Cardiomyoplasty: hemodynamic benefit to normal and depressed canine left ventricular function

This study examined the effects of cardiomyoplasty with vascular delay on canine normal and depressed left ventricular (LV) function. To improve viability of the latissimus dorsi muscle (LDM), vascular delay was performed 2 weeks before cardiomyoplasty in 10 mongrel dogs. Two weeks after cardiomyoplasty, LV function was evaluated by simultaneously measuring LV and aortic pressure, and aortic flow. The LDM was stimulated at a ratio of 1:4-1:7 synchronously with ventricular systole. Microspheres (90 mu) were sequentially injected into the left coronary artery to depress LV function. Data were acquired and analyzed on a beat to beat basis. Results were as follows: LDM stimulation significantly augmented LV systolic pressure (LVSP) from 138 +/- 2 to 161 +/- 2* mmHg, the peak rate of change of LV pressure (+dP/dt) from 1888 +/- 46 to 2584 +/- 43* mmHg/sec, aortic systolic pressure (AoSP) from 140 +/- 2 to 159 +/- 2* mmHg, stroke volume (SV) from 11.2 +/- 0.3 to 13.3 +/- 0.3* ml, stroke work (SW) from 19 +/- 1 to 26 +/- 1* gm.m, peak aortic flow (P Qa) from 5542 +/- 142 to 7190 +/- 161* ml/min, and decreased -dP/dt from -1683 +/- 31 to -1689 +/- 49* mmHg/sec (* = p < 0.05). Microsphere injections depressed LV function, but did not affect the magnitude of the net changes between stimulated and nonstimulated beats. However, the percent changes significantly increased. Preconditioning of LDM with vascular delay augments cardiac function in LDM assisted beats. This improved performance was present in both normal as well as depressed LV function groups. Thus, investigations of cardiomyoplasty may not necessarily require a model of severe myocardial dysfunction. Vascular delay offers an important preconditioning method of LDM to augment cardiac function in cardiomyoplasty.     

Study of muscular and ventricular function in dynamic cardiomyoplasty: a ten-year follow-up

BACKGROUND: The basic physiologic principle underlying cardiomyoplasty is long-term electrostimulation of a latissimus dorsi muscle (LDM) wrapped around the heart to obtain a phasic activity that could be integrated with ventricular kinetics. The aim of cardiomyoplasty is to prolong survival and to improve the quality of life of patients with severe chronic and irreversible myocardial failure by improving systolic contraction and correcting diastolic dysfunction. METHODS: To evaluate the long-term outcome of cardiomyoplasty, we investigated 82 patients electively undergoing this procedure in-our hospital. All patients had severe chronic heart failure that did not respond to optimal medical treatment. Patients had a mean age of 50 +/- 12 years (84% males). The cause of heart failure was ischemic (55%), idiopathic cardiomyopathy (34%), ventricular tumor (6%), and other (5%). The mean follow-up was 4.3 years. RESULTS: The mean New York Heart Association functional class improved after operation from 3.2 to 1.8. Average radioisotopic left ventricular ejection fraction increased from 17% +/- 6% to 28% +/- 3% (p < 0.05). Stroke volume index increased from 35 +/- 9 to 46 +/- 8 ml/beat/m2 (p < 0.05). The heart size remained stable at long term (evaluated by echo and computed tomography scanning). After cardiomyoplasty the number of successive hospitalizations resulting from congestive heart failure was reduced to 0.4 hospitalizations/patient/year (before operation 2.5, p < 0.05). Computed tomography scans showed at long-term a preserved LDM structure in 82% of patients who underwent operation. Survival probability at 7 years was 54% for the totality of patients, and 66% for patients who underwent operation in New York Heart Association functional class 3. Five patients underwent heart transplantation after cardiomyoplasty (mean delay 29 months), principally as a result of the natural evolution of their underlying heart disease, without major technical difficulties. CONCLUSIONS: Our 10-year clinical experience demonstrates that cardiomyoplasty increases ejection fraction, improves functional class, and ameliorates quality of life. Ventricular volumes and diameters remain stable long term. LDM structure is maintained long term if electrostimulation is performed avoiding excessive myostimulation. Patient selection is the most important determinant for early and late outcome. Late death in patients undergoing cardiomyoplasty is principally due to sudden death. Our future aim is to incorporate a cardioverter-defibrillator in the cardiomyostimulator, thus improving long-term results. Cardiomyoplasty may delay or prevent end-stage heart failure and the need for heart transplantation.     

