Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.     

Right and left ventricular pressure-volume response to respiratory maneuvers

With respiration, right ventricular end-diastolic volume fluctuates. We examined the importance of these right ventricular volume changes on left ventricular function. In six mongrel dogs, right and left ventricular volumes and pressures and esophageal pressure were simultaneously measured during normal respiration, Valsalva maneuver, and Mueller maneuver. The right and left ventricular volumes were calculated from cineradiographic positions of endocardial radiopaque markers. Increases in right ventricular volume were associated with changes in the left ventricular (LV) pressure-volume relationship. With normal respiration, right ventricular end-diastolic volume increased 2.3 +/- 0.7 ml during inspiration, LV transmural diastolic pressure was unchanged, and LV diastolic volume decreased slightly. This effect was accentuated by the Mueller maneuver; right ventricular end-diastolic volume increased 10.4 +/- 2.3 ml (P less than 0.05), while left ventricular end-diastolic pressure increased 3.6 mmHg (P less than 0.05) without a significant change in left ventricular end-diastolic volume. Conversely, with a Valsalva maneuver, right ventricular volume decreased 6.5 +/- 1.2 ml (P less than 0.05), and left ventricular end-diastolic pressure decreased 2.2 +/- 0.5 mmHg (P less than 0.05) despite an unchanged left ventricular end-diastolic volume. These changes in the left ventricular pressure-volume relationship, secondary to changes in right ventricular volumes, are probably due to ventricular interdependence. Ventricular interdependence may also be an additional factor for the decrease in left ventricular stroke volume during inspiration.     

Function of mature coronary collateral vessels and cardiac performance in the exercising dog

Formation of extensive collateral vessels after chronic constriction of a coronary artery in dogs can provide for similar increases in blood flow to native and collateralized regions of myocardium during exertion. Previous investigations have not compared myocardial blood flow and cardiac functional responses during exercise in constricted and nonconstricted (sham) animals. Thus we evaluated left ventricular performance and myocardial blood flow at rest and during mild, moderate, and severe exertion in sham-operated dogs and in dogs 2-3 mo after placement of an Ameroid occluder around the proximal left circumflex artery. Changes in double product, maximal left ventricular dP/dt, and pressure-work index were similar in both groups for each level of exertion. Despite similar increases in estimated myocardial O2 demand and similar diastolic perfusion pressures, average transmural myocardial blood flow increased less in the constrictor animals, particularly during severe exercise (2.74 +/- 0.22 vs. 1.45 +/- 0.29 ml X min-1 X g-1). The smaller increases in blood flow occurred equally in native and collateralized regions as well as in the papillary muscles and boundary areas between the native and collateralized regions. The differences in flow in the native and collateralized regions were uniform across the wall of the myocardium. We also observed smaller increases in stroke volume and cardiac output in the constrictor group, disparities which increased with increasing exertion (stroke volume, severe exercise = 0.92 +/- 0.13 vs. 0.53 +/- 0.09 ml/kg). We postulate that myocardial active hyperemia is limited either because the coronary vessels remaining after chronic circumflex occlusion cannot dilate sufficiently or that there is inappropriate active vasoconstriction during severe exertion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Compression induced by RV pressure overload decreases regional coronary blood flow in anesthetized dogs

Pulmonary artery constriction (PAC), a model of right ventricular (RV) pressure overload, flattens or inverts the septum and may flatten the left ventricular (LV) free wall. Finite element (FE) analysis predicts that such deformations may cause substantial compression. This study tests the hypothesis that deformation-induced myocardial compressive stress impedes coronary blood flow (CBF). Colored microspheres ( approximately 2 x 10(6)) were injected into the left atrium of 13 open-chest, anesthetized dogs under control conditions and during PAC, which decreased the end-diastolic transseptal pressure gradient (LV - RV) from 1.6 +/- 1.3 to -3.4 +/- 1.7 mmHg. Septal and LV deformation was assessed with the use of two-dimensional echocardiography, and by FE analysis, the hydrostatic component of stress was assessed. Postmortem, a 2.5-cm wide, LV equatorial ring was divided into 16 endocardial and epicardial samples. PAC decreased CBF in the FE-predicted compression zones, areas with the greatest compression having the greatest reductions in CBF. During PAC, compression reached a maximum of 25.3 +/- 1.8 mmHg on the (LV) endocardial sides of the RV insertion points, areas that saw CBF decrease from 1.05 +/- 0.08 to 0.68 +/- 0.05 ml.min(-1).g(-1) (P < 0.001), more than 30%. CBF decreased (from 1.08 +/- 0.07 to 0.81 +/- 0.07 ml.min(-1).g(-1); P < 0.001) on the RV side of the midseptum, an area with as much as 16.0 +/- 1.0 mmHg of compression. Overall, average compressions of 10 mmHg decreased CBF by approximately 30%. We conclude that acute RV pressure overload deforms the septum and LV and induces compressive stresses that reduce CBF substantially. This may help explain why some patients with pulmonary hypertension and no critical coronary disease have chest discomfort indistinguishable from angina pectoris.     

