Biomedical subjects

Robert H Helm

Publications and source records attributed to Robert H Helm.

3 recordsLinked to original sources

PubMed2005

Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts.

BACKGROUND: Cardiac dyssynchrony due to intraventricular conduction delay produces heterogeneous regional wall stress and worsens arrhythmia susceptibility in failing hearts. We examined whether chronic dyssynchrony per se induces regionally heterogeneous electrophysiological remodeling. METHODS AND RESULTS: Adult dogs (n=9) underwent left bundle branch radiofrequency ablation (QRS duration increased from 50+/-7 to 104+/-7 ms); 6 untreated dogs served as controls. A subset of ablated (n=3) and control (n=4) dogs underwent tagged MR imaging to confirm ablation-induced left ventricular (LV) dyssynchrony. Four weeks later, hearts were excised and early (anterior)- and late (lateral)-activated myocardial segments were isolated. Conduction velocity (CV), action potential duration (APD), and refractory period (RP) of paced, arterially perfused myocardial wedges were studied by extracellular and optical mapping, and arrhythmia susceptibility was assessed by programmed stimulation. Regional stress-response kinase, calcium cycling, and gap junction protein expression were assayed by Western blotting, and the subcellular distribution of connexin43 was analyzed by immunofluorescence microscopy. CV, APD, and RP were significantly reduced in the late-activated, lateral wall of dyssynchronous hearts compared to the anterior wall. Normal differences in CV (endocardial>epicardial) were reversed in the dyssynchronous lateral LV. While the total expression of connexin43 was unaltered in dyssynchronous models, its subcellular location was redistributed in late-activated myocardium from intercalated discs to lateral myocyte membranes. Arrhythmias were rare in tissue from normal and dyssynchronous models. Total expression of calcium-cycling proteins (sarcoplasmic reticulum Ca2+-ATPase and phospholamban) and the stress-response kinase phospho-ERK did not vary regionally in either model. CONCLUSIONS: Dyssynchrony even in the absence of LV dysfunction induces regionally specific changes in conduction and repolarization. These changes support a novel mechanism linking mechanical dyssynchrony to persistent electrophysiological remodeling and heterogeneity.

Action Potentials↗

PubMed2005

Cardiac dyssynchrony analysis using circumferential versus longitudinal strain: implications for assessing cardiac resynchronization.

BACKGROUND: QRS duration is commonly used to select heart failure patients for cardiac resynchronization therapy (CRT). However, not all patients respond to CRT, and recent data suggest that direct assessments of mechanical dyssynchrony may better predict chronic response. Echo-Doppler methods are being used increasingly, but these principally rely on longitudinal motion (epsilonll). It is unknown whether this analysis yields qualitative and/or quantitative results similar to those based on motion in the predominant muscle-fiber orientation (circumferential; epsiloncc). METHODS AND RESULTS: Both epsilonll and epsiloncc strains were calculated throughout the left ventricle from 3D MR-tagged images for the full cardiac cycle in dogs with cardiac failure and a left bundle conduction delay. Dyssynchrony was assessed from both temporal and regional strain variance analysis. CRT implemented by either biventricular (BiV) or left ventricular-only (LV) pacing enhanced systolic function similarly and correlated with improved dyssynchrony based on epsiloncc-based metrics. In contrast, longitudinal-based analyses revealed significant resynchronization with BiV but not LV for the overall cycle and correlated poorly with global functional benefit. Furthermore, unlike circumferential analysis, epsilonll-based indexes indicated resynchronization in diastole but much less in systole and had a lower dynamic range and higher intrasubject variance. CONCLUSIONS: Dyssynchrony assessed by longitudinal motion is less sensitive to dyssynchrony, follows different time courses than those from circumferential motion, and may manifest CRT benefit during specific cardiac phases depending on pacing mode. These results highlight potential limitations to epsilonll-based analyses and support further efforts to develop noninvasive synchrony measures based on circumferential deformation.

Animals↗

PubMed2004

Calcitonin gene-related peptide in vivo positive inotropy is attributable to regional sympatho-stimulation and is blunted in congestive heart failure.

Calcitonin gene-related peptide (CGRP) is a nonadrenergic/noncholinergic (NANC) peptide with vasodilatative/inotropic action that may benefit the failing heart. However, precise mechanisms for its in vivo inotropic action remain unclear. To assess this, dogs with normal or failing (sustained tachypacing) hearts were instrumented for pressure-dimension analysis. In control hearts, CGRP (20 pmol/kg per minute) enhanced cardiac contractility (eg, +33+/-4.2% in end-systolic elastance) and lowered afterload (-14.2+/-2% in systemic resistance, both P<0.001). The inotropic response was markedly blunted by heart failure (+6.5+/-2%; P<0.001 versus control), whereas arterial dilation remained unaltered (-19.3+/-5%). CGRP-positive inotropy was not attributable to reflex activation because similar changes were observed in the presence of a ganglionic blocker. However, it was fully prevented by the beta-receptor antagonist (timolol), identifying a dominant role of sympatho-stimulatory signaling. In control hearts, myocardial interstitial norepinephrine assessed by microdialysis almost doubled in response to CGRP infusion, whereas systemic plasma levels were unchanged. In addition, CGRP receptors were not observed in ventricular myocardium but were prominent in coronary arteries and the stellate ganglia. Ventricular myocytes isolated from normal and failing hearts displayed no inotropic response to CGRP, further supporting indirect sympatho-stimulation as the primary in vivo mechanism. In contrast, the peripheral vasodilatative capacity of CGRP was similar in femoral vascular rings from normal and failing hearts in dogs. Thus, CGRP-mediated positive inotropy is load-independent but indirect and attributable to myocardial sympathetic activation rather than receptor-coupled stimulation in canine hearts. This mechanism is suppressed in heart failure, so that afterload reduction accounts for CGRP-enhanced function in this setting.

Adrenergic beta-Agonists↗