Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy.

OBJECTIVES: This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling. BACKGROUND: The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure. METHODS: The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 5 mg/min). RESULTS: In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 +/- 8% (p < 0.001) and ventricular elastance (Ecs) by 53 +/- 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 +/- 12% and Ecs to -2 +/- 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Ecs and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion. CONCLUSIONS: Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.

Mechanism of acute mechanical benefit from VDD pacing in hypertrophied heart: similarity of responses in hypertrophic cardiomyopathy and hypertensive heart disease.

BACKGROUND: Dual-chamber pacing can improve symptoms in hypertrophic cardiomyopathy (HCM), but the mechanism remains unclear. We hypothesized that pacing generates discoordinate contraction and a rightward shift of the end-systolic pressure-volume relation (ESPVR) and that benefits from this mechanism do not depend on the presence of resting outflow pressure gradients or obstruction. METHODS AND RESULTS: Eleven patients with NYHA class III symptoms, 5 with HCM, and 6 with hypertensive hypertrophy and cavity obliteration, were studied by invasive conductance catheter methods. No patient had coronary artery or primary valvular disease. Pressure-volume relations were recorded before and during VDD pacing by use of a short (75-millisecond) PR interval to achieve preexcitation. Left ventricular cavity pressure was simultaneously recorded at basal and apical sites, with pressure at the basal site used to generate the ESPVRs. VDD pacing shifted the ESPVR rightward, increasing end-systolic volume by 45% (range, 17% to 151%; P=0.002). Resting and provokable gradients declined by 20% (range, -56% to +3%) and 30% (range, -65% to -12%), respectively (P<0.05). Preload declined by 3% to 10% because of the short PR interval. Preload-corrected contractility indexes and myocardial workload declined by approximately 10% (P<0.001). Diastolic compliance and relaxation time were unchanged. Pacing made apical pressure-volume loops discoordinate, limiting cavity obliteration and reducing distal systolic pressures. Results in both patient groups were similar. CONCLUSIONS: VDD pacing shifts the ESPVR rightward in HCM patients with cavity obliteration with or without obstruction, increasing end-systolic volumes and reducing apical cavity compression and cardiac work. These effects likely contribute to reduced metabolic demand and improved symptoms.

Synergistic exacerbation of diastolic stiffness from short-term tachycardia-induced cardiodepression and angiotensin II.

Synergistic interaction between angiotensin II (Ang II) and evolving cardiodepression may play an important role in worsening chamber function, particularly in diastole. To test this hypothesis, Ang II was infused at 10 or 17 ng.kg(-1).min(-1) in 18 conscious dogs 4 days before and during induction of subacute cardiodepression by 48-hour tachypacing. The lower dose yielded negligible systemic pressure changes. Twelve additional animals served as paced-only controls. Pressure-dimension relations were recorded, and serial endocardial biopsies were obtained to assess histological and metalloproteinase (MMP) changes. Forty-eight-hour pacing alone depressed systolic function but had little effect on diastolic stiffness. Ang II alone only modestly raised diastolic stiffness at both doses and enhanced contractility at the higher dose. These changes recovered toward baseline after a 7-day infusion. However, Ang II (at either dose) combined with 48-hour pacing markedly increased ventricular stiffness (110+/-26% over baseline) and end-diastolic pressure (22+/-1.7 mm Hg). In contrast, pacing-induced inotropic and relaxation abnormalities were not exacerbated by Ang II. Zymography revealed MMP activation (72- and 92-kD gelatinases and 52-kDa caseinase) after a 4-day Ang II infusion (at both doses), which persisted during pacing. Tachypacing initiated 24 hours after cessation of a 7-day Ang II infusion also resulted in diastolic stiffening and corresponded with MMP reactivation. Ang II also induced myocyte necrosis, inflammation, and subsequent interstitial fibrosis, but these changes correlated less with chamber mechanics. Thus, Ang II amplifies and accelerates diastolic dysfunction when combined with evolving cardiodepression. This phenomenon may also underlie Ang II influences in late-stage cardiomyopathy, when chamber distensibility declines.