Effects of coupled pacing on cardiac performance during acute atrial tachycardia and fibrillation: an old therapy revisited for a new reason

Atrial tachycardia (AT) and fibrillation (AF) result in rapid ventricular rates that are detrimental to optimal cardiac function. The purpose of this study was to determine whether the application of a coupled pacing (CP) regimen would improve ventricular function by decreasing the ventricular rate of mechanical contractions (VRMCs). We simulated AT by pacing either atrium at a rate that resulted in a rapid but regular ventricular rate in seven anesthetized dogs. AF was induced by increasing the atrial pacing rate until atrial activation did not follow the pacing. After the induction of either AT or AF, we applied CP after each intrinsic ventricular activation. We measured the VRMCs and left ventricular (LV) pressures and volumes via a pressure-conductance catheter. The marked reductions in VRMCs during CP resulted in increases in LV end-diastolic volume. The CP resulted in virtually no mechanical contractions, whereas the strength of contractions from the normal electrical activation increased. The increases in the positive LV rate of pressure development over time and LV ejection fraction during CP were the result of postextrasystolic potentiation. The average stroke work (area of the pressure-volume loops) increased as a result of CP during both AT and AF. Despite the large increases in stroke volume (approximately 2x) during CP, the changes in cardiac output were moderate because the VRMCs markedly decreased (approximately 1/2). We conclude that CP therapy may be a viable therapy for slowing the heart rate and improving cardiac performance in patients with AT and AF.     

Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats

The objective of this study was to determine whether elevated circulating levels of endothelin (ET)-1 are capable of mediating left ventricular (LV) mast cell degranulation and thereby induce matrix metalloproteinase (MMP) activation. After the administration of 20 pg/ml ET-1 to blood-perfused isolated rat hearts, LV tissue was analyzed for signs of mast cell degranulation and MMP activation. Relative to control, ET-1 produced extensive mast cell degranulation as well as a significant increase in myocardial water content (78.8 +/- 1.5% vs. 74.2 +/- 2.2%, P <0.01), a marked 107% increase in MMP-2 activity (P <0.05), and a substantial decrease in collagen volume fraction (0.69 +/- 0.09% vs. 0.99 +/- 0.04%, P <0.001). Although the myocardial edema would be expected to increase ventricular stiffness, compliance was not altered, and moderate ventricular dilatation was observed (end-diastolic volume at end-diastolic pressure of 0 mmHg of 330.2 +/- 22.1 vs. 298.9 +/- 17.4 microl in ET-1 treated vs. control, respectively, P=0.07). Additionally, pretreatment with the mast cell stabilizer nedocromil prevented ET-1-induced changes in MMP-2 activity, myocardial water content, collagen volume fraction, and end-diastolic volume. These findings demonstrate that ET-1 is a potent cardiac mast cell secretogogue and further indicate that ET-1-mediated mast cell degranulation is a potential mechanism responsible for myocardial remodeling.     

Effects of changes in left ventricular contractility on indexes of contractility in mice

Measurement of left ventricular (LV) function is often overlooked in murine studies, which have been used to analyze the effects of genetic manipulation on cardiac phenotype. The goal of this study was to address the effects of changes in LV contractility on indexes of contractility in mice. LV function was assessed in vivo in closed-chest mice by echocardiography and by LV catheterization using a conductance pressure-volume (P-V) catheter with three different interventions that alter contractility by 1) atrial pacing to increase inotropy by augmentation of the force-frequency relation (modest increment of inotropy), 2) dobutamine to maximize inotropy, and 3) esmolol infusion to decrease contractility. Load-independent parameters derived from P-V relations, such as slope of end-systolic P-V relations (ESPVR) and slope of the first maximal pressure derivative over time (dP/dt(max))-end-diastolic volume relation (dP/dt-EDV), and standard echocardiographic parameters were measured. The dP/dt-EDV changed the most among parameters after atrial pacing and dobutamine infusion (percent change, 162.8 +/- 95.9% and 271.0 +/- 44.0%, respectively). ESPVR was the most affected by a decrease in LV contractility during esmolol infusion (percent change, -49.8 +/- 8.3%). However, fractional shortening failed to detect changes in contractility during atrial pacing and esmolol infusion and its percent change was <20%. This study demonstrated that contractile parameters derived from P-V relations change the most during a change in LV contractility and should therefore best detect a small change in contractility in mice. Heart rate has a modest but significant effect on P-V relationship-derived indexes and must be considered in the evaluation of murine cardiac physiology.     

