Administration of a tumor necrosis factor inhibitor at the time of myocardial infarction attenuates subsequent ventricular remodeling.

BACKGROUND: Tumor necrosis factor (TNF) causes myocardial extracellular matrix remodeling and fibrosis in myocardial infarction and chronic heart failure models. Pre-clinical and clinical trials of TNF inhibition in chronic heart failure have shown conflicting results. This study examined the effects of the administration of a TNF inhibitor immediately after myocardial infarction on the development of heart failure. METHODS: Lewis rats underwent coronary artery ligation and then received either intravenous etanercept (n = 14), a soluble dimerized TNF receptor that inhibits TNF, or saline as control (n = 13). Leukocyte infiltration into the infarct borderzone was evaluated 4 days post-ligation in 7 animals (etanercept = 4, control = 3). After 6 weeks, the following parameters were evaluated in the remaining animals: cardiac function with a pressure-volume conductance catheter, left ventricular (LV) geometry, and borderzone collagenase activity. RESULTS: Etanercept rats had significantly less borderzone leukocyte infiltration 4 days post-infarction than controls (10.7 +/- 0.5 vs 18.0, +/-2.0 cells/high power field; p < 0.05). At 6 weeks, TNF inhibition resulted in significantly reduced borderzone collagenase activity (110 +/- 30 vs 470 +/- 140 activity units; p < 0.05) and increased LV wall thickness (2.1 +/- 0.1 vs 1.8 +/- 0.1 mm, p < 0.05). Etanercept rats had better systolic function as measured by maximum LV pressure (84 +/- 3 mm Hg vs 68 +/- 5 mm Hg, p < 0.05) and the maximum change in left ventricular pressure over time (maximum dP/dt) (3,110 +/- 230 vs 2,260 +/- 190 mm Hg/sec, p < 0.05), and better diastolic function as measured by minimum dP/dt (-3,060 +/- 240 vs -1,860 +/- 230 mm Hg/sec; p < 0.05) and the relaxation time constant (14.6 +/- 0.6 vs 17.9 +/- 1.2 msec; p < 0.05). CONCLUSIONS: TNF inhibition after infarction reduced leukocyte infiltration and extracellular matrix turnover and preserved cardiac function.     

Left stellate ganglion block has only small effects on left ventricular function in awake dogs before and after induction of heart failure

Left stellate ganglion block (LSGB) results in acute sympathetic denervation of the left ventricular (LV) posterobasal wall. We investigated the effects of LSGB in chronically instrumented awake dogs before and after the induction of pacing-induced congestive heart failure. Twelve dogs were instrumented for measurement of global hemodynamics [LV pressure (LVP)], its first derivative (dP/dt), cardiac output (CO), and regional myocardial function (systolic posterobasal segment length shortening, mean velocity [SLmv]). Before the induction of heart failure (n = 12), LSGB did not affect CO [3.2+/-1.4 (control, mean +/- SD) vs. 3.3+/-1.6 L/min (LSGB, P = 0.45)] and SLmv (11.1+/-4.0 vs. 10.8+/-4.0 mm/s, P = 0.16), but slightly reduced LVP (130+/-12 vs. 125+/-14 mm Hg, P = 0.04), dP/dt(max) (3614+/-755 vs. 3259+/-644 mm Hg/s, P = 0.003) and dP/dt(min) (-3153+/-663 vs. -2970+/-725 mm Hg/s, P = 0.03). During heart failure (n = 8), global hemodynamics [CO (2.8+/-1.2 vs. 2.7+/-1.2 L/min, P = 0.04), LVP (119+/-6 vs. 112+/-9 mm Hg, P = 0.01), dP/dt(max) (1945+/-520 vs. 1824+/-554 mm Hg/s, P = 0.03) and dP/dt(min) (-2402+/-678 vs. -2243+/-683 mm Hg/s, P = 0.04)], as well as regional myocardial function, were significantly different after LSGB [SLmv] (8.0+/-3.8 vs. 6.9+/-3.4 mm/s, P = 0.02)]. In conclusion, even during heart failure, the hemodynamic changes after LSGB are small, confirming its broad margin of safety.     

