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.     

Anti-metastatic and immunomodulating properties of the water extract from Celosia argentea seeds

Although dynamic cardiomyoplasty (DCMP) is currently being evaluated as an alternative to end-stage congestive heart failure, the overall results of DCMP are variable and inconclusive. We evaluated the effect of classic DCMP on systolic and diastolic cardiac function in normal heart using reliable indicators which minimize the influences of load conditions. Six experimental dogs were evaluated with the acute nonpreconditioning model. The slope of the linear preload recruitable stroke work relationship (Mw) showed a significant increase with latissimus dorsi muscle (LDM) stimulation (postwrap non-stimulation 59.1+/-6.3, postwrap stimulation 98.6+/-9.7 erg cm(-3) x 10(3); P < 0.01), and the x-intercept (V0) was unchanged; these were utilized as the indicators of left ventricular systolic function. The constant of pressure decay (tau) increased after LDM wrap (prewrap 45.8+/-6.0, postwrap nonstimulation 69.3+/-10.3, postwrap stimulation 72.3+/-13.9 ms; P < 0.05), and the peak filling rate was unchanged after LDM wrap, which were utilized as the indicators of diastolic function. We concluded that classic dynamic cardiomyoplasty is effective in assisting systolic cardiac function, but may to some degree have a detrimental effect on the diastolic cardiac function.     

Functional analysis of myocardial performance in murine hearts overexpressing the human beta 2-adrenergic receptor

Transgenic mice overexpressing the human beta 2-adrenergic receptor gene were compared with wild mice type in terms of cardiac function, using a modified work-performing isolated murine heart preparation and on-line computer analysis. A preload-dependent experiment was performed, in which venous return was gradually increased in 5 mmHg increments from 5 mmHg to 25 mmHg. At each preload, aortic flow, left atrial pressure and aortic pressure were measured in all hearts, and from these parameters stroke volume, contractility, and cardiac index (cardiac output divided by body weight in g) were calculated and compared between groups. At increasing preload levels, the heart rates ranged from 322 beats/min (+/-29) to 369 beats/min (+/-39) in control mice and from 469 beats/min (+/-36) to 540 beats/min (+/-39) in transgenic mice. Cardiac index increased from 138 microliters/min/g (+/-13) and 48 microliters/min/g (+/-5) for transgenic and control mice, respectively at 5 mmHg preload to 262 microliters/min/g (+/-51) and 167 microliters/min/g (+/-15), respectively at 20 mmHg preload. The contractility in the transgenic mice were significantly increased at lower preload levels compared to control mice (1420 mmHg/s +/- 204 v 1187 mmHg/s +/- 127). An increase in myocardial adrenergic receptor density (100-200 fold) leads to significantly higher indices of cardiac function in transgenic mice compared to control mice. The increased heart rate leading to a positive inotropic effect in the hearts of transgenic mice is, at least in part, due to the overexpression of adrenergic receptors. These findings suggest a possible alternative method of establishing a positive chronotropic and inotropic state without the use of pharmacological agents.     

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.     

Endothelin-1 receptor antagonism does not influence myocardial function in hypertensive dogs

BACKGROUND: As endothelin-1 exerts positive inotropic effects, the present study evaluated whether the hypotensive effects of the endothelin-1 receptor antagonist bosentan were partially related to a decrease in myocardial performance. METHODS: In group I, eight anaesthetized open-chest dogs with perinephritic hypertension received four cumulative doses of bosentan (B1-B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure-length loops obtained during vena cava occlusion. RESULTS: In group I, bosentan decreased left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dose dependently, reaching 21% and 23% respectively at B4 (LVSP from 190 +/- 8 to 150 +/- 5 mmHg, P < 0.001; MAP from 167 +/- 7 to 128 +/- 5 mmHg, P < 0.001). These effects were only related to peripheral vasodilatation, without depression of myocardial contractility, as systemic vascular resistance dropped (from 670 +/- 83 to 446 +/- 53 mmHg mL-1 min-1 x 10(4); P < 0.05), and the end-systolic pressure-length relationship (ESPLR) remained unchanged (4.0 +/- 0.4 vs. 4.3 +/- 0.7 mmHg mm-1 kg-1). Concomitantly with pressure decline, heart rate tended to increase in this group (from 150 +/- 4 to 156 +/- 6 beats min-1). When autonomic system was blocked (group II), administration of bosentan induced similar hypotensive effects as in group I (26% and 28% reduction in LVSP and MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 +/- 0.9 vs. 3.1 +/- 0.5mmHg-1 mm kg-1 ). Under these sympathetically blocked conditions, heart rate significantly fell after bosentan infusion (from 120 +/- 4 to 110 +/- 6 beats min-1, P < 0.001). CONCLUSIONS: Without influencing heart function, bosentan is an efficient and safe therapy that opens up new therapeutic perspectives in human essential hypertension.     

