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.

Clinical outcomes of point-of-care testing in the interventional radiology and invasive cardiology setting.

BACKGROUND: Point-of-care testing (POCT) can provide rapid test results, but its impact on patient care is not well documented. We investigated the ability of POCT to decrease inpatient and outpatient waiting times for cardiovascular procedures. METHODS: We prospectively studied, over a 7-month period, 216 patients requiring diagnostic laboratory testing for coagulation (prothrombin time/activated partial thromboplastin time) and/or renal function (urea nitrogen, creatinine, sodium, and potassium) before elective invasive cardiac and radiologic procedures. Overall patient management and workflow were examined in the initial phase. In phase 2, we implemented POCT but utilized central laboratory results for patient management. In phase 3, therapeutic decisions were based on POCT results. The final phase, phase 4, sought to optimize workflow around the availability of POCT. Patient wait and timing of phlebotomy, availability of laboratory results, and therapeutic action were monitored. Split sampling allowed comparability of POCT and central laboratory results throughout the study. RESULTS: In phase 1, 44% of central laboratory results were not available before the scheduled time for procedure (n = 135). Mean waiting times (arrival to procedure) were 188 +/- 54 min for patients who needed renal testing (phase 2; n = 14) and 171 +/- 76 min for those needing coagulation testing (n = 24). For patients needing renal testing, POCT decreased patient wait times (phases 3 and 4 combined, 141 +/- 52 min; n = 18; P = 0.02). For patients needing coagulation testing, wait times improved only when systematic changes were made in workflow (phase 4, 109 +/- 41 min; n = 12; P = 0.01). CONCLUSIONS: Although POCT has the potential to provide beneficial patient outcomes, merely moving testing from a central laboratory to the medical unit does not guarantee improved outcomes. Systematic changes in patient management may be required.

Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly.

OBJECTIVES: We tested the hypothesis that age-related arterial stiffening is matched by ventricular systolic stiffening, and that both enhance systolic pressure sensitivity to altered cardiac preload. BACKGROUND: Arterial rigidity with age likely enhances blood pressure sensitivity to ventricular filling volume shifts. Tandem increases in ventricular systolic stiffness may also occur and could potentially enhance this sensitivity. METHODS: Invasive left ventricular pressure-volume relations were measured by conductance catheter in 57 adults aged 19 to 93 years. Patients had normal heart function and no cardiac hypertrophy and were referred for catheterization to evaluate chest pain. Twenty-eight subjects had normal coronary angiography and hemodynamics, and the remaining had either systolic hypertension or coronary artery disease without infarction. Data recorded at rest and during transient preload reduction by inferior vena caval obstruction yielded systolic and diastolic left ventricular chamber and effective arterial stiffness and pulse pressure. RESULTS: Left ventricular volumes, ejection fraction and heart rate were unaltered by age, whereas vascular load and stiffening increased (p < 0.008). Arterial stiffening (Ea) was matched by increased ventricular systolic stiffness (Ees): Ees=0.91 x Ea + 0.53, (r=0.50, p < 0.0001), maintaining arterial-heart interaction (Ea/Ees ratio) age-independent. Ventricular systolic and diastolic stiffnesses correlated (r=0.51, p < 0.0001) and increased with age (p < 0.03). Both ventricular and vascular stiffening significantly increased systolic pressure sensitivity to cardiac preload (p < 0.006). CONCLUSIONS: Arterial stiffening with age is matched by ventricular systolic stiffening even without hypertrophy. The two effects contribute to elevating systolic pressure sensitivity to altered chamber filling. In addition to recognized baroreflex and autonomic dysfunction with age, combined stiffening could further enhance pressure lability with diuretics and postural shifts in the elderly.

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.

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.

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.

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.

Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants.