Left ventricular reshaping: effects on the pressure-volume relationship

OBJECTIVE: We tested whether the CardioClasp device (CardioClasp, Inc, Cincinnati, Ohio), a non-blood contact device, would improve left ventricular contractility by acutely reshaping the left ventricle and reducing left ventricular wall stress. METHODS: In dogs (n = 6) 4 weeks of ventricular pacing (210-240 ppm) induced severe heart failure. Left ventricular function was evaluated before and after placement of the CardioClasp device, which uses 2 indenting bars to reshape the left ventricle. Hemodynamics, echocardiography, and Sonometrics crystals dimension (Sonometrics Corporation, London, Ontario, Canada) were measured at steady state and during inferior vena caval occlusion. RESULTS: The CardioClasp device decreased the left ventricular end-diastolic anterior-posterior dimension by 22.8% +/- 1.9%, decreased left ventricular wall stress from 97.3 +/- 22.8 to 67.2 +/- 7.7 g/cm(2) (P =.003), and increased the fractional area of contraction from 21.3% +/- 10.5% to 31.3% +/- 18.1% (P =.002). The clasp did not alter left ventricular end-diastolic pressure, left ventricular pressure, left ventricular dP/dt, or cardiac output. With the CardioClasp device, the slope of the end-systolic pressure-volume relationship was increased from 1.87 +/- 0.47 to 3.22 +/- 1.55 mm Hg/mL (P =.02), the slope of preload recruitable stroke work versus end-diastolic volume was increased from 28.4 +/- 11.0 to 44.1 +/- 23.5 mm Hg (P =.02), and the slope of maximum dP/dt versus end-diastolic volume was increased from 10.6 +/- 4.6 to 18.6 +/- 7.4 mm Hg x s(-1) x mL(-1) (P =.01). The CardioClasp device increased the slope of the end-systolic pressure-volume relationship by 68.0% +/- 21.7%, the slope of preload recruitable stroke work versus end-diastolic volume by 50.7% +/- 18.1%, and the slope of maximum dP/dt versus end-diastolic volume by 85.7% +/- 28.9%. CONCLUSIONS: The CardioClasp device decreased left ventricular wall stress and increased the fractional area of contraction by reshaping the left ventricle. The CardioClasp device was able to maintain cardiac output and arterial pressure. The clasp increased global left ventricular contractility by increasing the slope of the end-systolic pressure-volume relationship, the slope of preload recruitable stroke work versus end-diastolic volume, and the slope of maximum dP/dt versus end-diastolic volume. In patients with heart failure, the CardioClasp device might be effective for clinical application.     

Toward a better understanding of the etiology of left ventricular dysfunction after mitral valve replacement: an experimental study with possible clinical implications

The relatively high morbidity and mortality of mitral valve replacement (MVR) appears to be related to an impairment in left ventricular (LV) function. This two-part investigation was designed to assess the effect of MVR on global LV function in an isolated heart preparation and to evaluate whether a mitral prosthesis with a flexible annulus would be of benefit. In Part I (14 pigs), the effects of each step in MVR were studied. Division of the chordae tendineae caused a severe deterioration in LV function (systolic pressure, 180 +/- 13 versus 120 +/- 10 mm Hg; p less than 0.05; developed pressure, 167 +/- 13 versus 108 +/- 11 mm Hg; p less than 0.05; first derivative of LV pressure [dP/dt], 2,630 +/- 300 versus 1,610 +/- 180 mm Hg/sec; p less than 0.05; balloon volume, 30 ml). Fixation of the mitral annulus prior to division of the chordae tendineae resulted in a small decrease (not significant) in LV function but had no effect after the chordae tendineae were divided. In Part II (10 pigs), two mitral annular prostheses were studied: a standard rigid prosthesis and a prosthesis of identical size but with a flexible annulus. LV function was better with the flexible than the rigid prosthesis (systolic pressure, 118 +/- 10 versus 89 +/- 5% control, p less than 0.02; developed pressure, 120 +/- 11 versus 87 +/- 5% control; p less than 0.02; dP/dt, 119 +/- 10 versus 85 +/- 4% control; p less than 0.02; balloon volume, 30 ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced functional recovery with venting during cardioplegic arrest in chronically damaged hearts

Thirty dogs with experimental myocardial infarction underwent cardiopulmonary bypass, hypothermic asanguineous K+ cardioplegia (1 hour), and reperfusion (30 minutes). Ten hearts were vented throughout, 5 only during arrest, and 5 only during reperfusion; 10 were not vented. Left ventricular (LV) performance and compliance were assessed by isovolumic (LV balloon) indexes before bypass and after reperfusion. Vented hearts recovered 116 +/- 8.3% of prearrest developed LV systolic pressure (DLVSP) and 131 +/- 13.6% of prearrest rate of rise of LV pressure (dP/dt). Nonvented hearts allowed to develop pressure during arrest (11.6 +/- 1.6 mm Hg) and reperfusion (65 +/- 4 mm Hg) recovered 50 +/- 3.9% of prearrest DLVSP and 55 +/- 5% of prearrest dP/dt (p less than 0.05). Reduction in LV compliance was comparable in both groups. Mitochondrial architecture (electron microscopy) was preserved in vented hearts, but was modestly disrupted in nonvented hearts, thus suggesting slight metabolic impairment. Functional recovery was nearly complete in hearts vented only during reperfusion (DLVSP, 94 +/- 10.4%; dP/dt, 89 +/- 12.6%), but venting only during arrest led to functional depression (DLVSP, 50 +/- 6.6%; dP/dt, 51 +/- 8%; p = 0.01). We conclude that venting chronically infarcted hearts during cardiac operations affords better myocardial protection by avoiding the damage that occurs during nonvented reperfusion.     