Effects of hypovolemia on aortic baroreflex control of heart rate in humans

INTRODUCTION: To test the hypothesis that hypovolemia can acutely increase the sensitivity of chronotropic baroreflex response, eight men (21-45 yr old) underwent measurements of heart rate response to aortic baroreceptor stimulation under normovolemic and hypovolemic conditions. METHODS: Hypovolemia was acutely induced by a bolus injection of 30 mg of furosemide. The sensitivity of the aortic-cardiac baroreflex was determined with a approximately 15 mmHg elevation in mean arterial pressure (MAP) induced by steady-state infusion of 30 to 97 micrograms.min-1 phenylephrine (PE) combined with approximately 13 mmHg lower body negative pressure (LBNP) to counteract central venous pressure elevations, and 17-19 mmHg neck pressure (NP) to offset increases in carotid sinus transmural pressure. The aortic-cardiac baroreflex gain was assessed by determining the ratio of the change in heart rate to the change in MAP (delta HR/delta MAP) between baseline and aortic baroreceptor isolated conditions (i.e., PE + LBNP + NP stage). RESULTS: When compared to normovolemia (3182 +/- 163 ml), furosemide-induced hypovolemia (2812 +/- 101 ml) resulted in an average 12% reduction in plasma volume (p = 0.05). Hypovolemia increased the average gain of the aortic-cardiac baroreflex by 68% (0.71 +/- 0.26 to 1.19 +/- 0.37 beats.min-1.mmHg-1; p = 0.0349) while it had no effect on the calculated response of the carotid-cardiac baroreflex. CONCLUSIONS: These results indicate that greater aortic baroreflex sensitivity observed in individuals who are physically untrained or have been exposed to microgravity may be explained by smaller vascular volume rather than differences in autonomic function associated with adaptations to lower aerobic capacity.     

Chronic L-arginine treatment increases cardiac cyclic guanosine 5'-monophosphate in rats with aortic stenosis: effects on left ventricular mass and beta-adrenergic contractile reserve

OBJECTIVES: We tested the hypothesis that nitric oxide (NO) cyclic guanosine 5'-monophosphate (GMP) signaling is deficient in pressure overload hypertrophy due to ascending aortic stenosis, and that long-term L-arginine treatment will increase cardiac cyclic GMP production and modify left ventricular (LV) pressure overload hypertrophy and beta-adrenergic contractile response. BACKGROUND: Nitric oxide cyclic GMP signaling is postulated to depress vascular growth, but its effects on cardiac hypertrophic growth are controversial. METHODS: Forty control rats and 40 rats with aortic stenosis left ventricular hypertrophy ([LVH] group) were randomized to receive either L-arginine (0.40 g/kg/day) or no drug for 6 weeks. RESULTS: The dose of L-arginine did not alter systemic blood pressure. Animals with LVH had similar LV constitutive nitric oxide synthase (cNOS) mRNA and protein levels, and LV cyclic GMP levels as compared with age-matched controls. In rats with LVH L-arginine treatment led to a 35% increase in cNOS protein levels (p = 0.09 vs untreated animals with LVH) and a 1.7-fold increase in LV cyclic GMP levels (p < 0.05 vs untreated animals with LVH). However, L-arginine treatment did not suppress LVH in the animals with aortic stenosis. In contrast, in vivo LV systolic pressure was depressed in L-arginine treated versus untreated rats with LVH (163 +/- 16 vs 198 +/- 10 mm Hg, p < 0.05). In addition, the contractile response to isoproterenol was blunted in both isolated intact hearts and isolated myocytes from L-arginine treated rats with LVH compared with untreated rats with LVH. This effect was mediated by a blunted increase in peak systolic intracellular calcium in response to beta-adrenergic stimulation. CONCLUSIONS: Left ventricular hypertrophy due to chronic mechanical systolic pressure overload is not characterized by a deficiency of LV cNOS and cyclic GMP levels. In rats with aortic stenosis, L-arginine treatment increased cardiac levels of cyclic GMP, but it did not modify cardiac mass in rats with aortic stenosis. However, long-term stimulation of NO-cyclic GMP signaling depressed in vivo LV systolic function in LVH rats and markedly blunted the contractile response to beta-adrenergic stimulation.     