Differential effects of left ventricular pacing sites in an acute canine model of contraction dyssynchrony

The goal of the present study was to assess the effects of left ventricular (LV) pacing sites (apex vs. free wall) on radial synchrony and global LV performance in a canine model of contraction dyssynchrony. Ultrasound tissue Doppler imaging and hemodynamic (LV pressure-volume) data were collected in seven anesthetized, opened-chest dogs. Right atrial (RA) pacing served as the control, and contraction dyssynchrony was created by simultaneous RA and right ventricular (RV) pacing to induce a left bundle-branch block-like contraction pattern. Cardiac resynchronization therapy (CRT) was implemented by adding simultaneous LV pacing to the RV pacing mode at either the LV apex (CRTa) or free wall (CRTf). A new index of synchrony was developed via pair-wise cross-correlation analysis of tissue Doppler radial strain from six midmyocardial cross-sectional regions, with a value of 15 indicating perfect synchrony. Compared with RA pacing, RV pacing significantly decreased radial synchrony (11.1 +/- 0.8 vs. 4.8 +/- 1.2, P < 0.01) and global LV performance (cardiac output: 2.0 +/- 0.3 vs. 1.4 +/- 0.1 l/min and stroke work: 137 +/- 22 vs. 60 +/- 14 mJ, P < 0.05). Although both CRTa and CRTf significantly improved radial synchrony, only CRTa markedly improved global function (cardiac output: 2.1 +/- 0.2 l/min and stroke work: 113 +/- 13 mJ, P < 0.01 vs. RV pacing). Furthermore, CRTa decreased LV end-systolic volume compared with RV pacing without any change in LV end-systolic pressure, indicating an augmented global LV contractile state. Thus, LV apical pacing appears to be a superior pacing site in the context of CRT. The dissociation between changes in synchrony and global LV performance with CRTf suggests that regional analysis from a single plane may not be sufficient to adequately characterize contraction synchrony.     

Biventricular pacing in the early postoperative period after cardiac surgery

Cardiac resynchronization therapy is not commonly used in the early postoperative period in patients undergoing cardiac surgery who have left ventricular (LV) dysfunction and a history of heart failure. We performed a prospective randomized clinical trial to compare atrial synchronous right ventricular (DDD RV) and biventricular (DDD BIV) pacing within 72 hours after cardiac surgery in patients with an EF ≤35 %, a QRS interval longer than 120 msec and who had LV dyssynchrony detected by real-time three-dimensional echocardiography (RT3DE). Epicardial pacing was provided by a modified Medtronic INSYNC III pacemaker. An LV epicardial pacing lead was implanted on the latest activated segment of the LV based on RT3DE. The study included 18 patients with ischemic heart disease, with or without valvular heart disease (14 men, 4 women, average age 71 years). Patients undergoing DDD BIV pacing had a statistically significant greater CO and CI (CO 6.7±1.8 l/min, CI 3.4±0.7 l/min/m(2)) than patients undergoing DDD RV pacing (CO 5.5±1.4 l/min, CI 2.8±0.7 l/min/m(2)), p<0.001. DDD BIV pacing in the early postoperative period after cardiac surgery corrects LV dyssynchrony and has better hemodynamic results than DDD RV pacing.     

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.     

