Effects of chronic angiotensin-converting enzyme inhibition on left ventricular and myocyte structure and function during recovery from chronic rapid pacing

LV and myocyte function and angiotensin converting enzyme (ACE) activity with ACE inhibitor (ACEI) treatment were examined in four groups of dogs (n = 6 each): (1) control; (2) with 4 weeks of recovery from chronic rapid pacing (REC: 216 beats/min), (3) ACEI for the first 14 days of REC (ACEI--14), and (4) ACEI for 28 days of REC (ACEI--28). Three additional control dogs were administered ACEI for 28 days. LV mass increased with REC compared to control (146 +/- 6 v 92 +/- 3 g, P < 0.05), was unaffected with ACEI--14, and was decreased with ACEI--28 compared to REC (111 +/- 8 g, P < 0.05). Myocyte function was decreased in REC compared to controls (43 +/- 3 v 63 +/- 3 microns/s, P < 0.05) and was similarly reduced with ACEI--14. However, with ACEI--28, myocyte shortening velocity was increased compared to REC (56 +/- 1 microns/s, P < 0.05). Myocyte beta-adrenergic response was decreased with REC and ACEI--14 compared to controls (53 +/- 9 and 57 +/- 14, respectively v 127 +/- 14 microns/s, P < 0.05). ACEI--28 resulted in a normalization of myocyte beta-adrenergic responsiveness (108 +/- 3 microns/s). LV myocardial ACE activity increased in REC compared to control (5.82 +/- 0.21 v 3.51 +/- 0.15 nmol/mg/min, P < 0.05). With ACEI--14 or ACEI--28, myocardial ACE activity was decreased compared to REC (4.16 +/- 0.06 and 4.08 +/- 0.23 nmol/mg/min; P < 0.05). In control dogs administered ACEI, there were no differences in any of these parameters compared to controls. The unique findings in this study were: (1) effects of ACEI treatment in this model of LV hypertrophy were time dependent with respect to LV mass and LV and myocyte function; and (2) the effect of ACEI treatment on the degree of LV hypertrophy appears to not be solely due modulation of myocardial ACE activity.     

Angiotensin converting enzyme inhibition, AT1 receptor inhibition, and combination therapy with pacing induced heart failure: effects on left ventricular performance and regional blood flow patterns

BACKGROUND: AT1 receptor activation has been demonstrated to cause increased vascular resistance properties which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT1 receptor blockade alone and combined ACEI and AT1 receptor blockade on LV pump function, systemic hemodynamics and regional blood flow patterns in the normal state and with the development of pacing induced CHF, both at rest and with treadmill induced exercise. METHODS AND RESULTS: Pigs (25 kg) were instrumented in order to measure cardiac output (CO), systemic (SVR) and pulmonary vascular (PVR) resistance, neurohormonal system activity, and myocardial blood flow distribution in the conscious state and assigned to one of 4 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 7); (2) ACEI (benazeprilat, 3.75 mg/day) and pacing (n = 7); (3) AT1 receptor blockade (valsartan, 60 mg/day) and rapid pacing (n = 7); and (4) ACEI and AT1 receptor blockade (benazeprilat/valsartan, 1/60 mg/day, respectively) and pacing (n = 7). Measurements were obtained at rest and with treadmill exercise (15 degrees, 3 miles/h; 10 min) in the normal control state and after the completion of the treatment protocols. With rapid pacing, CO was reduced at rest and with exercise compared to controls. ACEI or AT1 blockade normalized CO at rest, but remained lower than control values with exercise. Combination therapy normalized CO both at rest and with exercise. Resting SVR in the CHF group was higher than controls and SVR fell to a similar degree with exercise; all treatment groups reduced resting SVR. With exercise, SVR was reduced from rapid pacing values in the ACEI and combination therapy groups. PVR increased by over 4-fold in the rapid pacing group both at rest and with exercise, and was reduced in all treatment groups. In the combination therapy group, PVR was similar to control values with exercise. Plasma catecholamines and endothelin levels were increased by over 3-fold with chronic rapid pacing, and were reduced in all treatment groups. In the combination therapy group, the relative increase in catecholamines and endothelin with exercise were significantly blunted when compared to rapid pacing only values. LV myocardial blood flow at rest was reduced in the rapid pacing only and monotherapy groups, but was normalized with combination therapy. CONCLUSION: These findings suggest that with developing CHF, combined ACE inhibition and AT1 receptor blockade improved vascular resistive properties and regional blood flow distribution to a greater degree than that of either treatment alone. Thus, combined ACEI and AT1 receptor blockade may provide unique benefits in the setting of CHF.     

