortion. Using this, we were able to test whether cardiac energetics are further impaired acutely during exercise in HCM, and evaluate the impact on cardiac function.
Abstract and Introduction
Abstract
Aims. Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in the young, with an excess of exercise-related deaths. The HCM sarcomere mutations increase the energy cost of contraction and impaired resting cardiac energetics has been documented by measurement of phosphocreatine/ATP (PCr/ATP) using Phosphorus MR Spectroscopy (P MRS). We hypothesized that cardiac energetics are further impaired acutely during exercise in HCM and that this would have important functional consequences.
Methods and Results. P MRS was performed in 35 HCM patients and 20 age- and gender-matched normal volunteers at rest and during leg exercise with 2.5 kg ankle weights. Peak left-ventricular filling rates (PFRs) and myocardial perfusion reserve (MPRI) were calculated during adenosine stress. Resting PCr/ATP was significantly reduced in HCM (HCM: 1.71 ± 0.35, normal 2.14 ± 0.35 P < 0.0001). During exercise, there was a further reduction in PCr/ATP in HCM (1.56 ± 0.29, P = 0.02 compared with rest) but not in normals (2.16 ± 0.26, P = 0.98 compared with rest). There was no correlation between PCr/ATP reduction and cardiac mass, wall thickness, MPRI, or late-gadolinium enhancement. PFR and PCr/ATP were significantly correlated at rest (r = 0.48, P = 0.02) and stress (r = 0.53, P = 0.01).
Conclusion. During exercise, the pre-existing energetic deficit in HCM is further exacerbated independent of hypertrophy, perfusion reserve, or degree of fibrosis. This is in keeping with the change at the myofilament level. We offer a potential explanation for exercise-related diastolic dysfunction in HCM.
Introduction
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is the commonest cause of sudden cardiac death in the young, including competitive athletes. Despite being a common genetic cardiomyopathy, determining disease progression and risk stratification remains a clinical dilemma. With the availability of therapeutic measures that prevent sudden death (i.e. implantable cardioverter defibrillators), the identification of high-risk patients is now of even greater importance. Abnormal myocardial energy utilization has been implicated in playing a crucial role in the pathophysiology of HCM.
Original predictions based on data from in vitro studies of recombinant proteins, supported by evidence from animal models and patients, including HCM phenocopies (i.e. an HCM-like phenotype) strongly support the energy depletion hypothesis as a unifying mechanism causing disease in HCM.
Cardiac P MRS is the only technique that allows non-invasive measurement of cardiac high-energy phosphate metabolism in vivo. Impaired energetics (decreased PCr/ATP-ratios) have been documented in genetically modified animal models of HCM; in both symptomatic and asymptomatic patients with clinical features of HCM; and in genotyped HCM patients without overt hypertrophy (mutation carriers). In support of a potentially reversible abnormality in energy metabolism in HCM, Abozguia et al. demonstrated that the metabolic modulator, perhexiline, improves cardiac energetics and diastolic dysfunction in HCM.
While all previous studies of cardiac energetics in HCM have been conducted at rest, an energetic deficit would be expected to worsen, or only become unmasked, when cardiac workload is increased, e.g. during exercise. Furthermore, it is conceivable that the high incidence of exercise-related death in HCM may be explained by a possible further acute impairment of myocardial energetic resulting in ion-pump dysfunction, calcium overload, and ventricular arrhythmias. However, cardiac energetics during exercise conditions have not been previously examined in patients with HCM. The measurement of P MRS during exercise is technically challenging due to increased susceptibility for contamination from surrounding structures coupled with an acceptable scan time needed to acquire sufficient data while exercising. We developed a P MRS acquisition which was short enough to facilitate scanning during exercise and which effectively addresses issues of contamination and signal distortion. Using this, we were able to test whether cardiac energetics are further impaired acutely during exercise in HCM, and evaluate the impact on cardiac function.