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.     

Filling and arterial pressures as determinants of RV stroke volume in the sheep fetus

Right ventricular (RV) function was investigated in nine fetal lambs (125-130 days gestation) that were instrumented with pulmonary artery electromagnetic flow sensors and vascular catheters. Control arterial CO2 and O2 tension, pH, and hematocrit values were 46.1 +/- 1.6 (SD) Torr, 20.6 +/- 1.8 Torr, 7.39 +/- 0.02, and 31 +/- 5.3%, respectively. Control values for right ventricular output (247 +/- 75 ml X min-1 X kg-1), stroke volume (SV, 1.5 +/- 0.4 ml X kg-1), right atrial pressure (3.7 +/- 1.2 mmHg), heart rate (166 +/- 18 beats X min-1), and arterial pressure (AP, 43 +/- 4 mmHg) were unchanged by administration of atropine and propranolol. Withdrawal and infusion of fetal blood with or without concomitant infusion of nitroprusside or phenylephrine produced RV function curves at low, normal, and high arterial pressures. All function curves had a steep ascending limb and a plateau. The breakpoint joining the limbs of the control curve was right atrial pressure 3.4 +/- 1.2 mmHg and SV 1.5 +/- 0.4 ml X kg-1. Increased AP shifted the breakpoint downward. Linear regression of SV on AP from 15 to 95 mmHg at right atrial pressure greater than breakpoint was SV = -0.016 ml X kg-1 mmHg-1 X AP + 2.25 ml X kg-1.     

Effect of chronotropic and inotropic stimulation on the coronary pressure-flow relation in left ventricular hypertrophy

Left ventricular hypertrophy (LVH) secondary to chronic pressure overload is associated with increased susceptibility to myocardial hypoperfusion and ischemia during increased cardiac work. The present study was performed to study the effects of chronotropic and inotropic stimulation on the coronary pressure-flow relation of the hypertrophied left ventricle of dogs and to determine the individual contributions of increases in heart rate and contractility to the exaggerated exercise-induced increases in effective back pressure (pressure at zero flow; Pzf). Ascending aortic banding in seven dogs increased the LV to body weight ratio to 7.7 +/- 0.3 g/kg compared to 4.8 +/- 0.2 g/kg in 10 normal dogs (p < or = 0.01). Maximum coronary vasodilation was produced by intracoronary infusion of adenosine. During resting conditions maximum coronary blood flow in the pressure overloaded hypertrophied left ventricle was impaired by both an increase in Pzf (25.1 +/- 2.6 vs 13.8 +/- 1.2 mmHg in hypertrophied vs normal ventricles, respectively, p < or = 0.01) and a decrease in maximum coronary conductance (slope of the linear part of the pressure-flow relation, slopep > or = linear) (8.6 +/- 1.1 vs 12.7 +/- 0.9 ml/min/mmHg, p < or = 0.01). Right atrial pacing at 200 and 250 beats/min resulted in similar rightward shifts of the pressure-flow relation in hypertrophied and normal hearts with 3.1 +/- 0.8 and 4.7 +/- 0.8 mmHg increases in Pzf in LVH and normal dogs, respectively; stepwise multivariate regression analysis indicated that the exaggerated decrease in filling pressure (10 +/- 2 vs 6 +/-2 mmHg) and decrease in left ventricular systolic pressure (45 +/- 5 vs 3 +/- 3 mmHg, p < or = 0.01) may have blunted a greater rightward shift of the pressure-flow relation produced by atrial pacing in the hypertrophied hearts. Inotropic stimulation with dobutamine (10-20 micrograms/kg/min, i.v.) resulted in minimal flow changes in normal hearts but produced a 4.4 +/- 1.5 mmHg (p < or = 0.05) rightward shift of the pressure-flow relation in hypertrophied hearts. which correlated with a greater increase in left ventricular systolic pressure (83 +/- 16 vs 18 +/- 4 mmHg. p < or = 0.05). Exercise resulted in a rightward shift in both normal and hypertrophied left ventricles, but the increase in Pzf was significantly greater in the hypertrophied hearts (15.2 +/- 0.9 vs 10.3 +/- 0.9 mmHg. p < or = 0.05). Stepwise multivariate regression analysis indicated that not only increases in left ventricular filling pressure, but also increases in heart rate and LV systolic pressure contributed to the abnormally great increase in effective coronary back pressure which results in limitation of myocardial perfusion during exercise in the pressure overloaded hypertrophied left ventricle.     

