Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy

Pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy are at high risk of sudden cardiac death (SCD). We sought to identify the arrhythmic mechanism of SCD, the relation to changes in left ventricular (LV) function, and inducibility of malignant arrhythmias before SCD. Juvenile pigs (n = 72) were instrumented with chronic stenoses on proximal left anterior descending and circumflex arteries. Survival was only 29% 3 mo after instrumentation, and all deaths were sudden and without prodromal symptoms of heart failure. Triphenyltetrazolium chloride staining demonstrated necrosis in only nine animals averaging 2.3 +/- 0.9% of the LV, with no difference between SCD animals and survivors. Implantable loop recorders (n = 13) documented both ventricular fibrillation (n = 6) and bradyasystole (n = 2) as the arrhythmic mechanism of death. Although regional and global function were depressed [anteroseptal wall thickening 1.8 +/- 0.2 vs. 4.2 +/- 0.2 mm in Sham animals (P < 0.001); fractional shortening 21 +/- 2 vs. 31 +/- 1% in Sham animals (P < 0.01)], there were no differences between SCD animals and survivors. LV mass increased in animals with ischemic cardiomyopathy and was greater in animals with SCD (4.0 +/- 0.2 vs. 3.1 +/- 0.1 g/kg in survivors; P < 0.001). Serial programmed ventricular stimulation failed to induce any sustained arrhythmias. We conclude that pigs with viable dysfunctional myocardium and globally reduced LV function have a high rate of SCD with a spectrum of arrhythmias similar to patients with ischemic cardiomyopathy. The risk is independent of necrosis but appears to increase with LV hypertrophy. Like patients with ischemic cardiomyopathy, programmed stimulation is insensitive to predict SCD when viable dysfunctional myocardium is the pathological substrate.     

Activation of p38 MAPK and increased glucose transport in chronic hibernating swine myocardium

In preconditioned myocardium, activation of the mitogen-activated protein kinase (MAPK) p38 leads to increased glucose uptake via enhanced GLUT-4 translocation. Glucose uptake is also increased in chronic hibernating myocardium, but the role of p38 MAPK and GLUT-4 translocation has not been studied. Nine swine underwent instrumentation of the proximal left anterior descending coronary artery (LAD) with a small, external constrictor. At 3 mo after instrumentation, myocardial glucose uptake by PET imaging was higher in the LAD than in the remote region under basal, fasted conditions (0.08 +/- 0.02 vs. 0.04 +/- 0.01 micromol.min(-1).g(-1), P < 0.05). Compared with the remote region, the LAD region demonstrated increased membrane-bound GLUT-4 relative to total content (61 +/- 04 vs. 45 +/- 06%, P < 0.05), higher glycogen (28.37 +/- 4.41 vs. 19.26 +/- 1.87 mg/g wet wt, P < 0.05), and increased inducible nitric oxide synthase (NOS) activity (1.43 +/- 0.34 vs. 0.51 +/- 0.21 activity/mg protein, P < 0.05). p38 MAPK was 47 +/- 14% higher in the LAD than in the remote region (P < 0.05) and correlated well with the absolute degree of GLUT-4 membrane-bound translocation (r = 0.81, P < 0.01), relative increase in glycogen (r = 0.70, P < 0.05), and total NOS activity (r = 0.68, P < 0.05). In chronic hibernating myocardial tissue, p38 MAPK activation is increased under basal fasted conditions and correlates well with the increased degree of GLUT-4 translocation, glycogen accumulation, and NOS activity. As in preconditioned myocardium, activation of p38 MAPK may play an important role in the metabolic adaptations that characterize chronic hibernating myocardium.     

Less afterload sensitivity in short-term hibernating than in acutely ischemic and stunned myocardium

Short-term hibernating myocardium is characterized by reduced contractile function during persistent moderate ischemia, the recovery of metabolic parameters, and the absence of necrosis. To study the afterload dependence of regional wall excursion in short-term hibernating myocardium, in 11 enflurane-anesthetized swine the left anterior descending coronary artery was cannulated and hypoperfused for 90 min to reduce anterior systolic wall thickening (WT, sonomicrometry) by 60%. Under control conditions, at 5 and 90 min ischemia the descending thoracic aorta was acutely constricted to increase left ventricular (LV) pressure by 30 mmHg. Under control conditions, increased LV pressure resulted in decreased WT [i.e., a negative slope of the relationship between WT and LV end-systolic pressure: -11.2 +/- 4.2 (SD) microm/mmHg]. This slope was further significantly decreased at 5 min ischemia (-26.5 +/- 8.8 microm/mmHg) but returned toward control values in short-term hibernating myocardium at 90 min ischemia (-17.2 +/- 6.6 microm/mmHg). At 30 min reperfusion, the slope was once more significantly decreased (-27.8 +/- 8.1 microm/mmHg). In conclusion, WT in short-term hibernating myocardium is less afterload dependent than in acutely ischemic and reperfused myocardium.     