Chemoreflexes: an experimental study

HYPOTHESIS: Transmyocardial laser revascularization (TMLR) will not denervate the heart, because it does not destroy all of the afferents. This study was designed to determine if stimulation of cardiac sympathetic and vagal afferents from an area of the left ventricle treated with TMLR could evoke reflex effects, and thus whether TMLR would denervate the heart. METHODS: The effect of TMLR on reflexes evoked by chemically stimulating cardiac afferents was examined in 9 dogs. Bradykinin and capsaicin were applied topically or injected into the left anterior descending coronary artery before and after TMLR and after bilateral vagotomy and sympathectomy. Aortic (AoP) and left ventricular pressures (LVP) and electrocardiography were monitored. The first derivatives of LVP (dP/dt) were calculated. RESULTS: Topical bradykinin elicited variable hemodynamic responses. Topical capsaicin evoked pressor responses, increasing mean (+/- SEM) AoP (105+/-9 to 115+/-9 mm Hg; P<.001) and positive dP/dt (+dP/dt) (1032+/-81 to 1159+/-10 mm Hg/s; P<.01) before TMLR. Intracoronary capsaicin evoked a depressor response before TMLR. Pressor responses remained intact after TMLR with increases in mean AoP and +dP/dt (115+/-6 to 128+/-5 mm Hg and 1039+/-98 to 1136+/-100 mm Hg/s, respectively; P<.01). Depressor responses also remained intact after TMLR (91+/-10 vs 101+/-11 mm Hg [P<.02], and 865+/-104 vs 931+/-104 mm Hg/s [P<.05], respectively). Hemodynamic responses were diminished after bilateral vagotomy and abolished after bilateral sympathectomy. CONCLUSION: Since activation of cardiac afferent nerves and reflex responses remained intact after TMLR, but changed after vagotomy or sympathectomy, TMLR does not denervate the heart sufficiently to be the cause of improved angina after TMLR.     

Placental growth factor provides a novel local angiogenic therapy for ischemic cardiomyopathy

BACKGROUND: Heart failure occurs predominantly due to coronary artery disease and may be amenable to novel revascularization therapies. This study evaluated the effects of placental growth factor (PlGF), a potent angiogenic agent, in a rat model of ischemic cardiomyopathy. METHODS: Wistar rats underwent high proximal ligation of the left anterior descending coronary artery and direct injection of PlGF (n = 10) or saline as a control (n = 10) into the myocardium bordering the ischemic area. After 2 weeks, the following parameters were evaluated: ventricular function with an aortic flow probe and a pressure/volume conductance catheter, left ventricular (LV) geometry by histology, and angiogenesis by immunofluorescence. RESULTS: PlGF animals had increased angiogenesis compared to controls (22.8 +/- 3.5 vs. 12.4 +/- 3.2 endothelial cells/high-powered field, p < 0.03). PlGF animals had less ventricular cavity dilation (LV diameter 8.4 +/- 0.2 vs. 9.2 +/- 0.2 mm, p < 0.03) and increased border zone wall thickness (1.85 +/- 0.1 vs. 1.38 +/- 0.2 mm, p < 0.03). PlGF animals had improved cardiac function as measured by maximum LV pressure (95.7 +/- 4 vs. 73.7 +/- 2 mmHg, p = 0.001), maximum dP/dt (4206 +/- 362 vs. 2978 +/- 236 mmHg/sec, p = 0.007), and ejection fraction (25.7 +/- 2 vs. 18.6 +/- 1%, p = 0.02). CONCLUSIONS: Intramyocardial delivery of PlGF following a large myocardial infarction enhanced border zone angiogenesis, attenuated adverse ventricular remodeling, and preserved cardiac function. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure.     

Impact of acute myocardial edema on left ventricular function.