BACKGROUND: Experimental studies indicate that in addition to diastolic dysfunction, hypertrophied myocardium can display depressed contractile responses, particularly at rapid heart rates, compounding reserve limitations. This study tests whether such abnormalities exist in intact human subjects at physiological paced rates and, if so, whether they are linked to simultaneous rate-dependent deterioration in diastolic function. METHODS AND RESULTS: Ten subjects with left ventricular hypertrophy (LVH) and 8 normal control subjects were studied. Most LVH patients presented with dyspnea and/or pulmonary edema and had concentric hypertrophy. Since rapid pacing simultaneously alters cardiac filling volumes and pressures, pressure-volume relation analysis was used to better define changes in contractile response. Patients were instrumented with a conductance catheter and micromanometer for pressure-volume data recording and a balloon occluder at the right atrial-inferior vena caval junction to vary filling and thus generate function relations. Data were obtained at baseline and at three atrial pacing rates (100, 120, 150 min-1). In addition, single-beat force-interval data were used to indirectly examine calcium cycling kinetics. LVH subjects demonstrated baseline diastolic abnormalities, including prolonged relaxation, elevated end-diastolic pressure, and reduced chamber compliance. However, systolic function was similar to that in control subjects. With rapid pacing, normal subjects displayed a positive contractile response, whereas this was markedly diminished in LVH subjects. With abrupt termination of pacing and return to slower sinus rhythm, LVH subjects displayed greater initial potentiation followed by a more rapid decline than control subjects, suggesting abnormalities of calcium handling. Despite contractile abnormalities, diastolic function did not further deteriorate with rapid pacing and thus did not appear to be tightly linked to the systolic changes. CONCLUSIONS: Pacing stress in intact human LVH can result in systolic impairment superimposed on preexisting but not worsened diastolic dysfunction. Abnormal calcium handling probably contributes prominently to this response.

Diastolic compliance of hypertrophied ventricle is not acutely altered by pharmacologic agents influencing active processes.

OBJECTIVE: To test, by studying the acute effects of drugs that influence active processes, the hypothesis that in humans with marked ventricular hypertrophy, reduced chamber compliance is primarily caused by passive structural changes. DESIGN: An uncontrolled (before-after) study. SETTING: University Medical Center. PATIENTS: Fourteen patients with ventricular hypertrophy (19 +/- 4.5-mm diastolic-wall thickness) and normal resting systolic function were studied while they had invasive cardiac catheterization. INTERVENTION: Intravenous beta-blocker (esmolol) or calcium channel blocker (verapamil) or both. MEASUREMENTS: Left ventricular function was determined by pressure-volume relations. Volume was measured using conductance catheter, providing a continuous voltage signal proportional to chamber volume. Pressure was measured by micromanometer. Cardiac-specific assessment of change in chamber contractility and diastolic compliance due to each drug was determined. RESULTS: Both drugs lowered contractility by approximately 30% (P < 0.01). Esmolol slowed relaxation and reduced early peak filling rate, whereas verapamil delayed the time to peak filling (all P < 0.05). In contrast to the effects of both drugs on active contraction and early diastole, late-diastolic compliance was unaltered, and end-diastolic pressure-volume relations were almost identical. CONCLUSION: Neither beta-receptor nor calcium channel blockade acutely alters left ventricular compliance despite substantial active effects manifest in systole and early diastole. This supports the notion that chamber compliance is principally determined by passive structural elements in the heart rather than by active processes.

Effective arterial elastance as index of arterial vascular load in humans.

BACKGROUND: This study tested whether the simple ratio of ventricular end-systolic pressure to stroke volume, known as the effective arterial elastance (Ea), provides a valid measure of arterial load in humans with normal and aged hypertensive vasculatures. METHODS AND RESULTS: Ventricular pressure-volume and invasive aortic pressure and flow were simultaneously determined in 10 subjects (four young normotensive and six older hypertensive). Measurements were obtained at rest, during mechanically reduced preload, and after pharmacological interventions. Two measures of arterial load were compared: One was derived from aortic input impedance and arterial compliance data using an algebraic expression based on a three-element Windkessel model of the arterial system [Ea(Z)], and the other was more simply measured as the ratio of ventricular end-systolic pressure to stroke volume [Ea(PV)]. Although derived from completely different data sources and despite the simplifying assumptions of Ea(PV), both Ea(Z) and Ea(PV) were virtually identical over a broad range of altered conditions: Ea(PV) = 0.97.Ea(Z) + 0.17; n = 33, r2 = 0.98, SEE = 0.09, p less than 0.0001. Whereas Ea(PV) also correlated with mean arterial resistance, it exceeded resistance by as much as 25% in older hypertensive subjects (because of reduced compliance and wave reflections), which better indexed the arterial load effects on the ventricle. Simple methods to estimate Ea (PV) from routine arterial pressures were tested and validated. CONCLUSIONS: Ea(PV) provides a convenient, useful method to assess arterial load and its impact on the human ventricle. These results highlight effects of increased pulsatile load caused by aging or hypertension on the pressure-volume loop and indicate that this load and its effects on cardiac performance are often underestimated by mean arterial resistance but are better accounted for by Ea.