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg). At high Pcs, LV, aortic and diastolic circumflex arterial pressure, heart rate, myocardial oxygen consumption, and lactate extraction were unchanged; IMP in the subendocardium did not change (130/19 mmHg), whereas IMP in the subepicardium increased by 17 mmHg during systole and 10 mmHg during diastole (P < or = 0.001), independently of circumflex arterial pressure. Increasing Pcs did not change the slope of the PFR; however, coronary pressure at zero flow increased in the subepicardium (P < or = 0.008), whereas in the subendocardium it remained unchanged at 24 +/- 3 mmHg. Thus Pcs can regulate IMP independently of circumflex arterial pressure and consequently influence myocardial perfusion, especially in the subepicardial tissue layer of the LV.     

Vascular beta-adrenergic receptor system is dysfunctional after myocardial infarction

We identified abnormalities in the vascular beta-adrenergic receptor (beta-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured beta-AR-mediated hemodynamics, vascular reactivity, and the vascular beta-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/dt). LV dP/dt responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats (P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats (P < 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in beta-AR signaling (P < 0.05): decreases in beta-AR density (aorta: 58.7 +/- 6.0 vs. 35.7 +/- 1.9 fmol/mg membrane protein; carotid: 29.6 +/- 5.6 vs. 18.0 +/- 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 +/- 39 vs. 259 +/- 26 in the aorta and 115 +/- 30 vs. 202 +/- 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 +/- 0.10 vs. 0.31 +/- 0.06 pmol/mg protein and 2.3 +/- 0.3 vs. 1.2 +/- 0.1 pmol/mg protein, n = 5) with no change in Galpha(s) or Galpha(i )in the aorta. Thus in heart failure there are abnormalities in the vascular beta-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.     

The energetic state within hibernating myocardium is normal during dobutamine despite inhibition of ATP-dependent potassium channel opening with glibenclamide

Within hibernating myocardium, it is uncertain whether a normal energetic state is present at baseline and whether maintaining that energy state during a catecholamine challenge is dependent on ATP-dependent potassium channel opening. In this study, 16 swine underwent a thoracotomy with placement of an external constrictor on the left anterior descending coronary artery (LAD) (hibernation model). Seven additional swine underwent a sham operation. At 10 wk, the myocardial energetic state in the LAD region was assessed by (31)P-NMR spectroscopy, and the ratio of phosphocreatine to ATP (PCr/ATP) was determined at baseline, during glibenclamide treatment (0.5 mg/kg bolus with 50 microg/min iv), and during addition of dobutamine (40 microg x kg(-1) x min(-1) iv). At baseline, transmural blood flow in the LAD and remote region was 0.75 +/- 0.11 and 0.88 +/- 0.09 ml x min(-1) x g(-1), respectively (P < 0.01), in hibernating hearts and 0.83 +/- 0.12 and 0.88 +/- 0.15 ml x min(-1) x g(-1), respectively (not significant), in sham-operated hearts. Under basal conditions, PCr/ATP in the LAD region of hibernating and sham pigs was 2.15 +/- 0.04 and 2.11 +/- 0.05, respectively (not significant). In sham pigs, addition of dobutamine to glibenclamide increased the double product from 10.4 +/- 0.8 to 23.9 +/- 4.0 mmHg x beats x min(-1) x 1,000 (P < 0.05) and decreased transmural PCr/ATP from 2.06 +/- 0.06 to 1.69 +/- 0.06 (P < 0.05). Dobutamine increased the double product in hibernating pigs in a similar fashion and, despite a 40% lower blood flow response, induced an equivalent decrease in PCr/ATP from 2.04 +/- 0.04 to 1.73 +/- 0.08 (P < 0.05). In conclusion, we found that, in chronic hibernating swine myocardium with reduced basal blood flow and perfusion reserve, the transmural energetic state, defined by PCr/ATP, is normal during addition of dobutamine, despite inhibition of ATP-dependent potassium channel opening with glibenclamide. These data suggest that important adaptations other than the ATP-dependent potassium channel opening allow hibernating myocardium to operate over a lower range of the oxygen supply-demand relationship to protect against myocardial ischemia.     