Studies of the impact of myocardial edema on left ventricular (LV) systolic function show conflicting results. We sought to evaluate the impact of increased myocardial water content (MWC) on LV systolic and diastolic function. Anesthetized dogs (n = 12) were instrumented with myocardial ultrasonic crystals and an LV micromanometer. Systolic function was measured by preload recruitable stroke work (PRSW) and dP/dt(max). Diastolic function was measured by -dP/dt(max) and the isovolumic relaxation constant tau (t). Myocardial water content (MWC) was determined using microgravimetry. In six dogs (coronary sinus hypertension, CSH group) we produced myocardial edema by inflating a coronary sinus balloon for 2 h (30-40 mm Hg). In six other dogs (Plegisol, PLEG group) cardiopulmonary bypass (CPB) was initiated (12.3 +/- 0.8 min), the aorta was cross-clamped (117 +/- 19 s), and 700 mL 4 degrees C crystalloid, hyperkalemic cardioplegic solution (Plegisol) was administered into the aortic root (62 +/- 4 mm Hg). After declamping and reperfusion (7.2 +/- 1.0 min), the dogs were separated from CPB. Myocardial function parameters and MWC were measured for 2 h after edema generation. In the CSH group, MWC significantly increased from 75.9 +/- 0.3% to 77.6 +/- 0.3% (p < .05). In the PLEG group, MWC increased from 75.8 +/- 0.3% to 77.7 +/- 0.3% (p < .05). PRSW and dP/dt(max) did not decrease in either group. Diastolic parameters did not change significantly. We conclude that acute myocardial edema without myocardial injury does not impair LV function.     

Hemodynamic function in acute pancreatitis

Acute pancreatitis is often associated with impaired cardiovascular function. This study examined the systemic cardiovascular effect of acute pancreatitis induced by injection of autologous bile (0.5 ml/kg) into the canine pancreatic duct. After acute pancreatitis was induced, eight dogs were given no resuscitation (group 1, untreated pancreatitis), and lactated Ringer's solution was infused in 11 dogs (group II, treated pancreatitis) to maintain mean arterial pressure and pulmonary wedge pressure at control values. In the untreated pancreatitis group, mean arterial pressure, cardiac output, stroke volume, and stroke work values decreased (mean arterial pressure from 101 +/- 4 to 74 +/- 12 mm Hg, cardiac output from 118 +/- 7 to 56.2 +/- 1.1 ml/min/kg; stroke volume from 0.93 +/- 0.08 to 0.22 +/- 0.07 ml/beat/kg; p less than 0.05), whereas heart rate and peripheral resistance increased (heart rate from 125 +/- 7 to 185 +/- 10 beats/min, peripheral vascular resistance from 3130 +/- 410 to 4436 +/- 610 dynes/sec/cm5; p less than 0.05). Although coronary blood flow, endocardial-epicardial flow ratio, and myocardial oxygen delivery values decreased progressively in group I after induction of pancreatitis, these changes did not achieve statistical significance. All indices of cardiovascular function and coronary blood flow remained unchanged in group II. Neither dP/dt max, the maximal rate of left ventricular pressure increase, nor dP/dt at a developed pressure of 40 mm Hg (an index of myocardial contractility minimally affected by changes in preload and afterload) were depressed by bile-induced acute canine pancreatitis in either group. Our data indicate that the detrimental effects of acute pancreatitis on cardiovascular function are related solely to hypovolemia and reduced cardiac filling and not to humoral or reflex effects induced by the disease.     

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy

OBJECTIVE: Ischemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor. METHODS: Ischemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter. RESULTS: The saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 +/- 3.2 vs 9.6 +/- 3.1 CD34 + /vascular endothelial growth factor receptor 2-positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 +/- 5.5 versus 23.8 +/- 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 +/- 0.1 mm vs 10.1 +/- 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 +/- 0.19 vs 1.41 +/- 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 +/- 3.2 vs 71.7 +/- 3.1 mm Hg, P < .001; maximum dP/dt: 3513 +/- 303 vs 2602 +/- 201 mm Hg/s, P < .05; cardiac output: 21.3 +/- 2.7 vs 13.3 +/- 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 +/- 0.4 vs 0.5 +/- 0.2 mm Hg/microL, P < .01.) CONCLUSION: This novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy.     

Targeted overexpression of leukemia inhibitory factor to preserve myocardium in a rat model of postinfarction heart failure