Mechanisms of cardiomyoplasty: comparative effects of adynamic versus dynamic cardiomyoplasty

BACKGROUND: The apparent paradox seen in patients who have undergone dynamic cardiomyoplasty and shown substantial clinical and functional improvements with only modest hemodynamic changes may be due to inappropriate end points chosen for study, a result of incomplete understanding of mechanisms involved. The purpose of this study was to compare the relative role of the passive "girdling effect" and the dynamic "systolic squeezing effect" of the wrapped muscle in cardiomyoplasty. METHODS: The control group of 6 dogs underwent 4 weeks of rapid pacing (250 beats/min) to induce severe heart failure followed by 8 weeks of observation without rapid pacing. The trajectory of recovery in hemodynamics and cardiac dimensions was followed with echocardiography and Swan-Ganz catheters. In the "adynamic" cardiomyoplasty group (n=4), the left latissimus dorsi muscle was wrapped around the ventricles and allowed to stabilize and mature for 4 weeks. This was followed by rapid pacing and recovery as in the control group. In the "dynamic" cardiomyoplasty group (n=3), the same protocol for the adynamic group was followed except that a synchronizable cardiomyostimulator was attached to the thoracodorsal nerve of the muscle wrap. This allowed the latter to be transformed during the rapid-pacing phase and permitted dynamic squeezing of the muscle wrap to be generated by burst stimulation synchronized with cardiac contraction in a 1:2 ratio. RESULTS: Baseline data were comparable in all groups prior to rapid pacing. After 4 weeks of rapid pacing, the left ventricular ejection fraction was higher in the adynamic (27.0%+/-3.9%; p < 0.05) and dynamic (33.3%+/-2.3%; p < 0.02) cardiomyoplasty groups compared with controls (18.8%+/-8.3%). Similarly, ventricular dilatation in both systole and diastole was less in the adynamic (51.8+/-8.7 mL, [p < 0.002] and 38.2+/-7.2 mL [p < 0.001], respectively) and dynamic (62.0+/-7.2 [p < 0.02] and 41.3+/-3.5 mL [p < 0.005], respectively) cardiomyoplasty groups compared with controls. In the dynamic group, on and off studies were carried out after cessation of rapid pacing while the heart was still in severe failure, and they demonstrated a systolic squeezing effect in stimulated beats. Only this group recovered fully to baseline after 8 weeks. CONCLUSIONS: By reducing myocardial stress, both the passive girdling effect and the dynamic systolic squeezing effect have complementary roles in the mechanisms of dynamic cardiomyoplasty.     

Optimization of synchronization delay in latissimus dorsi dynamic cardiomyoplasty

BACKGROUND: Optimal synchronization delay (SD) for triggering the implanted cardiomyostimulators in patients undergoing latissimus dorsi dynamic cardiomyoplasty has not been clearly defined. Generally a synchronization delay time of 45 to 60 ms is used in the current practice, in which the implanted cardiomyostimulator stimulates the latissimus dorsi muscle 45 to 60 ms after mitral valve closure acquired with M-mode echocardiography. We investigated the effect of shortening or prolonging the delay time on cardiac functions. METHODS: We studied 10 patients who were in their first 2 years postoperatively. Three values for SD (SD = 0 ms, 45 to 60 ms, and 150 to 160 ms) were echocardiographically evaluated for their influence on both systolic and diastolic left ventricular parameters. RESULTS: Ejection fractions were 0.27 +/- 0.07, 0.28 +/- 0.07, and 0.32 +/- 0.06; peak aortic velocities were 0.85 +/- 0.8, 0.86 +/- 0.11, and 0.92 +/- 0.8 m/s; and velocity-time integrals were 0.16 +/- 0.03, 0.16 +/- 0.03, and 0.19 +/- 0.03 m for the SD values of 0, 45 to 60 ms, and 150 to 160 ms, respectively. Diastolic parameters were also measured. Isovolumetric diastolic relaxation time was 97.5 +/- 49, 97.20 +/- 44, and 111.8 +/- 49 ms; deceleration time was 83.67 +/- 32, 88.48 +/- 35, and 92.68 +/- 34 ms; and ratio or velocity-time integral of e wave to velocity-time integral of a wave was 3.09 +/- 0.98, 2.48 +/- 0.69, and 2.38 +/- 0.65 for the SD values of 0, 45 to 60 ms, and 150 to 160 ms, respectively. Systolic functions were better when SD was set at 150 to 160 ms, but there was a diastolic compromise. On the other hand, diastolic parameters were more favorable when SD = 0 (i.e., cardiomyostimulator triggered without delay) but the systolic assist was suboptimal. Systolic and diastolic parameters seemed relatively well-balanced with the current practice of setting the synchronization delay at 45 to 60 ms. CONCLUSIONS: The most favorable systolic effects were obtained with a prolonged delay of synchronization (150 to 160 ms), at some expense of diastolic functions. On the other hand, with a short or absent delay, diastolic parameters were improved but systolic parameters became suboptimal. Therefore, the current practice of setting the SD between 45 and 60 ms after echocardiographic mitral valve closure is suggested for the optimal timing for cardiomyostimulator stimulation in patients who have undergone latissimus dorsi dynamic cardiomyoplasty. Yet a great deal of individualization is necessary, and fixed preset values cannot definitely be determined because one setting does not fit all patients.     