Right and left ventricular geometry and myocyte contractile processes with dilated cardiomyopathy: myocyte growth and beta-adrenergic responsiveness

OBJECTIVES: Comparison of the effects of supraventricular tachycardia-induced dilated cardiomyopathy on left and right ventricular isolated myocyte geometry and function. BACKGROUND: Chronic ventricular tachycardia and supraventricular tachycardia cause left ventricular dilation and dysfunction in humans. However, it is unknown whether supraventricular tachycardia-induced dilated cardiomyopathy is a homogenous process for both the left and right ventricles. METHODS: Dilated cardiomyopathy was induced by rapid atrial pacing (240 beats/min, 3 weeks) in 5 pigs. Five age- and weight-matched pigs served as controls. Ventricular mass was measured, myocyte dimensions were obtained, and isolated right and left ventricular myocyte contractile performance was evaluated at baseline and after beta-adrenergic receptor stimulation. RESULTS: With the development of dilated cardiomyopathy, there was no change in left ventricular mass. In contrast, right ventricular mass was increased, as was right ventricular myocyte cross-sectional area. In the control group, baseline right ventricular myocyte contractile function was increased compared to left ventricular myocytes. beta-adrenergic receptor stimulation increased myocyte contractile function in both left and right ventricular myocytes. With supraventricular tachycardia-induced cardiomyopathy, both left and right ventricular myocyte contractile function and beta-adrenergic responsiveness were reduced. CONCLUSIONS: This study demonstrated differences in left and right ventricular myocyte growth with supraventricular tachycardia-induced dilated cardiomyopathy and this differential growth response was associated with changes in contractile performance. Thus, in this model of cardiomyopathic disease, left and right ventricular growth and changes in contractile performance are not a homogenous process.     

Altered ventricular and myocyte response to angiotensin II in pacing-induced heart failure

Alterations in the cardiac response to angiotensin II (Ang II) may contribute to the functional impairment in tachycardia-induced heart failure (congestive heart failure [CHF]). Accordingly, we studied the response to Ang II in eight conscious instrumented dogs before and after inducing CHF. Left ventricular (LV) performance was assessed by measuring LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before CHF, Ang II produced a load-dependent slowing of the time constant of LV relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure, the increases in LV diastolic pressure and time constant tau were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prevented by nitroprusside. Similar changes were also present after autonomic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, Ang II produced a negative inotropic effect and slowed the rate of relengthening. The effects in the intact LV and myocytes were reversed by an Ang II AT1 receptor blocker (losartan). We conclude that pacing-induced CHF alters the LV and myocyte response to Ang II, so that Ang II produces direct depressions in intact LV contraction, relaxation, and filling and exacerbates myocyte contractile dysfunction. These effects are mediated through the activation of AT1 receptors.     

Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart

BACKGROUND: The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT1) receptor in the failing human heart are not understood. METHODS AND RESULTS: Radioligand binding with 3H-ramiprilat was used to measure ACE protein in membrane preparations of hearts obtained from 36 subjects with idiopathic dilated cardiomyopathy (IDC), 8 subjects with primary pulmonary hypertension (PPH), and 32 organ donors with normal cardiac function (NF hearts). 125I-Ang II formation was measured in a subset of hearts. Saralasin (125I-(Sar1,Ile8)-Ang II) was used to measure total Ang II receptor density. AT1 and AT2 receptor binding were determined with the AT1 receptor antagonist losartan. Maximal ACE binding (Bmax) was 578+/-47 fmol/mg in IDC left ventricle (LV), 713+/-97 fmol/mg in PPH LV, and 325+/-27 fmol/mg in NF LV (P<0.001, IDC or PPH versus NF). In IDC, PPH, and NF right ventricles (RV), ACE Bmax was 737+/-78, 638+/-137, and 422+/-49 fmol/mg, respectively (P=0.02, IDC versus NF; P=0.08, PPH versus NF). 125I-Ang II formation correlated with ACE binding sites (r=0.60, P=0.00005). There was selective downregulation of the AT1 receptor subtype in failing PPH ventricles: 6.41+/-1.23 fmol/mg in PPH LV, 2.37+/-0.50 fmol/mg in PPH RV, 5.38+/-0.53 fmol/mg in NF LV, and 7.30+/-1.10 fmol/mg in NF RV (P=0.01, PPH RV versus PPH LV; P=0.0006, PPH RV versus NF RV). CONCLUSIONS: ACE binding sites are increased in both failing IDC and nonfailing PPH ventricles. In PPH hearts, the AT1 receptor is downregulated only in the failing RV.     