Reduced left ventricular compliance in human mitral stenosis. Role of reversible internal constraint.

BACKGROUND: The mechanisms of depressed left ventricular (LV) pump performance in human mitral stenosis (MS) remain poorly understood, because reduced filling alone affects many hemodynamic measurements. Therefore, pressure-volume relations were examined in nine subjects with MS and compared with eight age-matched normal controls. METHODS AND RESULTS: Data were obtained by conductance catheter/micromanometer technique with transient inferior vena cava occlusion used to alter load and generate pressure-volume relations. In a subset of patients (n = 5), data were obtained both acutely and at 3 months (n = 4) after balloon valvuloplasty. MS patients had reduced cardiac output (3.3 +/- 0.9 versus 5.6 +/- 1.7 l/min) and end-diastolic volume (68.0 +/- 6.9 versus 115 +/- 31 ml) versus controls (p less than 0.001), with a mean transvalvular gradient of 14 +/- 6 mm Hg and estimated valve area of 0.6 +/- 0.2 cm2. Systolic function as assessed by the end-systolic pressure-volume relation was virtually the same in MS and control subjects. In contrast, end-diastolic pressure-volume relations in MS were consistently shifted leftward and had an increased slope (lower compliance) at matched pressure ranges (6.5 +/- 3.0 versus 2.2 +/- 0.53 ml/mm Hg at a mean diastolic pressure of 8 mm Hg, p less than 0.001). This change was not a result of reduced LV filling or probably of increased right heart loading. Valvuloplasty acutely returned chamber compliance to near normal, a change that was sustained at 3-month follow-up. Systolic function was little altered at this time. CONCLUSIONS: These data indicate an impairment of diastolic function in human MS that can be acutely reversed by balloon valvuloplasty. Lowered LV compliance probably results from a functional restriction caused by ventricular attachment to a thickened and immobile valve apparatus.

Mechanism of global functional recovery despite sustained postischemic regional stunning.

BACKGROUND: The mechanisms whereby reperfusion of a 20-minute coronary occlusion result in global functional recovery despite persistent regional dysfunction were studied in 11 open-chest reflex-blocked dogs. METHODS AND RESULTS: Pressure-volume and pressure-thickness relations were simultaneously determined before, during, and after reperfusion of left anterior descending artery (LAD) occlusion. Wall thickness was determined by sonomicrometry in both ischemic and remote regions. Chamber systolic function was assessed by end-systolic pressure-volume relations (ESPVR) obtained by conductance catheter and defined by a slope (Ees) and volume shift at a common end-systolic pressure (delta Ves). LAD occlusion produced regional systolic thinning (-7 +/- 6%) and global left ventricular dysfunction (ESPVR shifted rightward (delta Ves = +8.6 +/- 5.1 ml, p less than 0.001) with no Ees change). After nearly 1 hour of reperfusion, LAD region thickening remained markedly reduced at 4 +/- 7% (versus 23 +/- 8%, control), yet chamber systolic function fully recovered (ESPVR shifted back leftward delta Ves = -8.9 +/- 6.5 ml). Ischemia induced a leftward shift and systolic thinning of LAD region pressure-thickness relations. Reperfusion returned end-systolic pressure-thickness relations halfway to their control position and diastolic relations fully to control position. This was primarily due to increased passive stiffening in about half the hearts and a partial return of active function in the remaining ones. The net effect was to eliminate systolic thinning over a physiological loading range, thus normalizing chamber systolic performance. Reflex activation, remote hyperfunction, or altered chamber loading did not account for the postreperfusion disparity between global and regional function. CONCLUSIONS: These data suggest a mechanism to account for greater functional benefits of reperfusion beyond that anticipated from regional wall motion analysis.