Left ventricular diastolic filling with an implantable ventricular assist device: beat to beat variability with overall improvement

OBJECTIVES: We studied the effects of left ventricular (LV) unloading by an implantable ventricular assist device on LV diastolic filling. BACKGROUND: Although many investigators have reported reliable systemic and peripheral circulatory support with implantable LV assist devices, little is known about their effect on cardiac performance. METHODS: Peak velocities of early diastolic filling, late diastolic filling, late to early filling ratio, deceleration time of early filling, diastolic filling period and atrial filling fraction were measured by intraoperative transesophageal Doppler echocardiography before and after insertion of an LV assist device in eight patients. A numerical model was developed to simulate this situation. RESULTS: Before device insertion, all patients showed either a restrictive or a monophasic transmitral flow pattern. After device insertion, transmitral flow showed rapid beat to beat variation in each patient, from abnormal relaxation to restrictive patterns. However, when the average values obtained from 10 consecutive beats were considered, overall filling was significantly normalized from baseline, with early filling velocity falling from 87 +/- 31 to 64 +/- 26 cm/s (p < 0.01) and late filling velocity rising from 8 +/- 11 to 32 +/- 23 cm/s (p < 0.05), resulting in an increase in the late to early filling ratio from 0.13 +/- 0.18 to 0.59 +/- 0.38 (p < 0.01) and a rise in the atrial filling fraction from 8 +/- 10% to 26 +/- 17% (p < 0.01). The deceleration time (from 112 +/- 40 to 160 +/- 44 ms, p < 0.05) and the filling period corrected by the RR interval (from 39 +/- 8% to 54 +/- 10%, p < 0.005) were also significantly prolonged. In the computer model, asynchronous LV assistance produced significant beat to beat variation in filling indexes, but overall a normalization of deceleration time as well as other variables. CONCLUSIONS: With LV assistance, transmitral flow showed rapidly varying patterns beat by beat in each patient, but overall diastolic filling tended to normalize with an increase of atrial contribution to the filling. Because of the variable nature of the transmitral flow pattern with the assist device, the timing of the device cycle must be considered when inferring diastolic function from transmitral flow pattern.     

A population-based prospective evaluation of risk of sudden cardiac death after operation for common congenital heart defects

1. Ischaemic cardiac preconditioning represents an important cardioprotective mechanism which limits myocardial ischaemic damage. The aim of this investigation was to assess the impact of dichloroacetate (DCA), a pyruvate dehydrogenase complex activator, on preconditioning. 2. Rat isolated hearts were perfused by use of the Langendorff technique, and were subjected to either preconditioning (3 x 4 or 3 x 6 min ischaemia) or continuous perfusion, followed by 30 min global ischaemia and 60 min reperfusion. DCA (3 mM) was either given throughout the protocol (pretreatment), during reperfusion only (post-treatment), or not at all. Throughout reperfusion mechanical performance was assessed as the rate-pressure product (RPP: left ventricular developed pressure x heart rate). 3. In non-preconditioned control hearts, mechanical performance was substantially (P < 0.001) depressed on reperfusion (the RPP after 60 min of reperfusion (RPP(t=60)) was 4,246+/-974 mmHg beats min(-1) compared to baseline value of 21,297+/-1,728 mmHg beats min(-1)). Preconditioning with either 3 x 4 min or 3 x 6 min cycles caused significant protection, as shown by enhanced recovery (RPP(t=60) = 7,818+/-1,138, P < 0.05, and 11,123+/-587 mmHg beats min(-1), P < 0.001, respectively). 4. Addition of DCA (3 mM) to hearts under baseline conditions significantly (P < 0.001) enhanced systolic function with an increased left ventricular developed pressure of 108+/-5 mmHg compared to 88.3+/-3.0 mmHg in the controls. 5. Pretreatment with 3 mM DCA had no effect on recovery of mechanical performance in the non-preconditioned hearts (RPP(t=60) = 3,640+/-1,235 mmHg beats min(-1)) while the beneficial effects of preconditioning were reduced in the preconditioned hearts (3 x 4 min: RPP(t=60) = 2,919+/-1,060 mmHg beats min(-1); 3 x 6 min: RPP(t=60) = 8,032+/-1,367 mmHg beats min(-1)). Therefore, DCA had increased the threshold for preconditioning. 6. By contrast, post-treatment of hearts with 3 mM DCA substantially improved recovery on reperfusion in all groups (RPP(t=60) = 5,827+/-1,328 (non-preconditioned), 14,022+/-3,743 (3 x 4 min; P < 0.01) and 23,219+/-1,374 (3 x 6 min; P < 0.001) mmHg beats min(-1)). 7. The results of the present investigation clearly show that pretreatment with DCA enhances baseline cardiac mechanical performance but increases the threshold for cardiac preconditioning. However, post-treatment with DCA substantially augments the beneficial effects of preconditioning.     

