Richard S. Tunin

Systolic Improvement and Mechanical Resynchronization Does Not Require Electrical Synchrony in the Dilated Failing Heart With Left Bundle-Branch Block

Background—Biventricular (BiV) and left ventricular (LV) pacing similarly augment systolic function in left bundle-branch block (LBBB)-failing hearts despite different electrical activation. We tested whether electrical synchrony is required to achieve mechanical synchronization and functional benefit from pacing. Methods and Results—Epicardial mapping, tagged MRI, and hemodynamics were obtained in dogs with LBBB-failing hearts during right atrial, LV, and BiV stimulation. BiV and LV both significantly improved chamber hemodynamics (eg, 25% increase in dP/dtmax and aortic pulse pressure) compared with atrial pacing-LBBB, and this improvement correlated with mechanical resynchronization. Electrical dispersion, however, decreased 13% with BiV but increased 23% with LV pacing (P <0.01). Conclusion—Improved mechanical synchrony and function do not require electrical synchrony. Mechanical coordination plays the dominant role in global systolic improvement with either pacing approach.

Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle.

This study tests the hypothesis that arterial vascular stiffening adversely influences in situ left ventricular contractile function and energetic efficiency. Ten reflex-blocked anesthetized dogs underwent a bypass operation in which a Dacron graft was sewn to the ascending aorta and connected to the infrarenal abdominal aorta via a plastic conduit. Flow was directed through either native aorta or plastic conduit by placement of vascular clamps. Arterial properties were measured from aortic pressure-flow data, and ventricular function was assessed by pressure-volume (PV) relations. Coronary sinus blood was drained via an extracorporeal circuit for direct measurement of myocardial O2 consumption (MVO2). Data at multiple steady-state preload volumes were combined to derive chamber function and energetics relations. Energetic efficiency was assessed by the inverse slope of the MVO2-PV area relation. Directing flow through plastic versus native aorta resulted in a 60-80% reduction in compliance but little change in mean resistance. Arterial pulse pressure rose from 34 to 99 mm Hg (p less than 0.001). Contractile function assessed by the end-systolic PV relation, stroke work-end-diastolic volume relation, and dP/dtmax at matched end-diastolic volume did not significantly change. However, MVO2 increased by 32% (p less than 0.01) and was matched by a rise in PV area, such that the MVO2-PV area relation and efficiency was unaltered. The MVO2 required to sustain a given stroke volume, however, increased from 20% to 40%, depending on the baseline level (p less than 0.001). Thus, whereas the contractile function and efficiency of normal hearts are not altered by ejection into a stiff vascular system, the energetic cost to the heart for maintaining adequate flow is increased. This suggests a mechanism whereby human vascular stiffening may yield little functional decrement at rest but limit reserve capacity under conditions of increased demand.

Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy

Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias. Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (>20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by >40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (P<0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (P<0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (P=0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF.

Regional alterations in protein expression in the dyssynchronous failing heart.

Background—Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. Methods and Results—Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial–paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. Conclusions—LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.

Intravenous Allopurinol Decreases Myocardial Oxygen Consumption and Increases Mechanical Efficiency in Dogs With Pacing-Induced Heart Failure

Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (n=10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt)(max) increased from 3103+/-162 to 3373+/-225 mm Hg/s (+8.3+/-3.2%; P=0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (n=5), this effect was larger; (dP/dt)(max) rose from 1602+/-190 to 1988+/-251 mm Hg/s (+24.4+/-8.7%; P=0.03), preload-recruitable stroke work increased from 55.8+/-9.1 to 84. 9+/-12.2 mm Hg (+28.1+/-5.3%; P=0.02), and ventricular elastance rose from 6.0+/-1.6 to 10.5+/-2.2 mm Hg/mm (P=0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49+/-4.6%; P=0. 002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; +122+/-42%; P=0.04). Moreover, xanthine oxidase activity was approximately 4-fold increased in failing versus control dog hearts (387+/-125 versus 78+/-72 pmol/min. mg(-1); P=0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure.