Preservation of ventricular function by treatment of ventricular fibrillation with phenylephrine.

Epinephrine promotes resuscitation from ventricular fibrillation because of its peripheral vasoconstrictive effects. However, the beta-adrenergic effects of epinephrine may be detrimental because of the stimulation of myocardial oxygen demand. To test whether functional recovery from fibrillation in hearts treated with a selective alpha-adrenergic agent is greater than in hearts treated with epinephrine, ventricular fibrillation was induced in eight isolated dog hearts while coronary perfusion pressure was maintained at 30 mm Hg. In random order, epinephrine (5 micrograms/min), phenylephrine (50 micrograms/min) or no drug was infused for 5 min. The heart was then defibrillated, the drug infusion stopped and coronary perfusion pressure increased to 100 mm Hg. Coronary blood flow (ml/min per 100 g), arteriovenous oxygen difference (ml O2/dl) and myocardial oxygen consumption (ml O2/min per 100 g) measured after 4 min of ventricular fibrillation were greater with epinephrine (mean +/- SD 30.9 +/- 11.7, 17.5 +/- 1.6 and 5.4 +/- 1.9, respectively) than with phenylephrine (24.4 +/- 6.0, 15.7 +/- 2.6 and 3.8 +/- 1.1, respectively) or no drug (19.8 +/- 5.2, 12.8 +/- 1.8 and 2.6 +/- 0.7, respectively) (p less than 0.05, p less than 0.05 and p less than 0.05, respectively). The slope of the end-systolic pressure-volume relation 10 min after defibrillation and restoration of normal coronary perfusion pressure was depressed (percent of prefibrillation value) most by epinephrine infusion (72 +/- 17%, n = 6), less by no drug infusion (82 +/- 12%, n = 4) and was increased after phenylephrine infusion (143 +/- 17%, n = 6) (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Does volume catheter parallel conductance vary during a cardiac cycle?

Absolute left ventricular volume measurement by the conductance (volume) catheter requires subtraction of the conductance contribution from structures extrinsic to the cavity blood pool. Previously, this parallel conductance volume (Vp) has been assumed constant throughout the cardiac cycle, and the technique described for its estimation in situ yields a single value. We present a new method for parallel conductance determination that yields multiple estimates during systole, enabling an assessment of Vp variability [Vp(t)]. For isolated blood-perfused ejecting canine left ventricles with empty (vented) right ventricles, Vp(t) displayed virtually no variation throughout systole. For in situ hearts, despite the presence of other cardiac chambers, Vp(t) also displayed little variation, with no statistically significant deviation from its mean value throughout systole. Volume signal simulations found the new technique to be less sensitive to signal noise and thus more robust than the one previously published. The isolated and in situ heart data indicate that for the left ventricle, the parallel conductance is relatively constant throughout normal ejection.

Influence of coronary occlusion during PTCA on end-systolic and end-diastolic pressure-volume relations in humans.