OBJECTIVE: Myocardial infarction leads to cardiomyocyte loss. The cytokine leukemia inhibitory factor regulates the differentiation and growth of embryonic and adult heart tissue. This study examined the effects of gene transfer of leukemia inhibitory factor in infarcted rat hearts. METHODS: Lewis rats underwent ligation of the left anterior descending coronary artery and direct injection of adenovirus encoding leukemia inhibitory factor (n = 10) or null transgene as control (n = 10) into the myocardium bordering the ischemic area. A sham operation group (n = 10) underwent thoracotomy without ligation. After 6 weeks, the following parameters were evaluated: cardiac function with a pressure-volume conductance catheter, left ventricular geometry and architecture by histologic methods; myocardial fibrosis by Masson trichrome staining, apoptosis by terminal deoxynucleotidal transferase-mediated deoxyuridine triphosphate nick-end labeling assay, and cardiomyocyte size by immunofluorescence. RESULTS: Rats with overexpression of leukemia inhibitory factor had more preserved myocardium and less fibrosis in both the infarct and its border zone. The border zone in leukemia inhibitory factor-treated animals contained fewer apoptotic nuclei (1.6% +/- 0.1% vs 3.3% +/- 0.2%, P < .05) than that in control animals and demonstrated cardiomyocytes with larger cross-sectional areas (910 +/- 60 microm 2 vs 480 +/- 30 microm 2 , P < .05). Leukemia inhibitory factor-treated animals had increased left ventricular wall thickness (2.1 +/- 0.1 mm vs 1.8 +/- 0.1 mm, P < .05) and less dilation of the left ventricular cavity (237 +/- 22 microL vs 301 +/- 16 microL, P < .05). They also had improved cardiac function, as measured by maximum change in pressure over time (3950 +/- 360 mm Hg/s vs 2750 +/- 230 mm Hg/s, P < .05) and the slopes of the maximum change in pressure over time-end-diastolic volume relationship (68 +/- 5 mm Hg/[s . microL] vs 46 +/- 6 mm Hg/[s . microL], P < .05) and the preload recruitable stroke work relationship (89 +/- 10 mm Hg vs 44 +/- 4 mm Hg, P < .05). CONCLUSIONS: Myocardial gene transfer of leukemia inhibitory factor preserved cardiac tissue, geometry, and function after myocardial infarction in rats.     

Comparison of tidal ventilation and high-frequency jet ventilation before and after cardiopulmonary bypass in dogs using two-dimensional transesophageal echocardiography

This study compared the use of high-frequency jet ventilation (HFJV) and tidal ventilation (TV) in a group of dogs with induced global myocardial ischemia before and after cardiopulmonary bypass. Transesophageal echocardiography was used to determine whether HFJV with its lower airway pressures could improve cardiac performance. The surgical procedure was separated into four study periods: closed chest before bypass, open chest before bypass, open chest after bypass, and closed chest after bypass. During each of these study periods, the dogs were randomly ventilated with alternate periods of TV and HFJV to maintain the PaCO2 at 34.3 +/- 3.3 mm Hg (mean +/- SEM). Cardiac output, stroke volume, systemic mean blood pressure, left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular dP/dt, left ventricular stroke work, and expiratory volumetric flows were higher during HFJV, whereas airway pressures and pulmonary vascular resistance were lower. Increases in cardiac output and stroke volume during HFJV were due to a combination of improved left ventricular contractility indicated by increased LV dP/dt and increased left ventricular end-diastolic volume accompanying decreased airway pressures. These data indicate that HFJV with its lower airway pressure is associated with significantly less impairment of cardiovascular function than TV in dogs with induced global myocardial ischemia.     

Single fibers of skeletal muscle as a novel graft for cell transplantation to the heart

OBJECTIVE: Skeletal myoblast transplantation is a promising alternative to treat heart failure. A single fiber, the minimal functional unit of skeletal muscle, retains skeletal myoblasts beneath the basal lamina. When surrounding muscle is injured, myoblasts migrate from the fiber into the damaged area to regenerate muscle. We hypothesized that such isolated fibers could be used as an efficient vehicle to deliver myoblasts into damaged myocardium, resulting in improved cardiac function. METHODS: Living single fibers of rat skeletal muscle were isolated, and their behavior was characterized in vitro. Single fibers were injected into the myocardium (at 4 sites, each receiving a single fiber) of rats in 2 models of heart failure induced either by means of doxorubicin administration or left coronary artery occlusion. RESULTS: Skeletal myoblasts dissociated from an isolated single fiber, proliferated, and differentiated into multinucleated myotubes in vitro. Within 3 days after grafting in vivo, original fibers provided putative myoblasts and disappeared. At 4 weeks, discrete loci consisting of several multinucleated myotubes were observed. Furthermore, single-fiber transplantation significantly improved cardiac function compared with the control treatment in either doxorubicin-treated hearts (maximum dP/dt, 4013.9 +/- 96.1 vs 3603.1 +/- 102.3 mm Hg/s; minimum dP/dt, -2313.7 +/- 75.1 vs. -2057.1 +/- 52.4 mm Hg/s) or ischemic hearts (maximum dP/dt, 3905.6 +/- 103.0 vs 3572.6 +/- 109.7 mm Hg/s; minimum dP/dt, -2336.1 +/- 69.7 vs -2106.4 +/- 74.2 mm Hg/s). CONCLUSION: Single-fiber transplantation acts as a vehicle for delivering putative skeletal myoblasts that appear to differentiate into myotubes within the myocardium. This was associated with improved function of failing hearts, suggesting its efficacy as a novel graft for cellular cardiomyoplasty.     

