Sumanth D. Prabhu

β-Adrenergic Blockade in Developing Heart Failure Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling

Background—Whether β-adrenergic blockade modulates myocardial expression of inflammatory cytokines and nitric oxide (NO) in heart failure is unclear. Methods and Results—We administered oral metoprolol or no therapy to rats for 12 weeks after large myocardial infarction and subsequently examined left ventricular (LV) remodeling; myocardial tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 expression; and NO. In untreated rats, echocardiography revealed significant (P<0.001) LV dilatation and systolic dysfunction compared with sham. Papillary muscle studies revealed isoproterenol hyporesponsiveness to be unaltered by NO synthase (NOS) inhibition. Circulating NO metabolites were undetectable. In noninfarcted myocardium, although inducible NOS (iNOS) mRNA was absent, TNF-α, IL-1β, and IL-6 mRNA and protein were markedly elevated compared with sham (P<0.001), with 2-fold higher expression (P<0.025) of IL-6 compared with TNF-α or IL-1β. Metoprolol administration starting 48 hours after infarction (1...BACKGROUND Whether beta-adrenergic blockade modulates myocardial expression of inflammatory cytokines and nitric oxide (NO) in heart failure is unclear. METHODS AND RESULTS We administered oral metoprolol or no therapy to rats for 12 weeks after large myocardial infarction and subsequently examined left ventricular (LV) remodeling; myocardial tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 expression; and NO. In untreated rats, echocardiography revealed significant (P<0.001) LV dilatation and systolic dysfunction compared with sham. Papillary muscle studies revealed isoproterenol hyporesponsiveness to be unaltered by NO synthase (NOS) inhibition. Circulating NO metabolites were undetectable. In noninfarcted myocardium, although inducible NOS (iNOS) mRNA was absent, TNF-alpha, IL-1beta, and IL-6 mRNA and protein were markedly elevated compared with sham (P<0.001), with 2-fold higher expression (P<0.025) of IL-6 compared with TNF-alpha or IL-1beta. Metoprolol administration starting 48 hours after infarction (1) attenuated (P<0.02) LV dilatation and systolic dysfunction, (2) preserved isoproterenol responsiveness (P<0.025) via NO-independent mechanisms, and (3) reduced myocardial gene expression and protein production of TNF-alpha and IL-1beta (P<0. 025) but not IL-6, which remained high. CONCLUSIONS During heart failure development, adrenergic activation contributes to increased myocardial expression of TNF-alpha and IL-1beta but not IL-6, and one mechanism underlying the beneficial effects of beta-adrenergic blockade may involve attenuation of TNF-alpha and IL-1beta expression independent of iNOS and NO.

Chronic β-Adrenergic Stimulation Induces Myocardial Proinflammatory Cytokine Expression

BACKGROUND The sympathetic nervous system and proinflammatory cytokines are believed to play key roles in the pathophysiology of congestive heart failure. To evaluate a possible relationship between these neurohormonal systems, we studied the effects of chronic beta-adrenergic stimulation on the myocardial and systemic elaboration of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. METHODS AND RESULTS Male rats received either L-isoproterenol (2.4 mg. kg(-1). d(-1), n=8) or saline (n=7) via miniosmotic pumps for 7 days. Myocardial cytokine expression was analyzed by both Northern and Western blotting and localized in the tissue using immunohistochemistry. ELISA was performed to measure circulating levels of cytokines. In myocardium from control animals, neither TNF-alpha nor IL-1beta were detected, whereas IL-6 was present at very low levels. Isoproterenol led to a significant (P<0.01) increase in mRNA and protein expression of all 3 cytokines. Immunohistochemistry did not detect immunoreactivity for either cytokine in myocardium from controls; however, all 3 cytokines were readily detected (P<0.05) throughout the myocardium, localized to resident cells and vessels, in animals treated with isoproterenol. Neither treatment group had detectable levels of cytokines in the serum. CONCLUSIONS Chronic beta-adrenergic stimulation induces myocardial, but not systemic, elaboration of TNF-alpha, IL-1beta, and IL-6.