The age-associated alterations in late diastolic function in mice are improved by caloric restriction

Caloric restriction reduces the magnitude of many age-related changes in rodents. Cardiac function is altered with senescence in mice, rats, and healthy humans. We examined the effects of life-long caloric restriction on diastolic and systolic cardiac function in situ using Doppler techniques in ad libitum-fed 30- to 32-month-old (AL) and calorically restricted (CR) 32- to 35-month-old female B6D2-F1 hybrid mice. The heart weight to body weight ratio was similar in AL (5.74 +/- .24 mg/g) and CR (5.68 +/- .20 mg/g) mice. Two systolic functional parameters known to decrease with age in both humans and mice, peak aortic velocity and aortic acceleration, were unchanged by CR compared to AL. In contrast, diastolic function was altered by caloric restriction. Although left ventricular peak early filling velocity (E) was not different between CR and AL, peak atrial filling velocity (A) was 50% lower in CR compared to AL (p < .001). The ratio of early diastolic filling to atrial filling (E/A ratio) was 64% higher in the CR (2.74 +/- .31) than the AL (1.55 +/- .07; p = .004). The fraction of ventricular filling due to atrial systole, the atrial filling fraction, was also reduced in CR (.21 +/- .04) compared to AL (.36 +/- .02; p = .007). These changes occurred in CR without alteration in E deceleration time, which is consistent with improved diastolic function in CR. Through mechanisms that remain unknown, lifelong caloric restriction may prevent the age-related impairments in late diastolic function but does not alter the impairments in systolic or early diastolic cardiac function.     

Hemodynamic response to in situ latissimus dorsi muscle stimulation: implications in dynamic cardiomyoplasty

Dynamic cardiomyoplasty (DCM) involves the electrical stimulation of a pedicled latissimus dorsi muscle flap wrapped around the falling ventricle as a means of cardiac assist. To further elucidate a potential neurohumoral mechanism for improvement of cardiac output after myoplasty, we evaluated the hemodynamic effects of in situ stimulation of the latissimus dorsi muscle (in the absence of cardiomyoplasty). In seven mongrel dogs, a nerve cuff electrode (Medtronic 6901) was placed around the left thoracodorsal nerve (TDN). This was attached to a pulse generator (Medtronic, Itrel 7420), delivering a 4.0 volt, 0.19 second on, 0.81 second off, 33 Hz, 210 microsecond pulse width, cyclic bursts similar to that used in DCM. Stroke volume index (SVI) and other hemodynamic parameters as well as plasma norepinephrine (NE) levels were measured at five stages: baseline, stimulator on at 0, 2, and 5 minutes, and stimulator off at 30 minutes after. The animals were then subjected to 4 weeks of rapid pacing at 240 beats/min (Medtronic 8329) to induce heart failure, and as the rapid pacing was discontinued, measurements were repeated as above. After rapid pacing, cardiac function was significantly depressed, and NE was elevated (133 +/- 69 versus 500 +/- 353 pg/mL, p < 0.05). In the normal hearts, TDN stimulation increased SVI, heart rate, systemic pressure, and NE levels. In heart failure, however, no significant changes in cardiac function and NE levels were noted. In conclusion, our data indicate that in the normal hearts, afferent impulses from TDN stimulation alone may augment cardiac function by means of a neurohumoral effect that is not seen in severe heart failure. The implications of these findings in DCM are discussed.     

Clinical features of relative focal hyperfusion in patients with intracerebral hemorrhage detected by contrast-enhanced xenon CT

Optimization of the skeletal muscle contraction during cardiac assist is important to achieve maximal cardiac assist and yet avoid overstimulation that may injure skeletal muscle. Dynamic cardiomyoplasty suffers from lack of an objective, reproducible, and accurate technique to measure skeletal muscle shortening fraction after wrap and training of the muscle. A recruitment curve is considered the best way to select the proper stimulation level to achieve supramaximal contraction without overstimulating the muscle. A fluoroscopic technique of determining latissimus dorsi recruitment curve was evaluated in five goats undergoing dynamic cardiomyoplasty with an anterior cardio-subcutaneous wrap. Two pairs of stainless steel targets (0.5 and 1 cm of diameter) were implanted on each side of the muscle wrap. One pair of sonomicrometer crystals was also implanted. Displacement of the targets was measured under fluoroscopy at five different stimulation levels. Correlation coefficients between targets on the inside surface of the wrap and the sonomicrometer crystals, and targets on the outside surface of the wrap and the sonomicrometer crystals were 0.71 (P < 0.05) and 0.60 (P < 0.05), respectively. Targets on the inside surface of the wrap were more accurate than targets on the outside surface of the wrap for measurement of skeletal muscle shortening fraction and establishment of a recruitment curve. Adverse effects from the targets were not observed.     