Vascular delay of the latissimus dorsi provides an early hemodynamic benefit in dynamic cardiomyoplasty.

OBJECTIVES: Dynamic cardiomyoplasty (CMP) as a surgical treatment for chronic heart failure improves functional class status for most patients. However, significant hemodynamic improvement with latissimus dorsi muscle (LDM) stimulation has not been consistent. The current protocols do not allow early LDM stimulation after CMP surgery. We hypothesized that vascular delay of LDM would increase myocardial assistance after CMP and allow early (48-h) LDM stimulation after CMP. METHODS: Mongrel dogs (n = 24) were divided in four groups: 1) controls (n = 6), single-stage CMP; 2) Group ES (n = 6), single-stage CMP with early LDM stimulation beginning 48 h, postoperatively; 3) Group VD (n = 6), vascular delay of the LDM followed by CMP without early LDM stimulation, and 4) Group VDES (n = 6), vascular delay of LDM (14-18 days), followed by CMP with early stimulation (48 h postoperatively). Two weeks after CMP, global cardiac dysfunction was induced by injecting microspheres into the left coronary artery. LDM-assisted (S) beats were compared with nonstimulated beats (NS) by measuring aortic pressure (AoP), LV pressure, aortic flow, and by calculating first derivative of LV contraction (+/-dP/dt), stroke volume (SV), and stroke work (SW). RESULTS: In ES, LDM stimulation had no effect on the hemodynamic parameters. In the other groups, LDM stimulation significantly (p < 0.05) increased AoP, LVP, dP/dt, SV, and SW. However, these increases were much larger in VD and VDES. In VD, LDM stimulation increased peak AoP by 21.5+/-3.8 mm Hg, LVP by 22.1+/-4.1 mm Hg, dP/dt by 512+/-163 mm Hg/sec, SV by 10.4+/-2.3 mL, and SW by 22.1+/-5.4 g/m(-1). Similarly, in VDES, LDM stimulation increased peak AoP by 24.1+/-4.7 mm Hg, LVP by 26.2+/-4.3 mm Hg, dP/dt by 619+/-47 mm Hg/sec, SV by 6.5+/-0.7 mL, and SW by 16.7+/-4.1 g/m(-1). CONCLUSIONS: In dogs with global LV dysfunction, CMP after vascular delay resulted in a significant improvement in hemodynamic function measured 2 weeks after surgery. This improvement was not provided by single-stage CMP with or without early stimulation. Vascular delay of the LDM before surgery may play an important role for early benefit after CMP, shorten the overall muscle training period, as well as increase hemodynamic response to LDM stimulation.     

Calcium antagonists improve cardiac mechanical performance after thermal trauma.

Burn trauma initiates a pathophysiologic cascade, which includes cardiac dysfunction and intramyocyte calcium accumulation. This study examined the hypothesis that therapeutic interventions which limit intracellular cardiac Ca(2+) accumulation after burn trauma will improve cardiac function. Guinea pigs were anesthetized (methoxyflurane), burned over 43% of total body surface area, and fluid resuscitated (FR) for 24 h. Burn guinea pigs were randomly divided into three groups: Group 1, FR alone, Group 2, FR plus dantrolene (10 mg/kg body wt, IV, 30 min, 8 and 22 h postburn), a drug which inhibits the Ca(2+) release channel (ryanodine receptor) of the cardiac sarcoplasmic reticulum, and Group 3, FR plus diltiazem (0.20-0.22 mg/kg given IV as a slow infusion over 6 h postburn), a drug which specifically blocks Ca(2+) slow channels; sham burn guinea pigs were given vehicle (Group 4), dantrolene (Group 5), or diltiazem (Group 6) as described above (respective controls). Cardiac dysfunction was impaired in fluid-treated burns (Group 1) compared to sham burns (Group 4) as indicated by reduced developed left ventricular pressure (LVP) (86 +/- 2 vs 52 +/- 3 mm Hg, P < 0.05), rate of LVP rise, (+dP/dt max, 1379 +/- 64 vs 909 +/- 44 mm Hg/s, P < 0.05), and LVP fall (-dP/dt max, 1184 +/- 31 vs 881 +/- 40 mm Hg/s, P < 0.05), and time to peak pressure (110 +/- 2 vs 102 +/- 2 ms, P < 0.05). In addition, [Ca(2+)](i) rose in cardiomyocytes harvested from fluid-treated burns (Group 1, 307 +/- 29 nM) compared to vehicle-treated controls (Group 4, 152 +/- 6 nM, P < 0.05). Neither calcium antagonist altered ventricular function or [Ca(2+)](i) in sham burns (Groups 5 and 6). In contrast, antagonists given after burn injury reduced cardiomyocyte [Ca(2+)](i) (Group 2, dantrolene-treated burns: 196 +/- 8 nM, and Group 3, diltiazem treated burns: 216 +/- 8 nM) and improved cardiac performance compared to that measured in burns given FR alone. Our data suggest that calcium antagonists given after burn trauma restored intracellular Ca(2+) homeostasis, decreased cardiac cell injury, and improved cardiac contractile function.     