Three-Dimensional Mapping of Optimal Left Ventricular Pacing Site for Cardiac Resynchronization

Background— The efficacy of cardiac resynchronization therapy (CRT) depends on placement of the left ventricular lead within the late-activated territory. The geographic extent and 3-dimensional distribution of left ventricular (LV) locations yielding optimal CRT remain unknown. Methods and Results— Normal or tachypacing-induced failing canine hearts made dyssynchronous by right ventricular free wall pacing or chronic left bundle-branch ablation were acutely instrumented with a nonconstraining epicardial elastic sock containing 128 electrodes interfaced with a computer-controlled stimulation/recording system. Biventricular CRT was performed using a fixed right ventricular site and randomly selected LV sites covering the entire free wall. For each LV site, global cardiac function (conductance catheter) and mechanical synchrony (magnetic resonance imaging tagging) were determined to yield 3-dimensional maps reflecting CRT impact. Optimal CRT was achieved from LV lateral wall sites, slightly more anterior than posterior and more apical than basal. LV sites yielding ≥70% of the maximal dP/dtmax increase covered ≈43% of the LV free wall. This distribution and size were similar in both normal and failing hearts. The region was similar for various systolic and diastolic parameters and correlated with 3-dimensional maps based on mechanical synchrony from magnetic resonance imaging strain analysis. Conclusions— In hearts with delayed lateral contraction, optimized CRT is achieved over a fairly broad area of LV lateral wall in both nonfailing and failing hearts, with modest anterior or posterior deviation still capable of providing effective CRT. Sites selected to achieve the most mechanical synchrony are generally similar to those that most improve global function, confirming a key assumption underlying the use of wall motion analysis to optimize CRT.

Repolarization Abnormalities, Arrhythmia and Sudden Death in Canine Tachycardia-Induced Cardiomyopathy☆

OBJECTIVESnThis study sought to determine whether the canine model of tachycardia-induced heart failure (HF) is an effective model for sudden cardiac death (SCD) in HF.nnnBACKGROUNDnSuch a well established HF model that also exhibits arrhythmias and SCD, along with repolarization abnormalities that could trigger them, may facilitate the study of SCD in HF, which still eludes effective treatment.nnnMETHODSnTwenty-five dogs were VVI-paced at 250 beats/min for 3 to 5 weeks. Electrocardiograms were obtained, and left ventricular endocardial monophasic action potentials (MAPs) were recorded at six sites at baseline and after HF. Weekly Holter recordings were made with pacing suspended for 24 h.nnnRESULTSnSix animals (24%) died suddenly, one with Holter-documented polymorphic ventricular tachycardia (VT). Holter recordings revealed an increased incidence of VT as HF progressed. Repolarization was significantly (p < 0.05) prolonged, as indexed by a corrected QT interval (mean [+/-SD] 311 +/- 25 to 338 +/- 25 ms) and MAP duration measured at 90% repolarization (MAPD90) (181 +/- 19 to 209 +/- 28 ms), and spatial MAPD90 dispersion rose by 40%. We further tested whether CsCl inhibition of repolarizing K+ currents, which are reportedly downregulated in HF, might preferentially prolong the MAPD90 in HF. With 1 mEq/kg body weight of CsCl, MAPD90 rose by 86 +/- 100 ms in dogs with HF versus only 28 +/- 16 ms in control animals (p = 0.002). Similar disparities in CsCl sensitivity were observed in myocytes isolated from normal and failing hearts.nnnCONCLUSIONSnTachycardia-induced HF exhibits malignant arrhythmia and SCD, along with prolonged, heterogeneous repolarization and heightened sensitivity to CsCl at chamber and cellular levels. Thus, it appears to be a useful model for studying mechanisms and therapy of SCD in HF.

Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure

OBJECTIVESnWe sought to test the efficacy of a passive elastic containment device to reverse chronic chamber remodeling and adrenergic down-regulation in the failing heart, yet still maintaining preload reserve.nnnBACKGROUNDnProgressive cardiac remodeling due to heart failure is thought to exacerbate underlying myocardial dysfunction. In a pressure-volume analysis, we tested the impact of limiting progressive cardiac dilation by an externally applied passive containment device on both basal and adrenergic-stimulated function in failing canine hearts.nnnMETHODSnIschemic dilated cardiomyopathy was induced by repeated intracoronary microembolizations in six dogs. The animals were studied before and three to six months after surgical implantation of a thin polyester mesh (cardiac support device [CSD]) that surrounded both cardiac ventricles. Pressure-volume relations were measured by a conductance micromanometer catheter.nnnRESULTSnLong-term use of the CSD lowered end-diastolic and end-systolic volumes by -19 +/- 4% and -22 +/- 8%, respectively (both p < 0.0001) and shifted the end-systolic pressure-volume relation to the left (p < 0.01), compatible with reverse remodeling. End-diastolic pressure and chamber diastolic stiffness did not significantly change. The systolic response to dobutamine markedly improved after CSD implantation (55 +/- 8% rise in ejection fraction after CSD vs. -10 +/- 8% before CSD, p < 0.05), in conjunction with a heightened adenylyl cyclase response to isoproterenol. There was no change in the density or affinity of beta-adrenergic receptors. Diastolic compliance was not adversely affected, and preload-recruitable function was preserved with the CSD, consistent with a lack of constriction.nnnCONCLUSIONSnReverse remodeling with reduced systolic wall stress and improved adrenergic signaling can be achieved by passive external support that does not generate diastolic constriction. This approach may prove useful in the treatment of chronic heart failure.

Adverse Influence of Systemic Vascular Stiffening on Cardiac Dysfunction and Adaptation to Acute Coronary Occlusion

BACKGROUNDn[corrected] Age is an independent risk factor for increased mortality from ischemic heart disease. Arterial stiffening with widening of the pulse pressure may contribute to this risk by exacerbating cardiac dysfunction after total coronary artery occlusion.nnnMETHODS AND RESULTSnTo test the above hypothesis, 14 open-chest dogs underwent surgery in which the intrathoracic aorta was bypassed with a stiff plastic tube. Directing ventricular outflow through the bypass widened the arterial pulse pressure from 41 to 115 mm Hg at similar mean pressure and flow. Hearts ejecting into the native aorta (NA) exhibited only modest dysfunction after two minutes of mid-left anterior descending coronary artery occlusion. However, the same occlusion applied during ejection into the bypass tube (BT) induced far more severe cardiodepression (ie, systolic pressure fell by -41+/-10 mm Hg for BT versus -15+/-3 mm Hg for NA, and end-systolic volume rose by 15+/-3 versus 6+/-2 mL), with a threefold greater decline in ejection fraction. This disparity was not due to higher baseline work loads because total pressure-volume area was similar in both cases. Furthermore, marked increases in basal work load and wall stress induced by angiotensin II infusion (in four additional studies) did not reproduce this behavior. Although peak systolic chamber stress was greater with the BT, this did not increase systolic dyskinesis as measured in the central ischemic zone. However, the total mass of myocardium that was rendered severely ischemic (ie, flow reduced by > or = 80%) was twice as large with BT ejection, likely expanding the region of dyskinesis. This disparity may relate to altered phasic coronary flow during BT ejection, which displays marked enhancement of systolic flow and renders the heart more vulnerable to diminished mean and systolic perfusion pressures.nnnCONCLUSIONSnCardiac ejection into a stiff systemic vasculature augments cardiac dysfunction and ischemia due to coronary occlusion by tightening the link between cardiac systolic performance and myocardial perfusion. This may contribute to the higher mortality risk from ischemic heart disease due to age.

Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization

Background— Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. Methods and Results— Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (−4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-&agr; increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1&agr;, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3&agr; and GSK3&bgr;) were more phosphorylated in DHF than CRT and thus less involved. Conclusions— CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.