Effects of dichloroacetate in patients with congestive heart failure

BACKGROUND: Conventional approaches to management of congestive heart failure (CHF) rely on drugs that increase myocardial contractility or reduce ventricular afterload. These approaches often improve cardiac symptoms and survival, but may be associated with significant deleterious effects. An alternative approach is to enhance myocardial energy production. Dichloroacetate (DCA) stimulates pyruvate dehydrogenase activity and accelerates aerobic glucose, pyruvate, and lactate metabolism in myocardial cells. These alterations would be expected to improve myocardial function. HYPOTHESIS: The purpose of the investigation was to assess the efficacy of DCA in patients with left ventricular systolic dysfunction and to examine the mechanism by which improvement occurs. METHODS: A total of 25 patients (16 men, 9 women; age range 31-72 years, mean 59) with CHF and ejection fraction < or = 40% received an intravenous infusion of 50 mg/kg DCA over 15 min. Indices of systolic and diastolic function were obtained by two-dimensional and Doppler echocardiography performed at baseline, 30 min, and 60 min following completion of DCA infusion. RESULTS: Baseline ventricular ejection fraction was 27.3 +/- 9.1%; 17 patients (68%) had nonischemic cardiomyopathy. Heart rate increased after DCA infusion from 73.9 +/- 14.5 to 79.2 +/- 14.9 beats/min at 60 min; p = 0.02. Left ventricular diastolic and systolic volumes increased at 30 min compared with baseline (248.7 +/- 98.1 vs. 259.6 +/- 99.6; p = 0.04, and 180.1 +/- 80.4 vs. 192.2 +/- 84.9; p = 0.002, respectively), but stroke volume (49.2 +/- 19.1 vs. 48.9 +/- 18.1; p = 0.9) and ejection fraction (27.3 +/- 9.1 vs. 25.7 +/- 9.8; p = 0.2) were unchanged. Indices of diastolic function were also unchanged. CONCLUSION: Dichloroacetate infusion in patients with CHF is not associated with improvement in noninvasively assessed left ventricular function.     

Biologic glue increases capillary ingrowth after cardiomyoplasty in an ischemic cardiomyopathy model

The authors investigated the multi-step mechanism of healing after cardiomyoplasty, focusing on the process of angiogenesis. The authors contend that enhancement of angiogenesis and prevention of ischemia-reperfusion injuries immediately after muscle mobilization will be effective in improving cardiomyoplasty results. After cardiomyoplasty, autologous biologic glue (ABG) was administered between the latissimus dorsi muscle (LDM) and myocardium. By 2 months, a new pseudo interlayer was present that bridged the gap between the LDM and myocardium. Neovascularization was visible in the form of numerous small capillaries. Marked degeneration of the LDM was noted, possibly caused by muscle ischemia-reperfusion damage after mobilization. Pockets were created of ischemic and nonischemic LDM to test for angiogenesis. One was left free of ABG (control); one received ABG only; one received ABG and pyrrolostatin. Some of the capillaries were large and had erythrocytes inside. biopsy samples showed 9.4 +/- 1.9% of the sample was occupied by blood vessels (compared with 3.6 +/- 0.7% in control muscle). These preliminary studies prove the feasibility of the authors' concept and provide evidence that angiogenesis can accelerate the healing process and provide an organic bridge between the LDM and myocardium after cardiomyoplasty.     