Early mitral deceleration and left atrial stiffness

Left ventricular (LV) filling deceleration time (DT) is determined by the sum of atrial and ventricular stiffnesses (KLA + KLV). If KLA, however, is close to zero, then DT would reflect KLV only. The purpose of this study was to quantify KLA during DT. In 15 patients, KLV was assessed, immediately after cardiopulmonary bypass, from E wave DT as derived from mitral tracings obtained by transesophageal echocardiography and computed according to a validated formula. In each patient, a left atrial (LA) volume curve was also obtained combining mitral and pulmonary vein (PV) cumulative flow plus LA volume measured at end diastole. Time-adjusted LA pressure was measured simultaneously with Doppler data in all patients. KLA was then calculated during the ascending limb of the V loop and during DT. LA volume decreased by 7.3 +/- 6.5 ml/m2 during the first of mitral DT, whereas LV volume increased 9.4 +/- 8.4 ml/m2 (both P < 0.001). There was a small amount of blood coming from the PV during the same time interval, with the cumulative flow averaging 3.2 +/- 2.4 ml/m(2) (P < 0.001). Mean LA pressure was 10.0 +/- 5.1 mmHg, and it did not change during DT [from 7.8 +/- 4.3 to 8.0 +/- 4.3 mmHg, not significant (NS)], making KLA, which averaged 0.46 +/- 0.39 mmHg/ml during the V loop, close to zero during DT [KLA(DT): from -0.002 +/- 0.08 to -0.001 +/- 0.031 mmHg/ml, NS]. KLV, as assessed noninvasively from DT, averaged 0.25 +/- 0.32 mmHg/ml. In conclusion, notwithstanding the significant decrement in LA volume, KLA does not change and can be considered not different from zero during DT. Thus KLA does not affect the estimation of KLV from Doppler parameters.     

Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium

The classical model of coronary physiology implies the presence of maximal microcirculatory vasodilation during myocardial ischemia. However, Doppler monitoring of coronary blood flow (CBF) documented severe microcirculatory vasoconstriction during pacing-induced ischemia in patients with coronary artery disease. This study investigates the mechanisms that underlie this paradoxical behavior in nine patients with stable angina and single-vessel coronary disease who were candidates for stenting. While transstenotic pressures were continuously monitored, input CBF (in ml/min) to the poststenotic myocardium was measured by Doppler catheter and angiographic cross-sectional area. Simultaneously, specific myocardial blood flow (MBF, in ml.min(-1).g(-1)) was measured by 133Xe washout. Perfused tissue mass was calculated as CBF/MBF. Measurements were obtained at baseline, during pacing-induced ischemia, and after stenting. CBF and distal coronary pressure values were also measured during pacing with intracoronary adenosine administration. During pacing, CBF decreased to 64 +/- 24% of baseline and increased to 265 +/- 100% of ischemic flow after adenosine administration. In contrast, pacing increased MBF to 184 +/- 66% of baseline, measured as a function of the increased rate-pressure product (r = 0.69; P < 0.05). Thus, during pacing, perfused myocardial mass drastically decreased from 30 +/- 23 to 12 +/- 11 g (P < 0.01). Distal coronary pressure remained stable during pacing but decreased after adenosine administration. Stenting increased perfused myocardial mass to 39 +/- 23 g (P < 0.05 vs. baseline) as a function of the increase in distal coronary pressure (r = 0.71; P < 0.02). In conclusion, the vasoconstrictor response to pacing-induced ischemia is heterogeneously distributed and excludes a tissue fraction from perfusion. Within perfused tissue, the metabolic demand still controls the vasomotor tone.     

TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling

The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.     

Hemodynamic effects of periodic obstructive apneas in sedated pigs with congestive heart failure.

Because of similar physiological changes such as increased left ventricular (LV) afterload and sympathetic tone, an exaggerated depression in cardiac output (CO) could be expected in patients with coexisting obstructive sleep apnea and congestive heart failure (CHF). To determine cardiovascular effects and mechanisms of periodic obstructive apnea in the presence of CHF, 11 sedated and chronically instrumented pigs with CHF (rapid pacing) were tested with upper airway occlusion under room air breathing (RA), O(2) breathing (O2), and room air breathing after hexamethonium (Hex). All conditions led to large negative swings in intrathoracic pressure (-30 to -39 Torr) and hypercapnia (PCO(2) approximately 60 Torr), and RA and Hex also caused hypoxia (to approximately 42 Torr). Relative to baseline, RA increased mean arterial pressure (from 97.5 +/- 5.0 to 107.3 +/- 5.7 Torr, P < 0.01), systemic vascular resistance, LV end-diastolic pressure, and LV end-systolic length while it decreased CO (from 2.17 +/- 0.27 to 1.52 +/- 0.31 l/min, P < 0.01), stroke volume (SV; from 23.5 +/- 2.4 to 16.0 +/- 4.0 ml, P < 0.01), and LV end-diastolic length (LVEDL). O2 and Hex decreased mean arterial pressure [from 102.3 +/- 4.1 to 16.0 +/- 4.0 Torr (P < 0.01) with O2 and from 86.0 +/- 8.5 to 78.1 +/- 8.7 Torr (P < 0.05) with Hex] and blunted the reduction in CO [from 2.09 +/- 0.15 to 1.78 +/- 0.18 l/ml for O2 and from 2.91 +/- 0.43 to 2.50 +/- 0.35 l/ml for Hex (both P < 0.05)] and SV. However, the reduction in LVEDL and LV end-diastolic pressure was the same as with RA. There was no change in systemic vascular resistance and LVEDL during O2 and Hex relative to baseline. In the CHF pigs during apnea, there was an exaggerated reduction in CO and SV relative to our previously published data from normal sedated pigs under similar conditions. The primary difference between CHF (present study) and the normal animals is that, in addition to increased LV afterload, there was a decrease in LV preload in CHF contributing to SV depression not seen in normal animals. The decrease in LV preload during apneas in CHF may be related to effects of ventricular interdependence.     