Comparison of continuous left ventricular volumes by transthoracic two-dimensional digital echo quantification with simultaneous conductance catheter measurements in patients with cardiac diseases.

Automated border detection enables real-time tracking of left ventricular (LV) volume by 2-dimensional transthoracic echocardiography. This technique has not been previously compared with simultaneously measured continuous LV volumes at rest or during transients in humans. We performed 18 studies in 16 patients (age 50 +/- 15 years, range 22 to 70; ejection fraction 63 +/- 20%, range 15% to 85%) in which continuous LV volumes acquired by digital echo quantification (DEQ) were compared with simultaneous conductance catheter volume obtained by cardiac catheterization. Both volume signals were calibrated by thermodilution-derived cardiac output and ventriculogram-derived ejection fraction. Volume traces acquired at rest were averaged to generate a comparison cycle. The averaged volume waveforms acquired by DEQ and by conductance catheter were similar during all phases of the cardiac cycle and significantly correlated (conductance catheter = slope. DEQ + intercept, slope = 0.94 +/- 0.09, intercept = 5 +/- 8 ml, r2 = 0.86 +/- 0.12, all p <0.0001). Steady-state hemodynamic parameters calculated using either averaged volume signal were significantly correlated. Transient obstruction of the inferior vena cava yielded a 45 +/- 13% decrease in end-diastolic volume. Successful recordings of DEQ volume during preload reduction were obtained in only 50% of studies. End-diastolic volumes from the 2 methods were significantly correlated (mean slope 0.88 +/- 0.31, mean intercept 14 +/- 37 ml, average r2 = 0.89 +/- 0.11, all p <0.01), as were end-systolic volumes: mean slope 0.80 +/- 0.43, intercept = -20 +/- 26 ml, r2 = 0.67 +/- 0.18, all p <0.05). We conclude that automated border detection technique by DEQ is reliable for noninvasive, transthoracic, continuous tracking of LV volumes at steady state, but has limitations in use during preload reduction maneuvers in humans.

Repolarization abnormalities, arrhythmia and sudden death in canine tachycardia-induced cardiomyopathy.

OBJECTIVES: This study sought to determine whether the canine model of tachycardia-induced heart failure (HF) is an effective model for sudden cardiac death (SCD) in HF. BACKGROUND: Such a well established HF model that also exhibits arrhythmias and SCD, along with repolarization abnormalities that could trigger them, may facilitate the study of SCD in HF, which still eludes effective treatment. METHODS: Twenty-five dogs were VVI-paced at 250 beats/min for 3 to 5 weeks. Electrocardiograms were obtained, and left ventricular endocardial monophasic action potentials (MAPs) were recorded at six sites at baseline and after HF. Weekly Holter recordings were made with pacing suspended for 24 h. RESULTS: Six animals (24%) died suddenly, one with Holter-documented polymorphic ventricular tachycardia (VT). Holter recordings revealed an increased incidence of VT as HF progressed. Repolarization was significantly (p < 0.05) prolonged, as indexed by a corrected QT interval (mean [+/-SD] 311 +/- 25 to 338 +/- 25 ms) and MAP duration measured at 90% repolarization (MAPD90) (181 +/- 19 to 209 +/- 28 ms), and spatial MAPD90 dispersion rose by 40%. We further tested whether CsCl inhibition of repolarizing K+ currents, which are reportedly downregulated in HF, might preferentially prolong the MAPD90 in HF. With 1 mEq/kg body weight of CsCl, MAPD90 rose by 86 +/- 100 ms in dogs with HF versus only 28 +/- 16 ms in control animals (p = 0.002). Similar disparities in CsCl sensitivity were observed in myocytes isolated from normal and failing hearts. CONCLUSIONS: Tachycardia-induced HF exhibits malignant arrhythmia and SCD, along with prolonged, heterogeneous repolarization and heightened sensitivity to CsCl at chamber and cellular levels. Thus, it appears to be a useful model for studying mechanisms and therapy of SCD in HF.

Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Validation of generalized transfer function.

BACKGROUND: Central aortic pressures and waveform convey important information about cardiovascular status, but direct measurements are invasive. Peripheral pressures can be measured noninvasively, and although they often differ substantially from central pressures, they may be mathematically transformed to approximate the latter. We tested this approach, examining intersubject and intrasubject variability and the validity of using a single averaged transformation, which would enhance its applicability. METHODS AND RESULTS: Invasive central aortic pressure by micromanometer and radial pressure by automated tonometry were measured in 20 patients at steady state and during hemodynamic transients (Valsalva maneuver, abdominal compression, nitroglycerin, or vena caval obstruction). For each patient, transfer functions (TFs) between aortic and radial pressures were calculated by parametric model and results averaged to yield individual TFs. A generalized TF was the average of individual functions. TFs varied among patients, with coefficients of variation for peak amplitude and frequency at peak amplitude of 24.9% and 16.9%, respectively. Intrapatient TF variance with altered loading (> 20% variation in peak amplitude) was observed in 28.5% of patients. Despite this, the generalized TF estimated central arterial pressures to < or = 0.2 +/- 3.8 mm Hg error, arterial compliance to 6 +/- 7% accuracy, and augmentation index to within -7% points (30 +/- 45% accuracy). Individual TFs were only marginally superior to the generalized TF for reconstructing central pressures. CONCLUSIONS: Central aortic pressures can be accurately estimated from radial tonometry with the use of a generalized TF. The reconstructed waveform can provide arterial compliance estimates but may underestimate the augmentation index because the latter requires greater fidelity reproduction of the wave contour.

Marked discordance between dynamic and passive diastolic pressure-volume relations in idiopathic hypertrophic cardiomyopathy.

BACKGROUND: Dynamic diastolic pressure-volume curves measured during filling (PVR fill) in patients with idiopathic hypertrophic cardiomyopathy (HCM) are often considerably shallower than would be anticipated if one assumed high chamber stiffness. We hypothesized that these curves deviate markedly from the passive end-diastolic pressure-volume relation (EDPVR) and explored the mechanisms for such a discordance. METHODS AND RESULTS: We used invasive pressure-volume analysis and conductance catheter methodology to study 42 patients. Nine had HCM, and the remaining patients comprised three comparison groups: 11 with normal left ventricular (LV) function, 13 with LV hypertrophy secondary to chronic hypertension (LVH-HTN), and 9 with idiopathic dilated cardiomyopathy (DCM). EDPVRs were recorded during balloon catheter obstruction of inferior vena cava inflow. In normal subjects, LVH-HTN patients, and DCM patients, PVR fill curves deviated only slightly from the passive EDPVR. In striking contrast, HCM patients displayed a flat PVR fill that was very different from the steep EDPVR. On reduction of preload, PVR fill relations in HCM shifted downward in parallel, with a net pressure decline at the same chamber volume of -10+/-4 mm Hg. This staircaselike shift was much less in the other patient groups (-2+/-2 mm Hg; P<.001). The unusual behavior in HCM could not be attributed directly to increased viscosity, enhanced pericardial constraint, or preload dependence of isovolumic relaxation. Regional heterogeneity of relaxation may play a role; however, we speculate that the major mechanism relates to the unique fiber and chamber architecture seen with HCM and possibly to enhanced ventricular interaction. CONCLUSIONS: Elevated LV filling pressures in HCM are not due simply to a stiff cavity but also reflect a major influence of offset pressures that vary with chamber loading. The large disparity between flat pressure-volume relations during filling and steep end-diastolic relations appears unique to HCM. This indicates that caution should be used in the interpretation of stiffness results derived from steady-state data and suggests that therapies that alter cavity geometry and/or reduce interaction may markedly influence LV diastolic pressures in HCM.

Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure.

Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with heart failure induced by 3 to 4 weeks of rapid ventricular pacing and from 16 nonpaced control dogs did not differ in cell surface area or resting membrane potential. Nevertheless, action potential duration (APD) was significantly prolonged in myocytes isolated from failing ventricles (APD at 90% repolarization, 1097 +/- 73 milliseconds [failing hearts, n = 30] versus 842 +/- 56 milliseconds [control hearts, n = 25]; P < .05), and the prominent repolarizing notch in phase 1 was dramatically attenuated. Basal L-type Ca2+ current and whole-cell Na+ current did not differ in cells from failing and from control hearts, but significant differences in K+ currents were observed. The density of the inward rectifier K+ current (IKl) was reduced in cells from failing hearts at test potentials below -90 mV (at -150 mV, -19.1 +/- 2.2 pA/pF [failing hearts, n = 18] versus -32.2 +/- 5.1 pA/pF [control hearts, n = 15]; P < .05). The small outward current component of IKl was also reduced in cells from failing hearts (at -60 mV, 1.7 +/- 0.2 pA/pF [failing hearts] versus 2.5 +/- 0.2 pA/pF [control hearts]; P < .05). The peak of the Ca(2+)-independent transient outward current (Ito) was dramatically reduced in myocytes isolated from failing hearts compared with nonfailing control hearts (at +80 mV, 7.0 +/- 0.9 pA/pF [failing hearts, n = 20] versus 20.4 +/- 3.2 pA/pF [control hearts, n = 15]; P < .001), while the steady state component was unchanged. There were no significant differences in Ito kinetics or single-channel conductance. A reduction in the number of functional Ito channels was demonstrated by nonstationary fluctuation analysis (0.4 +/- 0.03 channels per square micrometer [failing hearts, n = 5] versus 1.2 +/- 0.1 channels per square micrometer [control hearts, n = 3]; P < .001). Pharmacological reduction of Ito by 4-aminopyridine in control myocytes decreased the notch amplitude and prolonged the APD. Current clamp-release experiments in which current was injected for 8 milliseconds to reproduce the notch sufficed to shorten the APD significantly in cells from failing hearts. These data support the hypothesis that downregulation of Ito in pacing-induced heart failure is at least partially responsible for the action potential prolongation. Because the repolarization abnormalities mimic those in cells isolated from failing human ventricular myocardium, canine pacing-induced cardiomyopathy may provide insights into the development of repolarization abnormalities and the mechanisms of sudden death in patients with heart failure.

Acute cardiovascular effects of OPC-18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations.

BACKGROUND: OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. METHODS AND RESULTS: Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. CONCLUSIONS: OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.

Aortic dissection in a cardiac allograft recipient: a case report.

Ascending aortic dissection is rare in cardiac allograft recipients. Only two patients with dissection arising from the native aorta have been reported previously and, unfortunately, the diagnosis was made postmortem in each instance. We report the first case of successful surgical treatment of aortic dissection confined to the donor aorta in a recipient of an orthotopic cardiac allograft.

Reverse remodeling from cardiomyoplasty in human heart failure. External constraint versus active assist.

BACKGROUND: Cardiomyoplasty (CM) is a novel surgical therapy for dilated cardiomyopathy. In this procedure, the latissimus dorsi muscle is wrapped around the heart and chronically paced synchronously with ventricular systole. While studies have found symptomatic improvement from this therapy, the mechanisms by which CM confers benefit remain uncertain. This study sought to better define these mechanisms by means of serial pressure-volume relation analysis. METHODS AND RESULTS: Serial pressure-volume studies were performed by the conductance catheter method in three patients (total to date) with dilated cardiomyopathy (New York Heart Association class III) who underwent CM. Data were measured at baseline (before surgery) and at 6 and 12 months after CM. Chronic left ventricular (LV) systolic and diastolic changes induced by CM were evaluated with the stimulator in its stable pacing mode (every other beat) and after temporarily suspending pacing. CM-stimulated beats were compared with pacing-off beats to evaluate active systolic assist effects of CM. In each patient, CM resulted in a chronic lowering of cardiac end-diastolic volume and an increased ejection fraction. Most notably, the end-systolic pressure-volume relation shifted leftward, consistent with reversal of chronic chamber remodeling. In contrast, the diastolic pressure-volume relation was minimally altered, and the loops shifted down along the same baseline relation. These marked chronic changes in LV function measurable with CM stimulation off contrasted to only minor acute effects observed when the muscle wrap was activated. This suggests that the benefit of CM derived less from active systolic assist than from remodeling, perhaps because of an external elastic constraint. CONCLUSIONS: These data, while limited to a small number of patients, suggest that CM can reverse remodeling of the dilated failing heart. While systolic squeezing assist effects of CM may play a role in some patients, our study found that this was not required to achieve substantial benefits from the procedure. We speculate that CM may act more passively, like an elastic girdle around the heart, to help reverse chamber remodeling.