Dynamic cardiomyoplasty: clinical follow-up at 12 years

OBJECTIVE: The purpose of this study is to evaluate the long-term outcome of dynamic cardiomyoplasty. This surgical technique was conceived to assist the failing heart. The many proposed mechanisms of action of cardiomyoplasty are: (1) systolic assist; (2) limitation of ventricular dilation; (3) reduction of ventricular wall stress (sparing effect); (4) ventricular remodeling with an active girdling effect; (5) angiogenesis; and (6) a neurohumoral effect. METHODS: We investigated 95 patients in our hospital undergoing this procedure due to severe chronic heart failure, refractory to optimal medical treatment. Patients had a mean age of 51 +/- 12 years. The etiology of heart failure was ischemic 55%, idiopathic 34%, ventricular tumor 6%, and other 5%. The mean follow-up was 44 months. RESULTS: The mean New York Heart Association (NYHA) functional class improved postoperatively from 3.2 to 1.8. Average radioisotopic left ventricular (LV) ejection fraction increased from 17 +/- 5 to 27 +/- 4% (P < 0.05). Stroke volume index increased from 32 +/- 7 to 43 +/- 8 ml/beat per m2 (P < 0.05). The heart size remained stable over the long term. Following cardiomyoplasty, the number of hospitalizations due to congestive heart failure was reduced to 0.4 hospitalizations/patient per year (preoperative: 2.5, P < 0.05). Computed tomography scans showed at long term a preserved latissimus dorsi muscle structure in 84% of patients. Survival probability at 7 years is 54%. Six patients underwent heart transplant after cardiomyoplasty (mean delay: 25 months), due to the natural evolution of their underlying heart disease. There were no specific technical difficulties. CONCLUSIONS: Clinically, this procedure reverses heart failure, improves functional class and ameliorates quality of life. The latissimus dorsi muscle histological structure is maintained at long-term, when postoperative electrostimulation is performed, avoiding excessive stimulation. Cardiomyoplasty may delay or prevent the progression of heart failure and the indication of cardiac transplantation.     

Effects of cardiomyoplasty on right ventricular filling during volume loading

BACKGROUND: Although cardiomyoplasty (CMP) is thought to improve ventricular systolic function, its effects on ventricular diastolic function are not clear. Especially the effects on right ventricular diastolic filling have not been fully investigated. Because pericardial influences are more pronounced in the right ventricle than in the left ventricle, CMP with its external constraint may substantially impair right ventricular diastolic filling. METHODS: Fourteen purebred adult beagles were used in this study. Seven underwent left posterior CMP, and 7 underwent a sham operation with a pericardiotomy and served as controls. Four weeks later, the hemodynamic effects of CMP were evaluated by heart catheterization before and after volume loading (central venous infusion of 10 mg/kg of 4.5% albumin solution for 5 minutes). RESULTS: In the CMP group, mean right atrial pressure and right ventricular end-diastolic pressure increased significantly from 3.1 +/- 1.2 mm Hg to 6.1 +/- 2.0 mm Hg (p < 0.001) and from 4.0 +/- 1.8 mm Hg to 9.6 +/- 2.5 mm Hg (p < 0.001), respectively. Volume loading in the control group did not significantly increase either variable. Right ventricular end-diastolic volume and stroke volume did not change significantly (from 53 +/- 9.3 mL to 60 +/- 9.0 mL and from 20 +/- 2.3 mL to 21 +/- 3.2 mL, respectively) in the CMP group. In the control group, however, right ventricular end-diastolic volume and stroke volume increased significantly from 45 +/- 7.7 mL to 63 +/- 14 mL (p < 0.05) and from 18 +/- 4.3 mL to 22 +/- 4.2 mL (p < 0.05), respectively. CONCLUSIONS: These results suggest that CMP may reduce right ventricular compliance and restrict right ventricular diastolic filling in response to rapid volume loading because of its external constraint.     

Effect of myocardial hypertrophy on systolic and diastolic function in children: insights from the force-frequency and relaxation-frequency relationships

OBJECTIVE: The objective of this study was to evaluate the effect of myocardial hypertrophy on systolic and diastolic properties of the left ventricle in children. BACKGROUND: In children with myocardial hypertrophy, ejection phase indices are invariably increased. However, indices of force-generation, e.g., end-systolic elastance and invasive indices of diastolic properties, have been studied infrequently in children with myocardial hypertrophy. METHODS: We studied 10 children with congenital aortic stenosis or coarctation of aorta and nine control patients. Systolic properties were assessed from shortening fraction, end-systolic fiber elastance (Ef(es)) measured at resting heart rates, and force-frequency relationship measured at heart rates increasing from 110 to 160 beats per minute. Diastolic properties were assessed from time constant of relaxation (tau) at matched heart rates, chamber stiffness constant, myocardial stiffness constant, and relaxation-frequency relationship measured at gradually increasing heart rates. RESULTS: Ef(es) remained unchanged by myocardial hypertrophy, however, tau was prolonged (tauL: 27.3+/-2.3 vs. 21.8+/-2.2 ms, p < 0.001; and tauD: 43.2+/-3.1 vs. 34.3+/-3.3 ms, p < 0.001). Both chamber and myocardial stiffness constants remained unchanged. Incremental increases in heart rate produced incremental improvement in both contraction and relaxation. Slopes of force-frequency and relaxation-frequency relationships remained unchanged in the experimental group. However, the relaxation-frequency relationship manifested a parallel shift upward. CONCLUSIONS: In conscious, sedated children with myocardial hypertrophy, systolic function assessed by an index of force generation remains unchanged. However, relaxation is prolonged but passive diastolic properties remain unaffected. The combined effect of hypertrophy and heart rate does not alter the force-frequency and relaxation-frequency relationships.     