Inotropic reserve and histological appearance of hibernating myocardium in conscious pigs with ameroid-induced coronary stenosis

Inotropic reserve, demonstrated with administration of sympathomimetic amines, is characteristic of hibernating myocardium. The goal of this study was to determine whether inotropic reserve was present following chronic coronary artery constriction in the pig, which is one potential model of hibernating myocardium. The effects of isoproterenol were examined in five conscious pigs 21 +/- 2.1 days after ameroid implantation on the left circumflex coronary artery on measurements of left ventricular (LV) pressure, LV dP/dt, and regional wall thickening in the ameroid-dependent zone (posterior wall) and contralateral non-ischemic zone (anterior wall). Isoproterenol, 0.1 microgram/kg/min, increased LV dP/dt by 96 +/- 11%, heart rate by 43 +/- 13 beats/min, and normalized systolic wall thickening, slightly, but not significantly more in the ameroid-dependent zone (+1.57 +/- 0.31 mm) than in the contralateral non-ischemic zone (+1.04 +/- 0.31 mm), although the baseline wall thickening was reduced significantly in the ameroid-dependent zone. This occurred at a time when baseline myocardial blood flow was preserved and myocardial perfusion in the ameroid-dependent zone was derived in part from the native coronary circulation and also through collateral channels. Two weeks later histological evidence of lesions characteristic of hibernating myocardium, i.e., myofibrolysis and increased glycogen deposition, were observed. Thus, these histological changes and the confluence of chronically depressed regional function and residual inotropic reserve in the conscious pig with chronic ameroid-induced coronary constriction support this model for further study of hibernating myocardium.     

Cardiac afferents attenuate the muscle metaboreflex in the rat

The influence of cardiac afferents on the muscle metaboreflex was examined in 16 rats instrumented with a Silastic-tipped catheter in the pericardial space and right atrium, Doppler ultrasonic flow probe and a pneumatic vascular occluder around the terminal aorta, and a Teflon catheter in the thoracic aorta. In protocol I (cardiac efferent and afferent blockade), the muscle metaboreflex was examined under three experimental conditions: 1) control, 2) cardiac autonomic efferent blockade [intrapericardial methylscopolamine (10 micrograms/kg) and propranolol (50 micrograms/kg)], and 3) combined cardiac autonomic efferent and afferent blockade (intrapericardial procainamide, 2%). In protocol II (blood volume expansion), the muscle metaboreflex was examined before and after 15% blood volume expansion. Mild treadmill exercise (9 m/min, 10% grade) increased heart rate (71 +/- 9.4 beats/min), mean arterial pressure (12 +/- 2.0 mmHg), and terminal aortic blood flow velocity (6 +/- 1.0 kHz). During exercise, a reduction of terminal aortic blood flow velocity (10.5 +/- 1.1%) reduced mixed venous PO2 18 +/- 6%. The gain of the muscle metaboreflex in the control condition was 14.6 +/- 2.9 mmHg/kHz. Efferent blockade reduced the gain 51 +/- 7%. However, combined cardiac efferent and afferent blockade increased the gain 207 +/- 64% above the efferent blocked condition and restored the gain to levels above those obtained in the control condition (18.3 +/- 4.6 mmHg/kHz). In addition, 15% blood volume expansion reduced the gain of the muscle metaboreflex regulation of mean arterial pressure and heart rate (44 +/- 9.5% and 41 +/- 12.0%, respectively). Thus cardiac afferents tonically inhibit the pressor response to a reduction in terminal aortic blood flow velocity during exercise.     