Variable Effects of Cardiomyoplasty on Left Ventricular Function

Abstract: Cardiomyoplasty (CMP) has been considered as a possible treatment for patients with heart failure. Symptomatic improvements occur almost uniformly among survivors with CMP, but changes in left peak ventricular systolic pressure (PVSP) and stroke volume vary in patients. This study examined whether there is variability present shortly after cardiomyoplasty surgery. Cardiomyoplasty was performed in 11 mongrel dogs with normal ventricular function. Nine to twelve days after CMP, left ventricular (LV) function was evaluated by simultaneously measuring LV volume (conductance catheter) and pressurc (Millar catheter). The latissimus dorsi muscle (LDM) was stimulated synchronously with ventricular systole in a ratio of 1:4 to 1:7 to avoid muscle fatigue. Data were analyzed on a beat by beat basis. The PVSP, and maximum dP/dt (+dP/ dt ) increased, but the absolute value of minimum dP/dt (-dP/dt ) decreased in stimulated beats in 7 dogs while 4 dogs did not respond. The net changes in stimulated beats versus nonstimulated beats of PVSP were 6.1 ± 1.8 mm Hg (4.3%), of stroke work was 4.5 ± 1.9 gm. m (29.5%), of +dP/dt was 185 ± 47 mm Hg/s (So/,), and of -dP/dt was 168 ± 43 mm Hg/s (7.8%) (p < 0.05) for all these net changes in the responding group while these variations were not significant in the nonresponding group. From the results of our study, active LDM assist improves left ventricular systolic function, occurring in only 7 of 11 experiments. This improvement is inconsistent and varied individually. The integrity of the LDM, tightness of wrapping, and adhesions might contribute to the variability which is present early after surgery and before the LDM is converted into a fatigue resistance muscle.     

Circulatory support for right ventricular dysfunction

New modes of circulatory support for right ventricular dysfunction have recently been described. The present study compared the effectiveness of pulmonary artery balloon counterpulsation with a right ventricular assist device for support of surgically induced right ventricular dysfunction. Right ventricular hypertrophy was created in 16 neonatal lambs by pulmonary artery banding. Right ventricular dysfunction was produced in all animals by performing a right ventriculotomy and maintaining the pulmonary artery band. Four unassisted animals developed severe acute right heart failure and died. Six sheep had pulmonary artery balloon counterpulsation with a Dacron graft anastomosed to the proximal pulmonary artery as a reservoir for a 40 ml intra-aortic balloon after the onset of heart failure. The remaining six sheep had a pneumatically activated ventricular assist device inserted between the proximal pulmonary artery and the right ventricular apex. Periods of circulatory support with the balloon pump and the assist device on and off were compared. Decreases in right atrial pressure were observed with both balloon counterpulsation and right ventricular assistance: 14 +/- 1 to 11 +/- 1 mm Hg, p less than 0.0001, versus 19 +/- 2 to 12 +/- 2 mm Hg, p less than 0.0002, respectively. Cardiac output increased with both balloon counterpulsation and ventricular assistance: 1.45 +/- 0.16 to 2.03 +/- 0.13 L/min, p less than 0.001, versus 0.72 +/- 0.15 to 2.24 +/- 0.23 L/min, p less than 0.0002, respectively. Aortic systolic pressure increased in both support groups: 78 +/- 7 to 99 +/- 6 mm Hg, p less than 0.0004, versus 53 +/- 9 to 85 +/- 9 mm Hg, p less than 0.0001, respectively. Ventricular assistance produced greater changes in the right atrial pressure (39% +/- 6% versus 17% +/- 3%, p less than 0.01), cardiac output (153% +/- 39% versus 54% +/- 11%, p less than 0.05), and aortic systolic pressure (85% +/- 13% versus 39% +/- 9%, p less than 0.01). The insertion of a right ventricular assist device caused a significant increment in right ventricular dysfunction. These data, obtained with the devices in place but not operating, showed significantly increased right atrial and right ventricular end-diastolic pressures and approximately 50% less cardiac output than with the pulmonary artery balloon counterpulsation system. The results demonstrate that both modes of circulatory support were effective in reversing surgically induced right ventricular failure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Contraction-relaxation coupling and impaired left ventricular performance in coronary surgery patients