Right latissimus dorsi cardiomyoplasty augments left ventricular systolic performance

We hypothesized that the right latissimus dorsi cardiomyoplasty augments left ventricular performance. Five dogs underwent staged right latissimus dorsi cardiomyoplasty. Ventricular function was studied 1 to 3 weeks later. Left ventricular pressure was measured with a micromanometer and left ventricular dimensions with piezoelectric crystals. Inferior vena caval occlusion was used to vary preload. Pressure-volume data were collected with the muscle unstimulated and stimulated at 1:2 and 1:1 muscle/heart ratios. The end-systolic pressure-volume relation (mm Hg/mL), stroke work, preload recruitable stroke work, left ventricular end-diastolic volume, and the diastolic relaxation constant were calculated and expressed as mean +/- standard deviation. Stimulated beats at a 1:2 ratio showed an increase in stroke work of 42.1% (978 +/- 381 to 1,390 +/- 449 g.cm; p < 0.01) and preload recruitable stroke work of 28.8% (59.4 +/- 20.7 to 76.6 +/- 11.0 g.cm/cm3; p = 0.05) compared with the unstimulated beats. With the stimulator on at 1:1, smaller changes occurred: stroke work increased 9% (1,167 +/- 390 to 1,273 +/- 363 g.cm; not significant) and preload recruitable stroke work increased 27% (63.9 +/- 22.7 to 80.9 +/- 23.1 g.cm/cm3; p = 0.05). There were no significant changes in the end-systolic pressure-volume relation. The diastolic relaxation constant did not change at 1:1 (36 +/- 9.7 to 37 +/- 6.4 ms; not significant) or 1:2 (36 +/- 9.3 to 39 +/- 8.2 ms; not significant). Left ventricular end-diastolic volume was unchanged at 1:1 (34 +/- 10.7 to 32 +/- 10.3 mL) and at 1:2 (31 +/- 9.0 to 32 +/- 8.7 mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect on verapamil on ventricular function: studies in denervated human heart

Verapamil has complex influences on ventricular function owing to its direct myocardial effects, vasodilation, and reflex activation of the sympathetic nervous system. To investigate the direct myocardial effects of verapamil in humans independent of reflex sympathetic stimulation, we administered the drug to 13 recent heart transplant recipients with denervated ventricles. Hemodynamics and radionuclide angiograms were recorded at baseline, with altered loading conditions, and after intravenous (i.v.) verapamil (median dose 4 mg). Left ventricular (LV) systolic and diastolic function was analyzed by systolic pressure-volume relations (SPVR) and peak filling rate (PFR), respectively. Verapamil caused a decrease in blood pressure (BP) and heart rate (HR) with increases in right atrial pressure (RAP 6 +/- 3-8 +/- 3, p < 0.01) and pulmonary artery wedge pressure (PAWP, 9 +/- 3-11 +/- 3 mm Hg, p < 0.01) pressures. LV ejection fraction (EF) decreased (69 +/- 7-66 +/- 8%, p < 0.02) in association with an increase in LV end-systolic counts (3.45 +/- 1.27 to 4.72 +/- 1.78 kcts, p < 0.001). In 11 of 13 patients, the SPV point after verapamil administration was decreased from the line established during altered loading conditions. PFR (4.05 +/- 0.81 to 4.11 +/- 0.76 EDV/s) was unchanged. In the denervated ventricle, verapamil has negative chronotropic and inotropic effects with minimal effects on PFR.     

Exposure of the cryptic Arg-Gly-Asp sequence in thrombospondin-1 by protein disulfide isomerase