Effect of Tachycardia Heart Failure on the Restitution of Left Ventricular Function in Closed-Chest Dogs

BACKGROUND Cardiac mechanical restitution and relaxation restitution are thought to be physiological correlates of the recovery kinetics of Ca2+ release mechanisms and sequestration capacity of the sarcoplasmic reticulum (SR). Since congestive heart failure is characterized by abnormal intracellular Ca2+ handling, we sought to delineate changes in mechanical and relaxation restitution produced by heart failure. METHODS AND RESULTS Six dogs instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied under control conditions and after tachycardia heart failure (THF) produced by rapid LV pacing for 3 to 4 weeks. After priming at a basic cycle length of 375 ms, test pulses were delivered at graded extrasystolic intervals (ESIs). Mechanical response was assessed from single-beat elastance. Relaxation was assessed from the time constant of isovolumic relaxation (tau), the average rate of pressure fall during isovolumic relaxation (Ravg), and peak negative dP/dt, the first derivative of LV pressure. Normalized mechanical and relaxation responses plotted against ESI produced monoexponential curves of mechanical and relaxation restitution. THF depressed baseline contractile and relaxation parameters compared with control (end-systolic elastance, 4.7 +/- 0.4 versus 7.1 +/- 0.5 mm Hg/mL, P < .005; tau, 34.8 +/- 2.2 versus 26.7 +/- 1.2 ms, P < .05; all values mean +/- SEM). THF slowed mechanical restitution and delayed development of peak contractile response, with the time constant of mechanical restitution increasing from 61.8 +/- 6.9 to 100.2 +/- 9.6 ms, P < .01. THF abolished the biphasic behavior of relaxation restitution, and this relation was approximated by a single monoexponential function. There was no difference in the time constants of the first phase of relaxation restitution at control and after THF (TCR1, normalized 1/Ravg, 44.3 +/- 5.6 versus 42.0 +/- 8.5 ms, P = NS; TCR1, normalized (dP/dtmin)-1, 42.2 +/- 6.3 versus 36.7 +/- 4.3 ms, P = NS). CONCLUSIONS These results indicate that THF alters the recovery kinetics of SR Ca2+ release to a significantly greater extent than those of SR Ca2+ sequestration and that the abnormal time course of Ca2+ availability to the myofilaments is the rate-limiting step in the recovery of cardiac function after a depolarization.

Postextrasystolic Mechanical Restitution in Closed-Chest Dogs Effect of Heart Failure

BACKGROUND Postextrasystolic mechanical restitution (MRPES) is thought to be an expression of intracellular Ca2+ handling by cardiac sarcoplasmic reticulum (SR). Since congestive heart failure is characterized by abnormal intracellular Ca2+ homeostasis, we sought to delineate MRPES behavior before and after the production of heart failure to obtain insights into the relation between altered mechanical performance and Ca2+ handling. METHODS AND RESULTS Ten dogs instrumented with left ventricular (LV) micromanometers and piezoelectric dimension crystals were studied under control conditions; 6 dogs also were studied after tachycardia heart failure (THF) produced by rapid LV pacing for 4 weeks. After priming at a basic cycle length of 375 ms, test pulses were delivered at fixed extrasystolic intervals (ESIs; 300, 375, or 450 ms) and graded postextrasystolic intervals (PESIs). Postextrasystolic mechanical response was assessed using single-beat elastance. MRPES curves were constructed by expressing normalized mechanical response as a function of the PESI. Control MRPES was a monoexponential function whose time constant (TC) and PESI-axis intercept (PESI0) increased significantly (P < .01) with increases in the antecedent ESI. THF significantly slowed MRPES kinetics at each antecedent ESI (P < .025), increased normalized maximal contractile response (CRmax, P < .01), and shortened PESI0 (P < .025). Increases in the TC and CRmax were most pronounced with the smallest antecedent ESI (percent control postextrasystolic TC 363.7 +/- 60.5%, ESI of 300 ms versus 139.0 +/- 15.1%, ESI of 450 ms, P < .005; percent control CRmax 128.6 +/- 4.9%, ESI of 300 ms versus 104.9 +/- 1.0%, ESI of 450 ms; P < .005). CONCLUSIONS MRPES is much less dynamic in THF: The failing heart operates at lower levels of contractile performance after higher stimulation frequencies and cannot increase its speed of contractile recovery to compensate for higher heart rate. Prolongation of MRPES kinetics is consistent with depression of SR Ca2+ release mechanisms in THF and implicates this site in the loss of the capacity of the failing heart to maintain mechanical performance with tachycardia.