Antihypertensive effects of food-intake restriction in aortic coarctation hypertension

OBJECTIVE: To test the hypothesis that reductions in mean arterial pressure (MAP) induced by food-intake restriction in aortic coarctation hypertension are the result of a reduction of the sympathetic support of the MAP. We also wanted to determine whether the baroreflex control of the heart rate, and alpha- and beta-adrenergic responsivenesses were influenced by chronic food-intake restriction. METHODS: Four days after aortic coarctation, female Sprague-Dawley rats were assigned to a group that had access ad libitum to food (CON; n = 19) or to a food-intake-restricted group (FRG; n = 17) that was allowed 60% of the CON group's food intake per rat. After 3 weeks, carotid and jugular catheters were implanted for measurement of the MAP and infusion of drugs into conscious rats. The sympathetic contribution to the blood pressure was assessed by measuring the depressor response to ganglionic blockade by hexamethonium plus atropine (30.0 and 0.1 mg/kg intravenously). The baroreflex control of the heart rate was assessed by administering alternating bolus doses of phenylephrine and nitroprusside. The alpha-adrenergic sensitivity was assessed by measuring the response of the MAP to phenylephrine in areflexive rats (after ganglionic blockade), and the beta-adrenergic sensitivity was assessed by measuring the responses of the MAP and heart rate to isoproterenol administration both in reflexive and in areflexive rats. RESULTS: Four days after catheterization, both the MAP (CON 150 +/- 5 mmHg, FRG 116 +/- 4 mmHg) and the heart rate (CON 414 +/- 8 beats/min, FRG 365 +/- 11 beats/min) were significantly lower in rats of the FRG. That the sympathetic support of the MAP had diminished in FRG rats was evidenced by an attenuated depressor response to ganglionic blockade (40 +/- 3 versus 65 +/- 3 mmHg). FRG rats exhibited significantly greater reflex bradycardia in response to phenylephrine (slope -1.44+/- 0.07 versus -0.54 +/- 0.05 beats/min per mmHg), whereas their reflex tachycardia was not altered (slope -1.58 +/- 0.08 versus -1.53 +/- 0.13 beats/min per mmHg). FRG rats also displayed blunted responses of the heart rate and MAP to isoproterenol administration. CONCLUSION: Food-intake restriction attenuates the rise in MAP which occurs after aortic coarctation significantly. The antihypertensive effect of food-intake restriction may be mediated via a reduction in sympathetic tone.     

Efficacy of coronary artery bypass grafting in patients with a dilated left ventricle due to myocardial infarction