OBJECTIVES: Human cardiac muscle from failing heart shows a decrease in active tension development and a rise in diastolic tension at stimulation frequencies above 50-60 beats/min due to both systolic and diastolic dysfunction. We have investigated underlying changes in cellular [Ca2+]i regulation. METHODS: Single ventricular myocytes were isolated enzymatically from the explanted hearts of transplant recipients with ischemic cardiomyopathy (nhearts = 5 ncells = 15) or dilated cardiomyopathy (nhearts = 6, ncells = 19). Cells were studied during whole-cell patch clamp with fluo-3 and fura-red as [Ca2+]i indicators (36 +/- 1 degrees C). RESULTS: In current clamp mode (action potential recording), the amplitude of Ca2+ release from the sarcoplasmic reticulum (SR) decreased at stimulation frequencies above 0.5 Hz; this decrease was more pronounced for cells from dilated cardiomyopathy. Diastolic [Ca2+]i increased at 1 and 2 Hz for both groups. Action potential duration (APD90) decreased with frequency in all cells; in addition there was a drop in plateau potential of 10 +/- 1 mV for cells from ischemic cardiomyopathy and of 13 +/- 2 mV for cells from dilated cardiomyopathy. In voltage clamp mode the L-type Ca2+ current showed reversible decrease during stimulation at 1 and 2 Hz. Recovery from inactivation during a double pulse protocol was slow (75 +/- 3% at 500 ms, 89 +/- 3% at 1000 ms) and followed the decay of the [Ca2+]i transient. CONCLUSIONS: The negative force-frequency relation of the failing human heart is due to a decrease in Ca2+ release of the cardiac myocytes at frequencies > or = 0.5 Hz, more pronounced in dilated than in ischemic cardiomyopathy. Inhibition of ICaL at higher frequencies, at least partially related to an increase in diastolic [Ca2+]i, will contribute to this negative staircase because of a decrease in the trigger for Ca2+ release, and of decreased loading of the SR.     

Pneumothorax in the neonate

Dynamic cardiomyoplasty has been performed to reinforce the myocardium in the treatment of patients with severe cardiomyopathies. At the Heart Institute of S?o Paulo University Medical School, 36 patients were submitted to cardiomyoplasty between May 1988 and December 1993. The indications were idiopathic dilated cardiomyopathy in 31, ischemic cardiomyopathy in 3, and Chagas' disease cardiomyopathy in 2 patients. Twenty-eight patients were categorized in New York Heart Association (NYHA) Class III and 8 in Class IV despite the use of maximal medical therapy. There were no hospital deaths, and patients were followed up from 2 to 70 months (mean, 24 months). Besides the improvement of NYHA functional class from 3.2 +/- 0.6 to 1.6 +/- 0.9 at 6 months of follow-up, patients also presented significant changes in the left ventricular systolic and diastolic functions. Nevertheless, 16 patients died, and 2 patients were submitted to heart transplantation during late follow-up. Actuarial survival rates were 82.3% at 1 year, 61.5% at 2 years, and 38.8% at 5 years of follow-up. Otherwise, the analysis of factors influencing the outcome showed that long-term survival was significantly affected by preoperative functional class and by pulmonary vascular resistance. The 26 patients operated in NYHA functional Class III and with pulmonary vascular resistance below 4 Wood units presented survival rates of 72.7% at 2 years and of 63% at 5 years of follow-up. In conclusion dynamic cardiomyoplasty improves functional class and left ventricular function in patients with severe cardiomyopathies. However, the long-term survival after this surgical procedure may be limited by the patients' condition before the operation.     

Paradoxical hypertension after reversal of heart failure in patients treated with intensive vasodilator therapy

Hypertension is a major cause of heart failure, evolving from left ventricular hypertrophy to systolic and diastolic dysfunction. Although effective heart failure therapy has been associated with a lowering or no change in systemic arterial blood pressure in long-term follow-up, this study describes the symptomatic, clinical, and left ventricular functional response of a subgroup of heart failure patients with a prior history of hypertension who demonstrated a paradoxical hypertensive response despite high-dose vasodilator therapy. We prospectively identified 45 patients with a past history of hypertension who had become normotensive with symptomatic heart failure. Of these 45 heart failure patients, 12 became hypertensive while receiving therapy in follow-up, with systolic blood pressure > or = 140 mm Hg (Group A). The remaining 33 patients did not have a hypertensive response to therapy (Group B). In the 12 Group A patients, 60+/-10 years old, with symptomatic heart failure for 6.3+/-4.3 years, vasodilator therapy was intensified in the 2.0+/-0.5 years of follow-up, achieving final doses of enalapril 78+/-19 mg and isosorbide dinitrate 293 +/-106 mg per day. New York Heart Association classification improved from 2.9+/-0.8 to 1.3+/-0.5 (P < or = .0001), with a reduction in heart-failure-related hospitalizations. Left ventricular ejection fraction increased from 17+/-6% to 40+/-10% (P < .0001). Follow-up blood pressure at 1 to 3 months was unchanged. However, both systolic and diastolic blood pressure increased at final follow-up, rising from 116+/-14 to 154+/-13 mm Hg (P = .0001) and from 71+/-9 to 85+/-14 mm Hg (P = .004), respectively. Renal function remained unchanged. Although both groups had similar clinical responses, there were more blacks and women in the hypertensive Group A. Effectively, 12 of 45 (27%) heart failure patients with an antecedent history of hypertension demonstrated a paradoxical hypertensive response to vasodilator therapy. The recurrence of hypertension in a significant portion of patients successfully treated for heart failure has important clinical implications.     