Effects of gestational age on myocardial blood flow and coronary flow reserve in pressure-loaded ovine fetal hearts

To test the hypothesis that coronary flow and coronary flow reserve are developmentally regulated, we used fluorescent microspheres to investigate the effects of acute (6 h) pulmonary artery banding (PAB) on baseline and adenosine-enhanced right (RV) and left ventricular (LV) blood flow in two groups of twin ovine fetuses (100 and 128 days of gestation, term 145 days, n = 6 fetuses/group). Within each group, one fetus underwent PAB to constrict the main pulmonary artery diameter by 50%, and the other twin served as a nonbanded control. Physiological measurements were made 6 h after the surgery was completed; tissues were then harvested for analysis of selected genes that may be involved in the early phase of coronary vascular remodeling. Within each age group, arterial blood gas values, heart rate, and mean arterial blood pressure were similar between control and PAB fetuses. Baseline endocardial blood flow in both ventricles was greater in 100 than 128-day fetuses (RV: 341 +/- 20 vs. 230 +/- 17 ml*min(-1)*100 g(-1); LV: 258 +/- 18 vs. 172 +/- 23 ml*min(-1)*100 g(-1), both P < 0.05). In both age groups, RV and LV endocardial blood flows increased significantly in control animals during adenosine infusion and were greater in PAB compared with control fetuses. After PAB, adenosine further increased RV blood flow in 128-day fetuses (from 416 +/- 30 to 598 +/- 33 ml*min(-1)*g(-1), P < 0.05) but did not enhance blood flow in 100-day animals (490 +/- 59 to 545 +/- 42 ml*min(-1)*100 g(-1), P > 0.2). RV vascular endothelial growth factor and Flk-1 mRNA levels were increased relative to controls (P < 0.05) in 128 but not 100-day PAB fetuses. We conclude that in the ovine fetus, developmentally related differences exist in 1) baseline myocardial blood flows, 2) the adaptive response of myocardial blood flow to acute systolic pressure load, and 3) the responses of selected genes involved in vasculogenesis to increased load in the fetal myocardium.     

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.     

Left ventricular systolic torsion correlates global cardiac performance during dyssynchrony and cardiac resynchronization therapy