Contribution of external forces to left ventricular diastolic pressure. Implications for the clinical use of the Starling law.

OBJECTIVE: To test whether a substantial proportion of measured resting left ventricular diastolic pressure stems from forces external to the left ventricle (such as right-heart filling) in normal and chronically diseased hearts. DESIGN: Nonrandomized study with single intervention. SETTING: University hospital. PATIENTS: 29 patients referred for cardiac catheterization who had normal left ventricles and ejection fractions (n = 12); chronic heart disease due to idiopathic dilated cardiomyopathy (n = 6); ischemic heart disease (n = 6); or left ventricular hypertrophy (n = 5). INTERVENTION: Acute reduction of external forces imposed on the left ventricle using balloon obstruction of inferior vena caval inflow to the right heart. MEASUREMENTS: Continuous catheter-derived left ventricular pressure-volume data before and after abrupt obstruction of inferior vena caval inflow. Diastolic pressures were measured at the same volume just before atrial systole before and after sudden decrease of external (right-heart and pericardial) forces. The resulting decline in pressure was a measure of the contribution of these external forces to resting left ventricular diastolic pressure. RESULTS: The decline in pressure when external forces were released averaged -19% +/- 13% with minimal change in left ventricular end-diastolic volume (-3.66% +/- 6.7%) and cardiac output (-5% +/- 8%). In all patients combined, the decline in pressure when external forces (delta Pd) were released correlated with resting left ventricular diastolic pressure (LVPd) given by: delta Pd = 0.38 x (LVPd-6) [r = 0.86, P < 0.0001]. This indicates that when resting diastolic pressure was more than 6 mm Hg, almost 38% of the pressure was due to external factors. This percentage was similar among all subgroups. Furthermore, the left ventricular diastolic pressure could be reduced by this percentage with only minimal compromise to ventricular filling and cardiac output. CONCLUSIONS: A substantial proportion of measured resting left ventricular diastolic pressure stems from forces extrinsic to the left ventricle rather than from diastolic stiffness in the left ventricle itself. This markedly influences the dependence of cardiac output on filling pressure and has important implications for clinical application of the Starling law.

Assessment of ventricular function in dilated cardiomyopathies.

Regardless of its cause, systolic dysfunction in dilated cardiomyopathy triggers a wide variety of compensatory responses resulting in cardiac dilatation, fluid retention, and systemic vasoconstriction. Standard therapy with vasodilators, digoxin, and diuretics can provide symptomatic relief in many patients. However, many others do not respond adequately, and mortality from heart failure remains high. This has driven the search for novel therapies. To evaluate the efficacy and decipher mechanisms of action of these treatments, accurate assessments of left ventricular function are valuable. In particular, one seeks indexes that are cardiac-specific, in that they are minimally influenced by vascular loading conditions. An increasingly used "gold standard" that can achieve this goal is the invasively measured pressure-volume relation. Newer noninvasive methods have yielded several surrogates that have the key advantage of being applicable to chronic disease assessment. In this report, we review the current state-of-the-art in left ventricular function assessment, and describe recent advances in its noninvasive evaluation.