Chronic amlodipine treatment during the development of heart failure

BACKGROUND: This study examined the effects of chronic amlodipine treatment on left ventricular (LV) pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF) both at rest and with treadmill exercise. In an additional series of in vitro studies, LV myocyte contractile function was examined. METHODS AND RESULTS: Sixteen pigs were studied under normal control conditions and after the development of chronic pacing-induced CHF (240 bpm, 3 weeks, n=8) or chronic pacing and amlodipine (1.5 mg . kg-1 . d-1, n=8). Under ambient resting conditions, LV stroke volume (mL) was reduced with CHF compared with the normal control state (16+/-2 versus 31+/-2, P<0.05) and increased with concomitant amlodipine treatment (29+/-2, P<0.05). At rest, systemic and pulmonary vascular resistance (dyne . s-1 . cm-5) increased with CHF compared with the normal control state (3102+/-251 versus 2156+/-66 and 1066+/-140 versus 253+/-24, respectively, both P<0.05) and were reduced with amlodipine treatment (2108+/-199 and 480+/-74, respectively, P<0.05). With CHF, LV stroke volume remained reduced and was associated with a 40% reduction in myocardial blood flow during treadmill exercise, whereas chronic amlodipine treatment normalized LV stroke volume and improved myocardial blood flow. Resting and exercise-induced plasma norepinephrine levels were increased by >5-fold in the CHF group and were reduced by 50% from CHF values with chronic amlodipine treatment. Resting plasma endothelin (fmol/mL) increased with CHF compared with the normal state (10.4+/-0.9 versus 3.1+/-0.3, P<0.05) and was reduced with amlodipine treatment (6.6+/-1.1, P<0.5). With CHF, LV myocyte velocity of shortening ( microm/s) was reduced compared with normal controls (39+/-1 versus 64+/-1, P<0.05) and was increased with chronic amlodipine treatment (52+/-1, P<0.05). CONCLUSIONS: Chronic amlodipine treatment in this model of developing CHF produced favorable hemodynamic, neurohormonal, and contractile effects in the setting of developing CHF.     

Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis

BACKGROUND: We tested the hypotheses that long-term administration of the angiotensin-converting enzyme (ACE) inhibitor fosinopril will regress hypertrophy, modify the transition to heart failure, and prolong survival in rats with chronic left ventricular (LV) pressure overload due to ascending aortic stenosis. METHODS AND RESULTS: Aortic stenosis was created in weanling male Wistar rats by a stainless steel clip placed on the ascending aorta. Age-matched control animals underwent a sham operation (Sham group, n = 57). Six weeks after surgery, rats with aortic stenosis were randomized to receive either oral fosinopril 50 mg.kg-1.d-1 (Fos/LVH group, n = 38) or no drug (LVH group, n = 36) for 15 weeks. Pilot studies confirmed that this dosage produced significant inhibition of LV tissue ACE in vivo. Animals were monitored daily, and survival during the 15-week treatment period was assessed by actuarial analysis. At 15 weeks, in vivo LV systolic and diastolic pressures and heart rate were measured. To assess contractile function, the force-calcium relation was evaluated by use of the isovolumic buffer-perfused, balloon-in-LV heart preparation at comparable coronary flow rates per gram LV weight. Quantitative morphometry was performed. Mortality during the 15-week trial was significantly less in the Fos/LVH group than in the LVH group (3% versus 31%, P < .005). No deaths occurred in the Sham group. In vivo LV systolic pressure was similar between Fos/LVH and LVH hearts (223 +/- 10 versus 232 +/- 9 mm Hg) and significantly higher than the Sham group (99 +/- 3 mm Hg, P < .05). In vivo LV diastolic pressure was significantly lower in Fos/LVH hearts than in LVH hearts (10 +/- 2 versus 15 +/- 2 mm Hg), and both were significantly higher than in the Sham group (5 +/- 1 mm Hg, P < .05). Heart rate was similar among all groups. Despite equivalent elevation of LV systolic pressure, fosinopril resulted in regression of myocyte hypertrophy in Fos/LVH versus LVH (myocyte cell width, 14.8 +/- 0.5 versus 20.8 +/- 2.2 microns, P < .05) to normal levels (Sham, 16.3 +/- 0.9 microns). Quantitative morphometry demonstrated that the regression of LV myocyte hypertrophy in the Fos/LVH group was associated with a relative increase in the fractional volume of fibrillar collagen and noncollagen interstitium. In the isolated heart experiments, LV systolic developed pressure relative to perfusate [Ca2+] was significantly higher in Fos/LVH hearts than in LVH hearts. The improvement in systolic function was not related to any difference in myocardial high-energy phosphate levels, since LV ATP and creatine phosphate levels were similar in Fos/LVH and LVH hearts. CONCLUSIONS: In rats with ascending aortic stenosis, chronic ACE inhibition with fosinopril improved survival, decreased the extent of LV hypertrophy, and improved cardiac function despite persistent elevation of LV systolic pressure. The favorable effects of fosinopril may be related in part to inhibition of the effects of cardiac ACE on myocyte hypertrophy rather than to systemic hemodynamic mechanisms.     

The novel effects of 3,5,3'-triiodo-L-thyronine on myocyte contractile function and beta-adrenergic responsiveness in dilated cardiomyopathy

Medical management of patients with chronic left ventricular dysfunction continues to be a difficult problem. Recent clinical and experimental studies have suggested that 3,5,3'-triiodo-L-thyronine improves left ventricular pump function. However, whether 3,5,3'-triiodo-L-thyronine directly improves myocyte contractile function in cardiomyopathic states is unknown. Accordingly, this study examined the direct effects of 3,5,3'-triiodo-L-thyronine on isolated myocyte contractile function in cardiocytes obtained from control (n = 6) pigs and pigs with tachycardia-induced dilated cardiomyopathy (atrial pacing at 240 beats/min for 3 weeks; n = 6). Myocyte percent shortening and velocity of shortening were obtained at baseline and in the presence of 3,5,3'-triiodo-L-thyronine doses of 80 and 100 pmol/L. For both control and dilated cardiomyopathy groups, 3,5,3'-triiodo-L-thyronine caused a significant increase in myocyte contractile function. For example, a 100 pmol/L dose of 3,5,3'-triiodo-L-thyronine increased myocyte velocity of shortening by 51% in control myocytes and by 54% in dilated cardiomyopathy myocytes compared with baseline. A second series of experiments was performed to determine whether 3,5,3'-triiodo-L-thyronine altered the responsiveness of the beta-adrenergic receptor system in control and dilated cardiomyopathy myocytes. Myocyte contractile function was examined during beta-adrenergic stimulation with isoproterenol alone and in myocytes preincubated with 3,5,3'-triiodo-L-thyronine doses of 80 and 100 pmol/L to which isoproterenol was added. Isoproterenol alone increased velocity of shortening by 139% in control and by 233% in dilated cardiomyopathy myocytes compared with baseline. This was significantly greater than the increase with 3,5,3'-triiodo-L-thyronine alone. 3,5,3'-triiodo-L-thyronine followed by isoproterenol increased velocity of shortening by 245% in control and 313% in dilated cardiomyopathy myocytes compared with baseline. This was significantly greater than the response with 3,5,3'-triiodo-L-thyronine or isoproterenol alone and appeared to be greater than an additive response. The results from this study clearly demonstrated that 3,5,3'-triiodo-L-thyronine directly augmented myocyte contractile function in both control and dilated cardiomyopathy myocytes. In addition, 3,5,3'-triiodo-L-thyronine enhanced the contractile response to beta-adrenergic stimulation in dilated cardiomyopathy. This study provides unique evidence to suggest that 3,5,3'-triiodo-L-thyronine may be a useful adjunct to conventional inotropic support in the setting of advanced left ventricular dysfunction.     

Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat

BACKGROUND: After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density. The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure. METHODS AND RESULTS: Seven days after coronary ligation (MI), rats were randomized to enalapril (n = 8; 500 micrograms.kg-1.d-1), losartan (n = 9; 3 mg.kg-1.d-1), or placebo (n = 8) and treated for 6 weeks. Sham-operated rats (n = 10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg.kg-1.min-1 over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg.mL-1.min-1.g-1, all P < .05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol.mg protein-1.min-1, P < .05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol.mg protein-1.min-1, P < .05 versus MI-placebo). CONCLUSIONS: The present study demonstrates that both chronic ACE inhibition and AT1 receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV. These results suggest that inhibition of generation of angiotensin II and AT1 receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction.     

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) Control: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.     

Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function

The development of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated to play a significant role in tissue remodeling in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic activity. LV and myocyte function, collagen content, and MMP expression and zymographic activity were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycardia (SVT) in pigs. After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fractional shortening fell by 20%. At the level of the myocyte, percent shortening fell by 16% after 7 days of SVT, with no change in the steady-state velocity of shortening. Longer durations of SVT caused progressive LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a >50% increase in LV dimension, a 56% fall in LV fractional shortening, and a 33% decline in myocyte velocity of shortening. The decline in LV and myocyte function with 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, SVT causes time-dependent changes in LV geometry and function and the subsequent development of CHF. LV myocardial collagen content and confluence fell by >25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substrate gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increased by >100% from control values. Interstitial collagenase (MMP-1), stromelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by approximately 2-fold after 7 days of SVT. LV MMP zymographic activity and abundance remained elevated with longer durations of SVT. The results of the present study demonstrated that in this model of CHF, early changes in LV myocardial MMP zymographic activity and protein levels occurred with the initiation and progression of LV dilation and dysfunction. These findings suggest that an early contributory mechanism for the initiation of LV remodeling that occurred in this model of developing CHF is enhanced expression and potentially increased activity of LV myocardial MMPs.     

Myelination by transplanted human and mouse central nervous system tissue after long-term cryopreservation

BACKGROUND: There is limited information available regarding the effect of catheter ablation of the antioventricular (AV) junction on left ventricular (LV) function. Both deterioration and improvement in LV function have been reported following direct current (DC) ablation of the AV junction. The deterioration of LV function following DC ablation of the AV junction may be due to the accompanying barotrauma, DC arcing and direct coagulation, or even the effects of chronic ventricular pacing. If this deterioration of LV function was a result of the accompanying effects of DC shock, the use of radiofrequency ablation (RF) should not result in deterioration of LV function. AIM: To study LV function before and after different methods of AV junction ablation and in patients with chronic ventricular pacing without AV junction ablation. MATERIAL: This study assessed LV function in patients following RF ablation, low energy DC ablation of the AV junction and compared the results with our previously reported finding in patients who had AV junction ablation using high energy DC shock. A group of patients undergoing permanent single chamber ventricular pacemaker implantation without AV junction ablation were selected as controls. METHODS: All patients were paced in the ventricle at 110 beats/minute during LV function assessment by radionuclide angiography. Global LV function and segmental wall motion abnormalities were assessed before, immediately following and three months after ablation. RESULTS: In the high energy DC ablation group, a fall in global LV function (50 +/- 3.0% to 43 +/- 3.0%, p = 0.02) and impairment of segmental wall motion were detected. Low energy DC ablation resulted in segmental wall motion impairment similar to high energy DC but without affecting global ejection fraction (47.0% +/- 6.7 to 45.5% +/- 3.1, p > 0.05). Neither RF ablation (44.0% +/- 3.3 to 45.3% +/- 3.5, p > 0.05), nor chronic pacing (46.7% +/- 4.9 to 47.0% +/- 2.9 p > 0.05) had any effect on global or segmental LV function. CONCLUSIONS: Low energy DC or RF ablation of the AV junction does not affect global LV ejection fraction. The deterioration of global LV function after high energy DC shock ablation appears to be related to the accompanying effects of DC energy and not to the effects of chronic ventricular pacing.     