Left ventricular (LV) systolic torsion is a primary mechanism contributing to stroke volume (SV). We hypothesized that change in LV torsion parallels changes in global systolic performance during dyssynchrony and cardiac resynchronization therapy (CRT). Seven anesthetized open chest dogs had LV pressure-volume relationship. Apical, basal, and mid-LV cross-sectional echocardiographic images were studied by speckle tracking analysis. Right atrial (RA) pacing served as control. Right ventricular (RV) pacing simulated left bundle branch block. Simultaneous RV-LV free wall and RV-LV apex pacing (CRTfw and CRTa, respectively) modeled CRT. Dyssynchrony was defined as the time difference in peak strain between earliest and latest segments. Torsion was calculated as the maximum difference between the apical and basal rotation. RA pacing had minimal dyssynchrony (52 ± 36 ms). RV pacing induced dyssynchrony (189 ± 61 ms, P < 0.05). CRTa decreased dyssynchrony (46 ± 36 ms, P < 0.05 vs. RV pacing), whereas CRTfw did not (110 ± 96 ms). Torsion during baseline RA was 6.6 ± 3.7°. RV pacing decreased torsion (5.1 ± 3.6°, P < 0.05 vs. control), and reduced SV, stroke work (SW), and dP/dt(max) compared with RA (21 ± 5 vs. 17 ± 5 ml, 252 ± 61 vs. 151 ± 64 mJ, and 2,063 ± 456 vs. 1,603 ± 424 mmHg/s, respectively, P < 0.05). CRTa improved torsion, SV, SW, and dP/dt(max) compared with RV pacing (7.7 ± 4.7°, 23 ± 3 ml, 240 ± 50 mJ, and 1,947 ± 647 mmHg/s, respectively, P < 0.05), whereas CRTfw did not (5.1 ± 3.6°, 18 ± 5 ml, 175 ± 48 mJ, and 1,699 ± 432 mmHg/s, respectively, P < 0.05). LV torsion changes covaried across conditions with SW (y = 0.94x+12.27, r = 0.81, P < 0.0001) and SV (y = 0.66x+0.91, r = 0.81, P < 0.0001). LV dyssynchrony changes did not correlate with SW or SV (r = -0.12, P = 0.61 and r = 0.08, P = 0.73, respectively). Thus, we conclude that LV torsion is primarily altered by dyssynchrony, and CRT that restores LV performance also restores torsion.     

Effects of systolic and diastolic positive pleural pressure pulses with altered cardiac contractility.

Positive pleural pressure (Ppl) decreases left ventricular afterload and preload. The resulting change in cardiac output (CO) in response to these altered loading conditions varies with the baseline level of cardiac contractility. In an isolated canine heart-lung preparation, we studied the effects of positive Ppl applied phasically during systole or diastole on CO and on the cardiac function curve (the relationship between CO and left atrial transmural pressure). When baseline cardiac contractility was enhanced by epinephrine infusion, systolic and diastolic positive Ppl decreased CO equally (1,931 +/- 131 to 1,419 +/- 124 and 1,970 +/- 139 to 1,468 +/- 139 ml/min, P less than 0.01) and decreased the pressure gradient driving venous return. However, neither shifted the position of the cardiac function curve, suggesting that the predominant effect of positive Ppl was decreased preload. When baseline cardiac contractility was depressed by severe respiratory acidosis, diastolic positive Ppl pulses caused no significant change in CO (418 +/- 66 to 386 +/- 52 ml/min), the cardiac function curve, or the pressure gradient for venous return. However, systolic positive Ppl pulses increased CO from 415 +/- 70 to 483 +/- 65 ml/min (P less than 0.01) and significantly shifted the cardiac function curve to the left. Thus the effect of Ppl pulsations on CO works through different mechanisms, depending on the state of cardiac contractility.     

Tailoring cardiac resynchronization therapy using interventricular asynchrony. Validation of a simple model

This study explores the use of interventricular asynchrony (interVA) for optimizing cardiac resynchronization therapy (CRT), an idea emerging from a simple pathway model of conduction in the ventricles. Measurements were performed in six dogs with chronic left bundle branch block (LBBB) and in 29 patients of the Pacing Therapies for Congestive Heart Failure (PATH-CHF)-I study. In the dogs, intraventricular asynchrony (intraVA) was determined using left ventricular (LV) endocardial activation maps. In dogs and patients, the maximum rate of rise of LV pressure (LV dP/dt(max)) and the pulse pressure (PP) and interVA [time delay between upslope of LV and right ventricular (RV) pressure curves] were measured during LV, RV, and biventricular (BiV) pacing with various atrioventricular (AV) delays. Measurements in the canine hearts supported the pathway model in that optimal resynchronization occurred at approximately 50% reduction of intraVA and at an interVA value halfway that during LBBB and LV pacing. In patients with significant hemodynamic response during pacing (n = 22), intrinsic interVA and interVA at peak improvement (interVA(p)) varied widely between patients (from -83 to -15 ms and from -42 to +31 ms, respectively). However, the model predicted individual interVA(p) accurately (SD of +/-6 ms and +/-12 ms for LV dP/dt(max) and PP, respectively). At equal interVA, LV and BiV pacing produced equal hemodynamic response, but in 11 of 22 responders, BiV pacing reduced interVA insufficiently to reach the maximum hemodynamic response. LV pacing at short AV delay proved to result in better hemodynamics than predicted by the model, indicating that additional factors determine hemodynamics during LV preexcitation. Guided by a simple pathway model, interVA measurements accurately predict optimal hemodynamic performance in individual CRT patients.     

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.