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Biventricular pacemaker therapy improves exercise capacity in patients with non-obstructive hypertrophic cardiomyopathy via augmented diastolic filling on exercise.

ABSTRACT: AIMS:Treatment options for patients with non-obstructive hypertrophic cardiomyopathy (HCM) are limited. We sought to determine whether biventricular (BiV) pacing improves exercise capacity in HCM patients, and whether this is via augmented diastolic filling. METHODS AND RESULTS:Thirty-one patients with symptomatic non-obstructive HCM were enrolled. Following device implantation, patients underwent detailed assessment of exercise diastolic filling using radionuclide ventriculography in BiV and sham pacing modes. Patients then entered an 8-month crossover study of BiV and sham pacing in random order, to assess the effect on exercise capacity [peak oxygen consumption (VO2 )]. Patients were grouped on pre-specified analysis according to whether left ventricular end-diastolic volume increased (+LVEDV) or was unchanged/decreased (-LVEDV) with exercise at baseline. Twenty-nine patients (20 male, mean age 55?years) completed the study. There were 14?+LVEDV patients and 15 -LVEDV patients. Baseline peak VO2 was lower in -LVEDV patients vs. +LVEDV patients (16.2?±?0.9 vs. 19.9?±?1.1 mL/kg/min, P = 0.04). BiV pacing significantly increased exercise ?LVEDV (P = 0.004) and ?stroke volume (P = 0.008) in -LVEDV patients, but not in +LVEDV patients. Left ventricular ejection fraction and end-systolic elastance did not increase with BiV pacing in either group. This translated into significantly greater improvements in exercise capacity (peak VO2 ?+?1.4 mL/kg/min, P = 0.03) and quality of life scores (P = 0.02) in -LVEDV patients during the crossover study. There was no effect on left ventricular mechanical dyssynchrony in either group. CONCLUSION:Symptomatic patients with non-obstructive HCM may benefit from BiV pacing via augmentation of diastolic filling on exercise rather than contractile improvement. This may be due to relief of diastolic ventricular interaction. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT00504647.

SUBMITTER: Ahmed I

PROVIDER: S-EPMC7540697 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Biventricular pacemaker therapy improves exercise capacity in patients with non-obstructive hypertrophic cardiomyopathy via augmented diastolic filling on exercise.

Ahmed Ibrar I Loudon Brodie L BL Abozguia Khalid K Cameron Donnie D Shivu Ganesh N GN Phan Thanh T TT Maher Abdul A Stegemann Berthold B Chow Anthony A Marshall Howard H Nightingale Peter P Leyva Francisco F Vassiliou Vassilios S VS McKenna William J WJ Elliott Perry P Frenneaux Michael P MP

European journal of heart failure 20200123 7

<h4>Aims</h4>Treatment options for patients with non-obstructive hypertrophic cardiomyopathy (HCM) are limited. We sought to determine whether biventricular (BiV) pacing improves exercise capacity in HCM patients, and whether this is via augmented diastolic filling.<h4>Methods and results</h4>Thirty-one patients with symptomatic non-obstructive HCM were enrolled. Following device implantation, patients underwent detailed assessment of exercise diastolic filling using radionuclide ventriculograph ...[more]

PMID: 31975494

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Project description:AIMS:Several mutations in the ventricular myosin regulatory light chain (RLC) were identified to cause familial hypertrophic cardiomyopathy (FHC). Based on our previous cellular findings showing delayed calcium transients in electrically stimulated intact papillary muscle fibres from transgenic Tg-R58Q and Tg-N47K mice and, in addition, prolonged force transients in Tg-R58Q fibres, we hypothesized that the malignant FHC phenotype associated with the R58Q mutation is most likely related to diastolic dysfunction. METHODS AND RESULTS:Cardiac morphology and in vivo haemodynamics by echocardiography as well as cardiac function in isolated perfused working hearts were assessed in transgenic (Tg) mutant mice. The ATPase-pCa relationship was determined in myofibrils isolated from Tg mouse hearts. In addition, the effect of both mutations on RLC phosphorylation was examined in rapidly frozen ventricular samples from Tg mice. Significantly, decreased cardiac function was observed in isolated perfused working hearts from both Tg-R58Q and Tg-N47K mice. However, echocardiographic examination showed significant alterations in diastolic transmitral velocities and deceleration time only in Tg-R58Q myocardium. Likewise, changes in Ca(2+) sensitivity, cooperativity, and an elevated level of ATPase activity at low [Ca(2+)] were only observed in myofibrils from Tg-R58Q mice. In addition, the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles. CONCLUSION:Our results suggest that the N47K and R58Q mutations may act through similar mechanisms, leading to compensatory hypertrophy of the functionally compromised myocardium, but the malignant R58Q phenotype is most likely associated with more severe alterations in cardiac performance manifested as impaired relaxation and global diastolic dysfunction. At the molecular level, we suggest that by reducing the phosphorylation of RLC, the R58Q mutation decreases the kinetics of myosin cross-bridges, leading to an increased myofilament calcium sensitivity and to overall changes in intracellular Ca(2+) homeostasis.

Dataset Information

Biventricular pacemaker therapy improves exercise capacity in patients with non-obstructive hypertrophic cardiomyopathy via augmented diastolic filling on exercise.

Publications

Biventricular pacemaker therapy improves exercise capacity in patients with non-obstructive hypertrophic cardiomyopathy via augmented diastolic filling on exercise.

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