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (tau), and the first derivatives of LV pressure rise and fall (dP/dt(max) and dP/dt(min), respectively). During echocardiography, HR was lower in XK than AV mice (250 +/- 14 beats/min in XK vs. 453 +/- 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 +/- 0.08 mm in XK vs. 3.8 +/- 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 +/- 1.2% in XK vs. 40 +/- 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 +/- 24 beats/min) and XK (342 +/- 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 +/- 5 vs. 6.2 +/- 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/dt(max): 4,402 +/- 798 vs. 8,250 +/- 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (tau: 23 +/- 2 vs. 14 +/- 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.     

Cardiac diastolic dysfunction in conscious dogs with heart failure induced by chronic coronary microembolization

Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-microm diameter) for 24 +/- 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/dt(min)) decreased by 25 +/- 2% (P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 +/- 5% and 25 +/- 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = be(alpha*EDV)) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (alpha) increased by 62 +/- 10% (P < 0.05) and the stiffness constant (k) increased by 66 +/- 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 +/- 25% and 63 +/- 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.     

Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure

Increased glucose utilization and regional differences in contractile function are well-known alterations of the failing heart and play an important pathophysiological role. We tested whether, similar to functional derangement, changes in glucose uptake develop following a regional pattern. Heart failure was induced in 13 chronically instrumented minipigs by pacing the left ventricular (LV) free wall at 180 beats/min for 3 wk. Regional changes in contractile function and stress were assessed by magnetic resonance imaging, whereas regional flow and glucose uptake were measured by positron emission tomography utilizing, respectively, the radiotracers [(13)N]ammonia and (18)F-deoxyglucose. In heart failure, LV end-diastolic pressure was 20 +/- 4 mmHg, and ejection fraction was 35 +/- 4% (all P < 0.05 vs. control). Sustained pacing-induced dyssynchronous LV activation caused a more pronounced decrease in LV systolic thickening (7.45 +/- 3.42 vs. 30.62 +/- 8.73%, P < 0.05) and circumferential shortening (-4.62 +/- 1.0 vs. -7.33 +/- 1.2%, P < 0.05) in the anterior/anterior-lateral region (pacing site) compared with the inferoseptal region (opposite site). Conversely, flow was reduced significantly by approximately 32% compared with control and was lower in the opposite site region. Despite these nonhomogeneous alterations, regional end-systolic wall stress was uniformly increased by 60% in the failing LV. Similar to wall stress, glucose uptake markedly increased vs. control (0.24 +/- 0.004 vs. 0.07 +/- 0.01 micromol x min(-1) x g(-1), P < 0.05), with no significant regional differences. In conclusion, high-frequency pacing of the LV free wall causes a dyssynchronous pattern of contraction that leads to progressive cardiac failure with a marked mismatch between increased glucose uptake and regional contractile dysfunction.     

Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure

The objective of the present study was to test the hypothesis that endogenous beta(3)-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the beta(3)-AR inhibits cardiac contraction. In the failing myocardium, beta(3)-ARs are upregulated, suggesting that stimulation of beta(3)-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous beta(3)-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific beta(3)-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (E(es)) of the LV pressure-volume relation (18%, 6.2 +/- 0.9 vs. 7.3 +/- 1.2 mmHg/ml, P < 0.05) and the improved LV relaxation time constant (tau; 28.4 +/- 1.9 vs. 26.8 +/- 1.0 ms, P < 0.05). After CHF, the plasma norepinephrine concentration increased eightfold, and L-748,337 produced a larger increase in E(es) (34%, 3.8 +/- 0.7 vs. 5.1 +/- 0.8 mmHg/ml, P < 0.05) and a greater decrease in tau (46.4 +/- 4.2 vs. 41.0 +/- 3.9 ms, P < 0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8 +/- 0.9 vs. 6.8 +/- 0.9%, P < 0.05) and relengthening (33.5 +/- 4.2 vs. 39.7 +/- 4.0 microm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca(2+) concentration regulation. In CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function. Stimulation of beta(3)-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.     

Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats.

Previously, we demonstrated that intact female rats fed a standard rodent diet containing soybean products exhibit essentially no adverse left ventricular (LV) remodeling in response to aortocaval fistula-induced chronic volume overload. We hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection. To test this hypothesis, four groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(-)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats. Fistula groups developed LV hypertrophy, which was not reduced by dietary phytoestrogens [1,184 +/- 229 mg Fist-P(-) and 1,079 +/- 199 mg Fist-P(+) vs. 620 +/- 47 mg for combined Sham groups, P < 0.05]. Unstressed LV volume increased in Fist-P(-) rats (428 +/- 16 vs. 300 +/- 14 microl Sham, P < 0.0001), but it was not different from Sham for Fist-P(+) animals (286 +/- 17 microl). Fist-P(-) rats developed increased ventricular compliance (5.3 +/- 0.8 vs. 2.3 +/- 0.3 microl/mmHg Sham, P < 0.01), whereas Fist-P(+) rats had no change in compliance (2.8 +/- 0.4 mul/mmHg). Intrinsic ventricular contractility was maintained in the Fist-P(+) rats, but it was reduced (P < 0.001) in the Fist-P(-) rats [systolic pressure-volume slope: 1.04 +/- 0.03, 0.60 +/- 0.06, and 0.99 +/- 0.08 mmHg/microl, for Fist-P(+), Fist-P(-), and Sham, respectively]. These data indicate that dietary phytoestrogens contribute significantly to female cardioprotection against volume overload-induced adverse ventricular remodeling and that studies evaluating gender differences in cardiovascular remodeling must consider the influence of dietary phytoestrogens.     

A new model of congestive heart failure in rats

Current rodent models of ischemia/infarct or pressure-volume overload are not fully representative of human heart failure. We developed a new model of congestive heart failure (CHF) with both ischemic and stress injuries combined with fibrosis in the remote myocardium. Sprague-Dawley male rats were used. Ascending aortic banding (Ab) was performed to induce hypertrophy. Two months post-Ab, ischemia-reperfusion (I/R) injury was induced by ligating the left anterior descending (LAD) artery for 30 min. Permanent LAD ligation served as positive controls. A debanding (DeAb) procedure was performed after Ab or Ab + I/R to restore left ventricular (LV) loading properties. Cardiac function was assessed by echocardiography and in vivo hemodynamic analysis. Myocardial infarction (MI) size and myocardial fibrosis were assessed. LV hypertrophy was observed 4 mo post-Ab; however, systolic function was preserved. LV hypertrophy regressed within 1 mo after DeAb. I/R for 2 mo induced a small to moderate MI with mild impairment of LV function. Permanent LAD ligation for 2 mo induced large MI and significant cardiac dysfunction. Ab for 2 mo followed by I/R for 2 mo (Ab + I/R) resulted in moderate MI with significantly reduced ejection fraction (EF). DeAb post Ab + I/R to reduce afterload could not restore cardiac function. Perivascular fibrosis in remote myocardium after Ab + I/R + DeAb was associated with decreased cardiac function. We conclude that Ab plus I/R injury with aortic DeAb represents a novel model of CHF with increased fibrosis in remote myocardium. This model will allow the investigation of vascular and fibrotic mechanisms in CHF characterized by low EF, dilated LV, moderate infarction, near-normal aortic diameter, and reperfused coronary arteries.     

Cardiac dysfunction in aging conscious rats: altered cardiac cytoskeletal proteins as a potential mechanism

The objective of this study was to test the hypothesis that the mechanism mediating left ventricular (LV) dysfunction in the aging rat heart involves, in part, changes in cardiac cytoskeletal components. Our results show that there were no significant differences in heart rate, LV pressure, or LV diameter between conscious, instrumented young [5.9 +/- 0.3 mo (n = 9)] and old rats [30.6 +/- 0.1 mo (n = 10)]. However, the first derivative of LV pressure (LV dP/dt) was reduced (8,309 +/- 790 vs. 11,106 +/- 555 mmHg/s, P < 0.05) and isovolumic relaxation time (tau) was increased (8.7 +/- 0.7 vs. 6.3 +/- 0.6 ms, P < 0.05) in old vs. young rats, respectively. The differences in baseline LV function in young and old rats, which were modest, were accentuated after beta-adrenergic receptor stimulation with dobutamine (20 mug/kg), which increased LV dP/dt by 170 +/- 9% in young rats, significantly more (P < 0.05) than observed in old rats (115 +/- 5%). Volume loading in anesthetized rats demonstrated significantly impaired LV compliance in old rats, as measured by the LV end-diastolic pressure and dimension relationship. In old rat hearts, there was a significant (P < 0.05) increase in the percentage of LV collagen (2.4 +/- 0.2 vs. 1.3 +/- 0.2%), alpha-tubulin (92%), and beta-tubulin (2.3-fold), whereas intact desmin decreased by 51%. Thus the cardiomyopathy of aging in old, conscious rats may be due not only to increases in collagen but also to alterations in cytoskeletal proteins.     

