Mechanism of Acute Mechanical Benefit From VDD Pacing in Hypertrophied Heart

Pak, Peter H.; Maughan, W L; Baughman, Kenneth L.; Kieval, Robert S.; Kass, David A.

doi:10.1161/01.cir.98.3.242

Cited by 85 publications

(9 citation statements)

References 33 publications

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“…The relatively low-force generating capacity of cardiomyocytes and the inability to increase force on an increase in sarcomere length may in part underlie cardiac dysfunction and initiate compensatory hypertrophy. Pak et al 68 showed a blunted end-systolic pressure volume relation in patients with HCM, suggesting that the hearts were unable to properly recruit preload to augment contractility. The latter observation may be explained by cardiac remodeling.…”

Section: Discussionmentioning

confidence: 99%

Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

Sequeira

Wijnker

Nijenkamp

et al. 2013

Circulation Research

180

204

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Rationale High-myofilament Ca2+-sensitivity has been proposed as trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) based on in vitro and transgenic mice studies. However, myofilament Ca2+-sensitivity depends on protein phosphorylation and muscle length, and at present, data in human are scarce. Objective To investigate whether high-myofilament Ca2+-sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick- and thin-filament proteins. Methods and Results Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca2+-sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA)-targets compared with donors. After exogenous PKA treatment, myofilament Ca2+-sensitivity was either similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. Conclusions High-myofilament Ca2+-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein–protein interactions, and represents a common pathomechanism in HCM.

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Section: Discussionmentioning

confidence: 99%

Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

Sequeira

Wijnker

Nijenkamp

et al. 2013

Circulation Research

180

204

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“…If anything, inducing dyssynchrony on purpose by single-site ventricular pacing was found to benefit a group of HFpEF patients with severe concentric LVH and end-systolic cavity obliteration. 165, 166 The rationale was that such patients have excessive contraction and generating dyssynchrony increases end-systolic volume at rest, building back in some reserve capacity during exercise.…”

Section: New Therapeutic Avenues For Hfpefmentioning

confidence: 99%

Heart Failure With Preserved Ejection Fraction

Sharma

Kass

2014

Circulation Research

Self Cite

428

227

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The clinical syndrome comprised of heart failure symptoms but with a left ventricular ejection fraction that is not diminished, e.g. heart failure with a preserved ejection fraction (HFpEF), is increasingly the predominant form of HF in the developed world, and soon to reach epidemic proportions. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common co-morbidities. Importantly, its morbidity and mortality is on par with heart failure and a reduced ejection fraction, and as the list of failed treatments continues to grow, HFpEF clearly represents a major unmet medical need. The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and re-direct our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists. Here, we review recent translational and clinical research into HFpEF, give perspectives on its evolving demographics and epidemiology, the role of multi-organ deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions.

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“…This relationship also predicts that those with a substantially increased ventricular mass, such as with hypertrophic cardiomyopathy, would have less curvilinear ESPDR due to low γ, which is consistent with the steep and more linear ESPVR reported in humans with a hypertrophic left ventricle. 28 With this model, we developed a new method for ESPDR determination from a single control beat. The method relied on the fact that the late systolic P-D loop and the ESPDR curve follow similar regression curves (figure 2).…”

Section: Discussionmentioning

confidence: 99%

Novel, single-beat approach for determining both end-systolic pressure–dimension relationship and preload recruitable stroke work

2016

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ObjectiveThe end-systolic pressure–dimension relationship (ESPDR) and the preload recruitable stroke work (PRSW) relationship are load-insensitive measures of contractility, but their clinical application has been limited by the need to record multiple beats over a wide volume range. In this study, we therefore sought to validate a new method to concomitantly determine the ESPDR and the PRSW relationship from a single beat.MethodsPressure–dimension loops were recorded in 14 conscious dogs under various haemodynamic and pathological conditions. Multiple-beat PRSW relationship was determined for its slope (Mw) and for a dimension-axis intercept (Dw). The ESPDR represented by the formula , was estimated from a steady-state, single-beat late-systolic pressure–dimension relationship. The single-beat Mw was determined as an end-systolic pressure when the end-systolic dimension was equal to Dw.ResultsA strong correlation was observed between multiple-beat and single-beat ESPDRs (zero-stress dimension; r=0.98, p<0.0001). The single-beat estimation of Mw calculated using the wall thickness was strongly correlated with the actual Mw (r=0.93, p<0.0001) and was sensitive enough to detect the change in contractility by dobutamine infusion (p<0.001) and by tachycardia-induced heart failure (p<0.001). Similar results were obtained for Mw estimated without information on wall thickness.ConclusionsMw can be interpreted as an end-systolic pressure when the end-systolic dimension is equal to Dw. By using the non-linear ESPDR, accurate single-beat estimation of the ESPDR and Mw is possible even without information on wall thickness. These results should enhance the applicability of pressure–volume framework to clinical medicine.

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Mechanism of Acute Mechanical Benefit From VDD Pacing in Hypertrophied Heart

Abstract: VDD pacing shifts the ESPVR rightward in HCM patients with cavity obliteration with or without obstruction, increasing end-systolic volumes and reducing apical cavity compression and cardiac work. These effects likely contribute to reduced metabolic demand and improved symptoms.

Cited by 85 publications

References 33 publications

Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations

Heart Failure With Preserved Ejection Fraction

Novel, single-beat approach for determining both end-systolic pressure–dimension relationship and preload recruitable stroke work

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