Syncope: Current diagnosis and treatment

The patient with syncope often poses a formidable diagnostic challenge. A large number of underlying causes must be considered, ranging in severity from benign to life-threatening. A careful, systematic clinical evaluation beginning with a history, physical examination, and ECG will establish the diagnosis in most patients, and the judicious use of specialized testing will confirm or uncover the cause in many of the remaining cases. Further basic and clinical research into the pathogenesis and treatment of neurocardiogenic syncope, the role of HUT testing in neurally mediated syncope, and the optimal use of EPS in patients with cardiac disease will markedly improve our management of these patients in the future.

Hemodynamic effects of nitric oxide synthase inhibition at steady state and following tumor necrosis factor-α-induced myodepression

OBJECTIVE Nitric oxide (NO) has been proposed as a common mediator of tumor necrosis factor-alpha (TNF alpha)-induced vasodilation and myocardial dysfunction. Accordingly, we performed an extensive assessment of the influence of NO synthase inhibition on left ventricle (LV) and circulatory performance in conscious dogs at steady state and after establishment of TNF alpha mediated myodepression. METHODS Autonomically blocked, chronically instrumented dogs were studied at steady state and 6 h after initiation of a 1-h rhTNF alpha infusion (40 micrograms/kg). Ventricular performance was evaluated using the pressure-volume framework. Dogs were then treated with either NG-nitro-L-arginine methylester (L-NAME, 40 mg/kg bolus) or angiotensin II (250-500 ng/kg). RESULTS L-NAME, under control conditions or following recombinant human (rh) TNF alpha-induced ventricular dysfunction, produced marked increases in afterload with attendant increases in LV pressure, volume, and prolonged isovolumic relaxation without adversely influencing coronary blood flow. regardless of whether the dogs received rhTNF alpha, L-NAME did not affect the slopes of the end-systolic pressure-volume and stroke-work (SW)-end-diastolic volume (EDV) relations (force-based measure of contractility), whereas the slope of the dP/dtmax-EDV relation, a velocity dependent parameter of LV systolic function, declined. Overall ventricular performance, as seen by the circulation, was reduced by L-NAME in control as well as rhTNF alpha-treated dogs, evidenced by rightward shifts of the SW-EDV and dP/dtmax-EDV relations. Similar findings were observed in the separate cohorts of dogs, at steady state and 6 h after rhTNF alpha, following angiotensin II at matched systolic pressure. CONCLUSIONS Systemic NO synthase inhibition with L-NAME does not acutely reverse rhTNF alpha-induced myocardial dysfunction. The detrimental influence of L-NAME on LV size, relaxation, and velocity-based measures of contractility is likely attributable to its effects on increasing afterload.

Observations on the Relation of PVA and MVO2 in Closed Chest Dogs

Energy utilization is a key process underlying all cellular function. In excitable contractile tissue, such as the myocardium, energy use is particularly important since the mechanical work performed requires a high rate of energy consumption. In addition to routine needs for basal metabolism and maintenance of transmembrane gradients, cardiac tissue requires energy to support beat-to-beat cyclical calcium movement, and to allow contractile elements to generate force and to shorten. In the absence of sufficient energy, cardiac performance deteriorates rapidly.