Structural and functional changes in left ventricle during normotensive and preeclamptic pregnancy

Increased cardiac output in pregnancy is associated with cardiac remodeling and possible reduction in contractility, which may worsen in preeclampsia. Left ventricular (LV) geometry and function were compared between nonpregnant controls (n = 12) and normotensive (n = 44) and preeclamptic (n = 15) pregnant women using echocardiography. Load-independent comparisons of LV systolic function compared end-systolic stress (ESS) and rate-corrected velocity of circumferential fiber shortening (V(CFC)). Mean arterial pressures were 101 +/- 14 mmHg in preeclampsia, 76 +/- 6 mmHg in normotensive pregnancy, and 78 +/- 6 mmHg in controls (P < 0.005 vs. preeclampsia). LV mass increased during normotensive pregnancy (66 +/- 13 to 76 +/- 16 g/m(2); P < 0.05; controls, 65 +/- 10 g/m(2); P < 0.05) and was greater in preeclampsia (90 +/- 18 g/m(2); P < 0.05). In normotensive pregnancy, ESS decreased (59 +/- 9 to 52 +/- 11 g/cm(2); P < 0.05; controls, 66 +/- 14 g/cm(2); P < 0.005). ESS was greater in preeclampsia (60 +/- 14 g/cm(2); P < 0.05). In controls, there was an inverse relationship between ESS and V(CFC) (r = -0.78). The ESS-V(CFC) relationships in normotensive and preeclamptic pregnancy were unchanged from controls. We conclude that LV hypertrophy in normotensive and preeclamptic pregnancy matches changes in cardiac work, and LV contractility is preserved.     

Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O(2) 4-5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 +/- 33.1 vs. HC 184.4 +/- 21.2 ml x min(-1) x kg(-1), P < 0.01), maximal rate of LV pressure rise in systole (+dP/dt), and maximal rate of LV pressure fall in diastole (-dP/dt). CIH led to significant cell injury in the left myocardium, including elevated LV myocyte size, measured by cell surface area (CIH 3,564 +/- 354 vs. HC 2,628 +/- 242 microm(2), P < 0.05) and cell length (CIH 148 +/- 23 vs. HC 115 +/- 16 microm, P < 0.05), elevated terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-stained positive cell number (CIH 98 +/- 45 vs. HC 15 +/- 13, P < 0.01), elevated caspase-3 activity (906 +/- 249 vs. 2,275 +/- 1,169 pmol x min(-1) x mg(-1), P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, beta-myosin heavy chain, and myosin light chain-2. However, there was no difference between groups in sarcomere contractility of isolated LV myocytes, or in LV collagen deposition on trichrome-stained slices. In conclusion, CIH-mediated LV global dysfunction is associated with myocyte hypertrophy and apoptosis at the cellular level.     

Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)-adrenergic receptors

Effects of cardiac specific overexpression of beta(2)-adrenergic receptors (beta(2)-AR) on the development of heart failure (HF) were studied in wild-type (WT) and transgenic (TG) mice following myocardial infarction (MI) by coronary artery occlusion. Animals were studied by echocardiography at weeks 7 to 8 and by catheterization at week 9 after surgery. Post-infarct mortality, due to HF or cardiac rupture, was not different among WT mice, and there was no difference in infarct size (IS). Compared with the sham-operated group (all P < 0.01), WT mice with moderate (<36%) and large (>36%) IS developed lung congestion, cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV end-diastolic pressure (LVEDP), and suppressed maximal rate of increase of LV pressure (LV dP/dt(max)) and fractional shortening (FS). Whereas changes in organ weights and echo parameters were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate (dP/dt(max) 4,862 +/- 133 vs. 3,694 +/- 191 mmHg/s) and large IS groups (dP/dt(max) 4,556 +/- 252 vs. 3,145 +/- 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%, P < 0.05) and LVEDP levels (6 +/- 0.3 vs. 9 +/- 0.8 mmHg, P < 0.05) were also lower in TG than in WT mice with large IS. Thus beta(2)-AR overexpression preserved LV contractility following MI without adverse consequence.     