Mechanism of beta-adrenergic receptor upregulation induced by ACE inhibition in cultured neonatal rat cardiac myocytes: roles of bradykinin and protein kinase C

BACKGROUND: Although bradykinin is thought to contribute to the effects of ACE inhibitors on the cardiovascular system, its precise role remains to be elucidated. Evidence suggests that bradykinin might be important in the upregulation of beta-adrenergic receptors (beta-ARs) induced by ACE inhibitors, and the role of bradykinin in this effect has now been investigated with cultured neonatal rat cardiac myocytes. METHODS AND RESULTS: The density of beta-ARs on the myocyte surface was determined with a binding assay with [3H]CGP-12177. Incubation of cultured myocytes for 24 hours with the ACE inhibitor captopril (1 micromol/L) increased beta-AR density by 35% and enhanced the response of cells to isoproterenol but not to forskolin. Neither an angiotensin-II type 1 (AT1) receptor antagonist, CV-11974, nor angiotensin-I affected beta-AR density. However, the bradykinin B2 receptor antagonist Hoe 140 abolished the effect of captopril on beta-AR upregulation in a dose-dependent manner. The protein kinase C inhibitor staurosporine (20 nmol/L) but neither indomethacin nor L-NAME also inhibited captopril-induced upregulation of beta-ARs. Exogenous bradykinin increased the spontaneous beating frequency of cultured myocytes and Hoe 140 abolished this effect. Bradykinin level in the medium increased 1.4-fold by the treatment of cultured myocytes with captopril for 24 hours. CONCLUSIONS: The results suggest that captopril enhances beta-AR responsiveness by inducing beta-AR upregulation and that the latter effect is mediated by activation of bradykinin B2 receptors and protein kinase C. These observations also offer insight into the different roles of ACE inhibitors and AT1 receptor antagonists in the treatment of heart failure.     

Acute phase proteins: alpha-1-acid glycoprotein (AGP) and alpha-1 antichymotrypsin (ACT) in serum of patients with cerebral ischemic stroke

BACKGROUND: Because of methods required for obtaining isolated left ventricular myocytes, evaluation of the contractile function of isolated left ventricular myocytes in normal human patients has been limited. Accordingly, the goal of the present study was to develop a means to isolate human left ventricular myocytes from small myocardial biopsy specimens collected from patients undergoing elective coronary artery bypass operations and to characterize indices of myocyte contractile performance. METHODS: Myocardial biopsy specimens were obtained from the anterior left ventricular free wall of 22 patients undergoing coronary artery bypass operations. Myocytes were isolated from these myocardial samples by means of a stepwise enzymatic digestion method and micro-trituration techniques. Isolated left ventricular myocyte contractile function was assessed by computer-assisted high-speed videomicroscopy under basal conditions and in response to beta-adrenergic receptor stimulation with isoproterenol. RESULTS: A total of 804 viable left ventricular myocytes were successfully examined from all of the myocardial biopsy specimens with an average of 37+/-4 myocytes per patient. All myocytes contracted homogeneously at a field stimulation of 1 Hz with an average percent shortening of 3.7%+/-0.1% and shortening velocity of 51.3+/-1.3 microm/s. After beta-adrenergic receptor stimulation with isoproterenol, percent shortening and shortening velocity increased 149% and 118% above baseline, respectively (P < .05). CONCLUSION: The unique results of the present study demonstrated that a high yield of myocytes could be obtained from human left ventricular biopsy specimens taken during cardiac operations. These myocytes exhibited stable contractile performance and maintained the capacity to respond to an inotropic stimulus. The methods described herein provide a basis by which future studies could investigate intrinsic and extrinsic influences on left ventricular myocyte contractility in human beings.     

Analysis of mumps vaccine failure by means of avidity testing for mumps virus-specific immunoglobulin G

Rapid ventricular pacing (RVP) in dogs creates a well characterized model of dilated cardiomyopathy. Standard pacing protocols use RVP at 240-260 beats/min for 2-4 weeks, and result in high mortality rates if continued longer. The authors describe a modification of RVP that results in significant heart failure by 4 weeks, but can be continued for up to 10 weeks with low mortality. Nineteen mongrels underwent RVP at 215 beats/min for 10 weeks. Serial pressure-volume analysis and echocardiography were performed in this model to assess longitudinally changes in left ventricular (LV) function and volumes. The mortality rate was 10%. Significant progressive LV dysfunction with concomitant LV enlargement was observed throughout the pacing period. Finally, norepinephrine levels were elevated at the end of pacing, consistent with an activated sympathetic system. This modified RVP protocol permits long-term pacing with a low mortality rate and results in progressive heart failure throughout the pacing period. This model would be useful in the long-term evaluation of newer surgical and medical therapies of the failing heart.     