This study was designed to clarify the efficacy of coronary artery bypass grafting (CABG) on left ventricular (LV) function in 16 patients with a dilated LV due to myocardial infarction (LV end-systolic volume index: LVESVI >60 ml/m2). All had attained complete revascularization. To estimate the LV wall motion quantitatively using echocardiography, a wall motion score (WMS) was used (LV was divided into 17 segments with a four-point scale: akinesis=3, severe hypokinesis=2, hypokinesis=1, normal=0 and then summed). Exercise stress tests were performed after surgery, revealing that anginal symptoms had vanished in all the patients. In 5 patients with a preoperative end-systolic volume index (ESVI) >100 ml/m2, the ejection fraction (EF) did not change, and both were under 30% (before to after: 26+/-4 to 26+/-4%). Neither the ESVI (148+/-50 to 133+/-39 ml/m2) nor the end-diastolic volume index (end-diastolic volume index (EDVI): 198+/-62 to 180+/-37 ml/m2) changed; the WMS did not change (33+/-2 to 33+/-3). During exercise, in spite of the increase in heart rate (HR) (at rest, 81+/-20; HR during exercise, 111+/-21 beats/min, p<0.005) and LV end-diastolic pressure (EDP) (22+/-9; 35+/-13 mmHg, p<0.02), both cardiac index (CI) (2.4+/-0.3; 2.6+/-0.4 L/min x m2) and minute work (MW: 4.0+/-1.1; 4.1+/-0.4 kg x M/min) did not increase. In 11 patients with a preoperative ESVI <100 ml/m2, EF was extremely increased in 5 patients (more than 10%, 35+/-4 to 60+/-6%, p<0.005=improved subgroup) in whom the EDVI (130+/-16 to 120+/-13 ml/m2) did not change whereas the ESVI (82+/-14 to 48+/-7 ml/m2) was reduced. However, in the 6 remaining patients (ie nonimproved subgroup), neither ESVI (78+/-8 to 74+/-12 ml/m2), EDVI (115+/-10 to 115+/-20 ml/m2) nor EF (31+/-7 to 35+/-3%) changed. During exercise, HR (at rest, 88+/-13; during exercise, 108+/-11 beats/min, p<0.005), LVEDP (20+/-6; 29+/-7 mmHg, p<0.01), CI (2.5+/-0.6; 3.3+/-0.5 L/min x m2, p<0.05), MW (4.6+/-1.0; 6.5+/-1.5 kg x M/min, p<0.05) increased. The WMS in the nonimproved subgroup did not change (29+/-6 to 27+/-2), but in the improved subgroup it reduced after surgery (27+/-3 to 19+/-4, p<0.01). These data suggested that CABG in patients with a dilated LV was effective against anginal symptoms, but was restricted to left ventricular function. It may be possible to estimate postoperative LV function, including exercise tolerance, from the preoperative LVESVI.     

Influence of one bout of intensive running on lymphocyte micronucleus frequencies in endurance-trained and untrained men

This clinical investigation was designed to determine the effect of changes in loading patterns on left ventricular (LV) relaxation when heart rate was maintained constant. Not only were changes noted in total load or time in which load is changed, but also the contour of the ascending aortic systolic pressure wave. Twenty patients were studied. LV and ascending aortic pressure were measured by a multisensor catheter under baseline conditions (C) and after an intravenous injection of 2.5 microg angiotensin (A) and sublingual administration of 0.3 mg nitroglycerin (N). A bipolar pacing catheter was placed in the right atrium to maintain a constant heart rate throughout the protocol. The augmentation index (AI), which characterizes the contour of the ascending aortic systolic pressure wave, was defined as the ratio of the height of the late systolic shoulder/peak to that of the early systolic shoulder/peak in the pulse. The rate of isovolumic LV pressure decline was calculated as a time constant (Tau). Ascending aortic systolic pressures (mmHg) were 127+/-29 (C), 158+/-20 (A) and 109+/-15 (N). AI were 1.61+/-1.14 (C), 2.08+/-1.11 (A) and 1.27+/-1.14 (N). Tau values (msec) were 49+/-4 (C), 54+/-4 (A) and 45+/-5 (N). Tau was prolonged proportionally with increasing AI (p<0.001, r=0.64). It was concluded that late systolic pressure augmentation in the ascending aorta is one important factor that influences the rate of isovolumic left ventricular pressure decline in humans.     

Acute alterations in systolic ventricular interdependence-mechanical dependence of right ventricle on left ventricle following acute alteration of right ventricular free wall

The purpose of the study was to examine whether systolic ventricular interdependence can be acutely altered by changes in the mechanical properties of the ventricular wall. In eight acute canine studies, we released an aortic constriction during diastole. We measured right ventricular (RV) pressure changes (dPr) caused by sudden changes in left ventricular (LV) pressure (dPl). Measurements were obtained during control, 10 min after right coronary artery occlusion, and then 15 min after injecting glutaraldehyde into the RV free wall. By superimposing the pressure tracings of the beats immediately before and after the aortic release, the instantaneous pressure difference ratio (dPr/dPl) was calculated during systole. Maximal value of the pressure difference ratio decreased from control 0.11 +/- 0.04 to ischemia 0.08 +/- 0.03; (p < 0.05) and increased with glutaraldehyde 0.15 +/- 0.06; (p < 0.05). Thus, acute ischemia in RV free wall decreased the magnitude of systolic ventricular interdependence from LV to RV, while glutaraldehyde, which stiffens the RV free wall, increased the magnitude.     