BACKGROUND: Dependence of left ventricular (LV) relaxation on cardiac systolic load is a function of myocardial contractility. The authors hypothesized that, if a tight coupling would exist between LV contraction and relaxation, the changes in relaxation rate with an increase in cardiac systolic load would be related to the changes in LV contraction. METHODS: Coronary surgery patients (n = 120) with preoperative ejection fraction >40% were included. High-fidelity LV pressure tracings (n = 120) and transgastric transesophageal echocardiographic data (n = 40) were obtained. Hearts were paced at a fixed rate of 90 beats/min. Effects on contraction were evaluated by analysis of changes in dP/dt(max) and stroke area. Effects on relaxation were assessed by analysis of R (slope of the relation between tau and end-systolic pressure). Correlations were calculated with linear regression analysis using Pearson's coefficient r. RESULTS: Baseline LV end-diastolic pressure was 10+/-3 mm Hg (mean +/- SD). During leg raising, systolic LV pressure increased from 93+/-9 to 107+/-11 mm Hg. The change in dP/dt(max) was variable and ranged from -181 to +254 mm Hg/s. A similar variability was observed with the changes in stroke area, which ranged from -2.0 to +5.5 cm2. Changes in dP/dt(max) and in stroke area were closely related to individual R values (r = 0.87, P<0.001; and r = 0.81, P<0.001, respectively) and to corresponding changes in LV end-diastolic pressure (r = 0.81, P< 0.001; and r = 0.74, P<0.001, respectively). CONCLUSIONS: A tight coupling was observed between contraction and relaxation. Leg raising identified patients who developed a load-dependent impairment of LV performance and increased load dependence of LV relaxation.     

Effects of chronic tachycardia-induced cardiomyopathy on the beta-adrenergic receptor system.

Chronic supraventricular (or ventricular) tachycardia causes a dilated cardiomyopathy. Effective treatment requires ablation of the tachycardia using antiarrhythmic agents, cryoablation, electroablation, or surgical interruption/excision. However, the underlying pathophysiologic mechanisms responsible for the development of supraventricular tachycardia-induced cardiomyopathy have not been fully identified. We hypothesized that chronic supraventricular tachycardia is associated with significant changes in the beta-adrenergic system that may have implications for the pathophysiology and treatment of supraventricular tachycardia-induced cardiomyopathy. Accordingly, we examined the relationship between left ventricular function, plasma norepinephrine level, beta-receptor number and affinity, and response to a beta-agonist (isoproterenol) infusion in eight control pigs and eight pigs subjected to supraventricular pacing-induced tachycardia (240 beats/min for 3 weeks). Left ventricular function was measured using simultaneous echocardiography and catheterization. Left ventricular end-diastolic dimension and pressure increased in pigs with supraventricular tachycardia (5.1 +/- 0.4 cm and 27 +/- 2 mm Hg) versus control pigs (3.8 +/- 0.3 cm and 8 +/- 2 mm Hg), p < 0.05. Left ventricular fractional shortening decreased in supraventricular tachycardia (10 +/- 1%) versus control pigs (34 +/- 1%), p < 0.05. In addition, in the pigs with supraventricular tachycardia the fractional shortening versus left ventricular end-systolic stress relationship fell below the control relationship. Plasma norepinephrine level (measured by high-performance liquid chromatography) increased in pigs with supraventricular tachycardia (3592 +/- 1606 pg/ml plasma) versus control pigs (323 +/- 74 pg/ml plasma), p < 0.05. beta-Receptor number and affinity (measured by [3H]dihydroalprenolol binding) did not change in supraventricular tachycardia (98.6 +/- 11.5 fmol/mg protein and 7.2 +/- 1.1 nmol) versus control pigs (99.1 +/- 9.4 fmol/mg protein and 6.8 +/- 0.5 nmol). The response to isoproterenol infusion (10 micrograms/kg) in supraventricular tachycardia was blunted: the absolute increase in left ventricular peak (+)dP/dt was reduced in supraventricular tachycardia (833 +/- 233 mm Hg/sec) versus control pigs (2180 +/- 139 mm Hg/sec), p < 0.05. Chronic supraventricular tachycardia caused a decreased contractile state, increased plasma norepinephrine level, and caused no change in beta-receptor number or affinity; however, the response to beta-agonist infusion was blunted. These results suggest that chronic supraventricular tachycardia is associated with uncoupling of the beta-receptor from subsequent intracellular components of the beta-adrenergic system. Therefore medical management of chronic supraventricular tachycardia-induced cardiomyopathy before and immediately after definitive ablation may require use of pharmacologic agents whose actions do not depend on an intact beta-adrenergic pathway.