AAIR versus DDDR pacing in patients with impaired sinus node chronotropy: an echocardiographic and cardiopulmonary study

The aim of this study was to compare AAIR and DDDR pacing at rest and during exercise. We studied 15 patients (10 men, age 65 +/- 6 years) who had been paced for at least 3 months with activity sensor rate modulated dual chamber pacemakers. All had sick sinus syndrome (SSS) with impaired sinus node chronotropy. The patients underwent a resting echocardiographic evaluation of systolic and diastolic LV function at 60 beats/min during AAIR and DDDR pacing with an AV delay, which ensured complete ventricular activation capture. Cardiac output (CO) was also measured during pacing at 100 beats/min in both pacing modes. Subsequently, the oxygen consumption (VO2AT) and VO2AT pulse at the anaerobic threshold were measured during exercise in AAIR mode and in DDDR mode with an AV delay of 120 ms. The indices of diastolic function showed no significant differences between the two pacing modes, except for patients with a stimulus-R interval > 220 ms, for whom the time velocity integral of LV filling and LV inflow time were significantly lower under AAI than under DDD pacing. At 60 beats/min, CO was higher under AAI than under DDD mode only when the stimulus-R interval was below 220 ms. For stimulus-R intervals longer than 220 ms, and also during pacing at 100 beats/min, the CO was higher in DDD mode. The stimulus-R interval decreased in all patients during exercise. The time to anaerobic threshold, VO2AT, and VO2AT pulse showed no significant differences between the two pacing modes. Our results indicate that, at rest, although AAIR pacing does not improve diastolic function in patients with SSS, it maintains a higher CO than does DDDR pacing in cases where the stimulus-R interval is not excessively prolonged. On exertion, the two pacing modes appear to be equally effective, at least in cases where the stimulus-R interval decreases in AAIR mode.     

Relationships between myocardial bioenergetic and left ventricular function in hearts with volume-overload hypertrophy

BACKGROUND: Left ventricular (LV) hypertrophy secondary to volume overload can result in alterations in myocardial bioenergetics and LV dysfunction. This study examined whether bioenergetic abnormalities contribute to the pump dysfunction. METHODS AND RESULTS: Severe mitral regurgitation (MR) was produced in 10 dogs by disruption of the chordal apparatus. Hemodynamics and ventricular function were examined 11.7 months later under baseline conditions and during treadmill exercise. Myocardial high-energy phosphates were measured by using magnetic resonance spectroscopy at rest, during coronary vasodilation with adenosine, and during oxidative stress induced by rapid pacing and dobutamine. Chronic MR caused a 30% increase in LV mass and a 65% increase in LV volume. In MR animals, the hemodynamic and LV function were normal at rest, but abnormalities developed during beta-blockade and exercise. Myocardial creatine phosphate-to-ATP ratios were significantly lower in each layer across the LV wall in MR hearts than normal hearts. Myocardial blood flow and coronary reserve were normal in MR hearts. Moreover, hyperperfusion did not correct the abnormal bioenergetics. Despite altered bioenergetics at rest, the MR hearts tolerated rapid pacing and dobutamine infusion well. CONCLUSIONS: In volume-overloaded LV hypertrophied hearts, alterations in myocardial high-energy phosphate levels do not induce abnormal mechanical performance at rest but may be related to a decreased contractile reserve during exercise.     