Mechanisms of nitrate accumulation in plasma during pacing-induced heart failure in conscious dogs

The goal of this study was to understand the mechanisms behind the changes in plasma NOx during heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks (n = 14) and then 240 bpm for 1 week (n = 7). Hemodynamics, arterial blood gases, plasma NOx, and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 +/- 6 to 135 +/- 9 bpm), and LV dP/dt fell (2810 +/- 82 to 1471 +/- 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 +/- 0.7 to 25 +/- 0.8 mm Hg), and diastolic wall stress quadrupled (11 +/- 1.3 to 43 +/- 6.0 g/cm2, all P < 0.05). These changes occurred during a doubling in plasma NOx (5.5 +/- 1.5 to 10 +/- 1.6 microM, P < 0.05). There were no changes in plasma NOx through 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 +/- 0.32 to 1.21 +/- 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NOx did not correlate with LV dP/dt or systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NOx rose in direct relation to plasma creatinine levels (Y = 4.8X + 2.8, r2 = 0.84), suggesting that the rise in plasma NOx during heart failure is due to decreased renal function not increased NO production.     

Delayed stimulation of the latissimus dorsi may result in disuse atrophy

BACKGROUND: The latissimus dorsi is usually left unstimulated for 2 weeks after cardiomyoplasty to allow the muscle to recover from the loss of the collateral circulation. To determine whether the 2-week delay may cause muscle atrophy, we randomized 15 mongrel dogs to a control group or a disuse atrophy group. METHODS: The collateral circulation to the latissimus dorsi was ligated in all animals before cardiomyoplasty to reduce the risk of ischemic injury to the muscle during mobilization. Two weeks after collateral ligation, the atrophy group had the tendinous attachment of the latissimus dorsi severed and then 2 weeks later underwent cardiomyoplasty. The control group had a 2-week delay after collateral ligation followed by cardiomyoplasty. Biopsies were performed before collateral ligation and before cardiomyoplasty. After heart failure was induced, hemodynamic function was assessed during synchronized contraction of the latissimus dorsi by measuring the maximum systolic elastance, stroke volume, preload recruitable stroke work index, and diastolic compliance. RESULTS: Comparison of muscle morphology between the two groups demonstrated the presence of muscle atrophy in those animals that had been randomized to the atrophy protocol. During synchronized contraction of the latissimus dorsi, there was no significant increase in maximum systolic elastance in either group. However, both stroke volume and pulmonary recruitable stroke work index were significantly higher in the control animals during assisted beats. The left ventricle was less compliant in the atrophy group, suggesting that muscle atrophy had adversely affected diastolic function. CONCLUSIONS: Delayed electrical stimulation of the latissimus dorsi may result in atrophy and loss of function.     

Color-coded measures of myocardial velocity throughout the cardiac cycle by tissue Doppler imaging to quantify regional left ventricular function

TDI is a new echocardiographic technique that calculates and displays color-coded myocardial velocity on-line. To determine the feasibility of endocardial velocity throughout the cardiac cycle as a means to quantify regional function, 20 normal subjects aged 30 +/- 5 years and 12 patients with heart disease aged 62 +/- 17 years were studied with a prototype TDI system. TDI M-mode images were acquired by using a multicolored velocity map (display range, -30 to 30 mm/sec; temporal resolution, 90 Hz). Color-coded velocity data were then converted to numeric values off-line at 50 msec intervals. Posterior wall velocities throughout the cardiac cycle by TDI were closely correlated with velocity calculations from the first derivative of routine digitized M-mode tracings (group mean r = 0.88 +/- 0.03, SEE = 7.0 +/- 1.1 mm/sec). Anteroseptal TDI color-coded systolic velocity occurred 164 +/- 84 msec from the onset of the electrocardiographic QRS compared with 203 +/- 33 msec in the posterior wall (P < 0.05) in normal subjects, consistent with normal electrical activation. Significant differences in systolic and diastolic posterior wall TDI velocity data were observed in patients with hypokinetic or akinetic segments assessed by independent routine study when compared with normal controls. Calculated systolic and early diastolic posterior wall TDI indexes correlated significantly with percentage of wall thickening. Of abnormal anteroseptal segments, TDI systolic time velocity integrals were significantly different than normal and correlated with percentage of wall thickening. TDI has potential to quantitatively assess regional left ventricular function.