Hemodynamic determinants of the time-course of fall in canine left ventricular pressure

The hemodynamic determinants of the time-course of fall in isovolumic left ventricular pressure were assessed in isolated canine left ventricular preparations. Pressure fall was studied in isovolumic beats or during prolonged isovolumic diastole after ejection. Pressure fall was studied in isovolumic relaxation for isovolumic and ejecting beats (r less than or equal to 0.98) and was therefore characterized by a time constant, T. Higher heart rates shortened T slightly from 52.6 +/- 4.5 ms at 110/min to 48.2 +/- 6.0 ms at 160/min (P less than 0.01, n = 8). Higher ventricular volumes under isovolumic conditions resulted in higher peak left ventricular pressure but no significant change in T. T did shorten from 67.1 +/- 5.0 ms in isovolumic beats to 45.8 +/- 2.9 ms in the ejecting beats (P less than 0.001, n = 14). In the ejecting beats, peak systolic pressure was lower, and end-systolic volume smaller. To differentiate the effects of systolic shortening during ejection from those of lower systolic pressure and smaller end-systolic volume, beats with large end-diastolic volumes were compared to beats with smaller end-diastolic volumes. The beats with smaller end-diastolic volumes exhibited less shortening but similar end-systolic volumes and peak systolic pressure. T again shortened to a greater extent in the beats with greater systolic shortening. Calcium chloride and acetylstrophanthidin resulted in no significant change in T, but norepinephrine, which accelerates active relaxation, resulted in a significant shortening of T (65.6 +/- 13.4 vs. 46.3 +/- 7.0 ms, P less than 0.02). During recovery from ischemia, T increased significantly from 59.3 +/- 9.6 to 76.8 +/- 13.1 ms when compared with the preischemic control beat (P less than 0.05). Thus, the present studies show that the time-course of isovolumic pressure fall subsequent to maximum negative dP/dt is exponential, independent of systolic stress and end-systolic fiber length, and minimally dependent on heart rate. T may be an index of the activity of the active cardiac relaxing system and appears dependent on systolic fiber shortening.     

Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury

Several studies report that among the antioxidant agents used to reduce injury after myocardial ischemia/reperfusion, analogues of vitamin E (VE) seem to have a significant efficacy. Raxofelast is a potent antioxidant agent under investigation, structurally related to VE, having an excellent bioavailability and favourable physicochemical properties. We assessed raxofelast in a rat model of myocardial damage induced by 1 h of left coronary artery occlusion followed by 6 h of reperfusion. Myocardial ischemia/reperfusion produced: wide tissue necrosis (50.3+/-10.3%); membrane peroxidation, evaluated by assessing cardiac malondialdehyde (MAL) (87.8+/-15.8 nmol/g tissuev 9.53+/-2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73+/-1.86 DeltaABS/mlv 1.61+/-0.45 DeltaABS/ml); endogenous antioxidant wasting [cardiac VE=23.5+/-10.2 nmol/g tissuev 61.4+/-13.4 nmol/g tissue, cardiac reduced glutatione (GSH)=2.15+/-1.23 micromol/g proteinv 7.34+/-0.92 micromol/g protein and cardiac superoxide dismutase (SOD)=8.9+/-4.1 U/mg proteinv 17. 5+/-4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4+/-5.8 mmHgv 85.3+/-6.2 mmHg); heart rate (HR) (275+/-35 beats/minv 368+/-34 beats/min) and left-ventricular derivative developed force (LV dP/dtmax) (1050+/-187 mmHg/sv 2520+/-194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23+/-2.1 U/g tissuev 0.92+/-0.12 U/g tissue). Administration of raxofelast (25, 50 and 100 mg/kg i.p. 5 min after occlusion) limited myocardial necrosis (22.3+/-14.8%P<0. 005, following the highest dose), reduced lipid peroxidation (MAL=43. 5+/-14.7 nmol/g tissueP<0.001 and CD=4.01+/-2.21 DeltaABS/mlP<0.001, following the highest dose), restored the endogenous antioxidants VE (52.8+/-14.2 nmol/g tissueP<0.001, following the highest dose), SOD (14.2+/-2.7 U/mg proteinP<0.001, following the highest dose) and GSH (4.92+/-1.33 micromol/g proteinP<0.005, following the highest dose), improved hemodynamic parameters (MAP=68.1+/-5.3 mmHgP<0.05, HR=317+/-27 beats/minP<0.05, LV dP/dtmax=1427+/-143 mmHg/sP<0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO=5.1+/-1.5 U/g tissueP<0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.