Preservation of myocyte contractile function after hypothermic, hyperkalemic cardioplegic arrest with 2, 3-butanedione monoxime

One proposed contributory mechanism for depressed ventricular performance after hypothermic, hyperkalemic cardioplegic arrest is a reduction in myocyte contractile function caused by alterations in intracellular calcium homeostasis. Because 2,3-butanedione monoxime decreases intracellular calcium transients, this study tested the hypothesis that 2,3-butanedione monoxime supplementation of the hyperkalemic cardioplegic solution could preserve isolated myocyte contractile function after hypothermic, hyperkalemic cardioplegic arrest. Myocytes were isolated from the left ventricles of six pigs. Magnitude and velocity of myocyte shortening were measured after 2 hours of incubation under normothermic conditions (37 degrees C, standard medium), hypothermic, hyperkalemic cardioplegic arrest (4 degrees C in Ringer's solution with 20 mEq potassium chloride and 20 mmol/L 2,3-butanedione monoxime). Because beta-adrenergic agonists are commonly employed after cardioplegic arrest, myocyte contractile function was examined in the presence of the beta-agonist isoproterenol (25 nmol/L). Hypothermic, hyperkalemic cardioplegic arrest and rewarming reduced the velocity (32%) and percentage of myocyte shortening (27%, p < 0.05). Supplementation with 2,3 butanedione monoxime normalized myocyte contractile function after hypothermic, hyperkalemic cardioplegic arrest. Although beta-adrenergic stimulation significantly increased myocyte contractile function under normothermic conditions and after hypothermic, hyperkalemic cardioplegic arrest, contractile function of myocytes exposed to beta-agonist after hypothermic, hyperkalemic cardioplegic arrest remained significantly reduced relative to the normothermic control group. Supplementation with 2,3-butanedione monoxime restored beta-adrenergic responsiveness of myocytes after hypothermic, hyperkalemic cardioplegic arrest. Thus, supplementation of a hyperkalemic cardioplegic solution with 2,3-butanedione monoxime had direct and beneficial effects on myocyte contractile function and beta-adrenergic responsiveness after cardioplegic arrest. A potential mechanism for the effects of 2,3-butanedione monoxime includes modulation of intracellular calcium transients or alterations in sensitivity to calcium. Supplementation with 2,3-butanedione monoxime may have clinical utility in improving myocardial contractile function after hypothermic, hyperkalemic cardioplegic arrest.     

The distributional clines in P susceptibility causing by the P family transposable element in Drosophila melanogaster population of China

BACKGROUND: Recombinant human growth hormone (rhGH) has shown beneficial effects on cardiac function after myocardial infarction (MI) in rats. High-dose angiotensin II (AT1) receptor blockade in normal rats inhibited the hypertrophic effect of growth hormone (GH), therefore we investigated whether GH effects after MI would be enhanced by giving it in sequence after remodeling had been inhibited by prior AT1 blockade (losartan, L). METHODS AND RESULTS: Rats given losartan for 10 weeks after MI followed by rhGH for 2 weeks (2 mg/kg twice a day, GH plus losartan) were compared with rats given losartan for 10 weeks followed by placebo for 2 weeks (placebo plus losartan group) and with untreated controls (n = 17-20/group). Average MI sizes and left ventricular (LV) end diastolic (ED) dimensions (echocardiography) did not differ between groups. In GH and losartan, body weight (BW) was increased but left ventricular weight (LVW)/BW was reduced, and the LV fractional shortening and LV dP/dtmax (catheter tip micromanometer) were increased compared with the control group (20.3 vs 15.4% and 5579 vs 4699 mmHg/s, respectively, P < .05). The cardiac index also was significantly increased. In the placebo plus losartan group, the LVW/BW was also reduced and the cardiac index increased versus controls. Stroke volume was increased in GH plus losartan group compared with both placebo plus losartan and controls, and the systemic vascular resistance was significantly decreased only in the GH plus losartan group. The ED posterior wall thickness (noninfarcted wall) was increased in GH plus losartan compared with both control and placebo plus losartan. Left ventricular end diastolic pressure reduction was not significant in GH plus losartan group versus controls but was reduced in placebo plus losartan group, whereas LV relaxation (tau) was improved in both groups versus control rats. Thus, persistent remodeling effects caused by prior AT1 blockade undoubtedly contributed to some responses, but short-term GH given in sequence after chronic AT1 blockade had favorable actions on the failing heart and peripheral circulation by increasing LV wall thickness with partial reversal of unfavorable remodeling, lowering of vascular resistance, improvement of LV contractility, and enhanced LV systolic function and cardiac index relatively late after experimental MI.