Comparison of effects of exercise and diuretic on left ventricular geometry, mass, and insulin resistance in older hypertensive adults

To compare the effects of exercise training and hydrochlorothiazide on left ventricular (LV) geometry and mass, blood pressure (BP), and hyperinsulinemia in older hypertensive adults, we studied 28 patients randomized either to a group (age 66.4 +/- 1.3 yr; n = 16) that exercised or to a group (age 65.3 +/- 1.2 yr; n = 12) that received hydrochlorothiazide for 6 mo. Endurance exercise training induced a 15% increase in peak aerobic power. The reduction in systolic BP was twofold greater with thiazide than with exercise (26.6 +/- 12.2 vs. 11.5 +/- 10.9 mmHg). Exercise and thiazide reduced LV wall thickness, LV mass index (14% in each group), and the LV wall thickness-to-radius ratio (h/r) similarly (exercise: before 0.48 +/- 0.2, after 0.42 +/- 0.01; thiazide: before 0.47 +/- 0.04, after 0.40 +/- 0.04; P = 0.017). The reductions in systolic BP and h/r were correlated in the exercise group (r = 0.70, P = 0.005) but not in the thiazide group. Exercise training reduced glucose-stimulated hyperinsulinemia (before: 13.65 +/- 2.6 vs. 9.84 +/- 1.5 mU.ml(-1).min; P = 0.04) and insulin resistance. Thiazide did not affect plasma insulin levels. The results suggest that although exercise is less effective in reducing systolic BP than thiazide, it can induce regression of LV hypertrophy similar in magnitude to thiazide. Unlike hydrochlorothiazide, exercise training can improve insulin resistance and aerobic capacity in older hypertensive people.     

Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dt(max)) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 +/- 1.4 to 23 +/- 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure (P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dt(max). Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.     

Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the alpha-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 +/- 3 vs. MMP 51 +/- 12 microl; P = 0.003] and systolic (C 7 +/- 2 vs. MMP 28 +/- 14 microl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 +/- 4 vs. MMP 23 +/- 3 microl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 +/- 7% vs. MMP 48 +/- 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 +/- 84 vs. MMP 78 +/- 49 mW/microl(2); P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 +/- 1.5 vs. MMP 4.7 +/- 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury.     

Cytokines are not a requisite part of the pathophysiology leading to cardiac decompensation

An increase in circulating levels of proinflammatory cytokines has been proposed as an important pathogenic factor contributing to cardiac injury during chronic heart failure. To determine whether plasma levels of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) increase during pacing-induced heart failure, we paced the hearts of seven dogs at 210 beats/min for 3 weeks and at 240 beats/min for an additional week to induce severe clinical signs of cardiac decompensation. Hemodynamic measurements and blood samples from the aorta and coronary sinus (CS) were taken at control, at 3 weeks, and in end-stage failure. Decompensated heart failure occurred at 29 +/- 1.8 days, when left ventricular (LV) end-diastolic pressure was 25 +/- 1.3 mmHg, LV systolic pressure was 92 +/- 4 mmHg, mean arterial pressure was 77 +/- 3 mmHg, and dP/dtmax was 1219 +/- 73 (all P < 0.05 vs control). Arterial concentration of IL-6 was 12 +/- 4.0 U/ml at control, 11 +/- 2.7 U/ml at 3 weeks, and 10 +/- 1.7 U/ml in end-stage failure (NS). At the same time points, IL-6 in CS plasma was 12 +/- 3.5, 13 +/- 2.8 and 11 +/- 2.4 U/ml, respectively (NS vs control and vs arterial concentrations). TNF-alpha did not reach detectable concentrations in arterial or CS blood at any time. TNF-alpha and IL-6 concentrations did not increase in arterial blood, were not released in the CS from the heart during the development of pacing-induced heart failure, and can not universally be implicated in the pathogenesis of all forms of cardiac dysfunction. Our findings are consistent with other data from patients in which severe heart failure was not associated with increased levels of circulating cytokines.