The influence of acute coronary occlusion on systolic and diastolic left ventricular pressure-volume relations was studied in 10 patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Pressure-volume relations were obtained by conductance catheter and micromanometer techniques and with volume load altered by transient inferior vena caval occlusion. End-systolic and end-diastolic pressure-volume relations were obtained at baseline, during 60-90 seconds of ischemia, and at return to baseline after angioplasty balloon deflation. Coronary occlusion significantly altered systolic and diastolic chamber function. Systolic dysfunction was characterized by a reproducible rightward shift of the end-systolic pressure-volume relation (+25.4 +/- 18.4 ml) that was greater for proximal left anterior descending and circumflex coronary artery occlusions (+41 ml) than for distal or right coronary artery occlusions (+15.4 ml, p less than 0.05). Occlusion also lowered chamber systolic function indexes, such as the end-systolic pressure-volume relation slope (from 4.2 to 2.8 mm Hg/ml) and preload recruitable stroke work (from 97 to 78.6 mm Hg). All systolic (and diastolic) changes were resolved with successful angioplasty. Diastolic abnormalities during angioplasty were characterized by prolonged pressure relaxation and an upward shift of the resting diastolic pressure-volume data and by an apparent increase in chamber elastic stiffness. However, when end-diastolic data from multiple beats during inferior vena caval occlusion were compared, control and ischemic end-diastolic pressure-volume relations displayed little or no difference. Thus, elevations in resting diastolic pressure-volume relations and apparent increase in chamber elastic stiffness during coronary occlusion in humans appear dominated by altered right ventricular or pericardial loading. These data indicate that pressure-volume analysis is useful in assessing the functional significance of coronary lesions and reperfusion.

Determinants of end-systolic pressure-volume relations during acute regional ischemia in situ.

The influence of extent and location of regional ischemia, baseline left ventricular systolic function, and autonomic reflexes on in situ left ventricular end-systolic pressure-volume relations (ESPVRs) during coronary occlusion were studied in 13 open-chest dogs. Circumflex or left anterior descending arteries were randomly occluded (at proximal or distal sites) for 3 minutes in reflex-blocked (n = 6, hexamethonium/vagotomy) and unblocked (n = 7) animals. Pressure-volume data were obtained by the conductance-catheter technique, with ESPVRs determined by transient inferior vena caval occlusion. Ischemic zone size was estimated for each occlusion by radiolabeled microspheres. The relative influence of each variable on ESPVR change with ischemia was determined by multiple regression analysis. As in previous studies, regional ischemia displaced ESPVRs to the right by an amount that varied directly with ischemic bed size (y = +0.48x, r = 0.76, p less than 0.001). However, in contrast to previous data, coronary occlusion also reduced the ESPVR slope (end-systolic elastance, Ees) in the majority of cases. The extent of slope change was primarily dependent on the baseline elastance (Eesbase), such that the higher the initial elastance, the larger its subsequent reduction for any amount of ischemia (delta Ees = -0.78Eesbase, r = 0.94, p less than 0.001). Active reflexes added an offset constant to this relation (+3.15 mm Hg/ml, p less than 0.001). In addition, Ees fell slightly more with larger ischemic regions. Thus, although previous studies have reported primarily rightward parallel shifts in ESPVR with regional ischemia, the present data also demonstrate that the slope of the relation is often reduced. Greater baseline elastances typical of in situ, as opposed to isolated, ventricles probably explain the differences in apparent responses.

Electrophysiological effect of volume load in isolated canine hearts.

In isolated isovolumic ventricles and in in situ ventricles under nonsteady-state conditions, alterations in load have been shown to affect electrophysiological properties via contraction-excitation feedback. However, the effect of alterations in loading conditions on electrophysiological properties in normal ventricles under physiological loading conditions remains unknown. Furthermore, the arrhythmogenic significance of these load-induced electrophysiological changes is uncertain. We increased end-diastolic volume (27 +/- 4 ml vs. 51 +/- 6 ml) and assessed conduction, refractoriness, ventricular fibrillation thresholds (VFTs), and inducibility of ventricular arrhythmias in 14 isolated blood-perfused ejecting canine ventricles under steady-state conditions. We also examined the effect of increased end-diastolic volume on refractoriness and monophasic action potential (MAP) duration and contour under isovolumic versus ejecting conditions. Under ejecting conditions, increased end-diastolic volume resulted in very small (less than 1.5%) changes in the absolute refractory period (10 mA) and in local activation time but no change in local electrogram duration, overall dispersion of refractoriness, MAP duration or contour, VFT, or inducibility of ventricular arrhythmias. Increased volume loading under isovolumic conditions resulted in a very slight (less than 1%) shortening of MAP duration and refractoriness but had no effect on the MAP contour. These findings provide strong evidence that alterations in volume load are of little electrophysiological or arrhythmogenic importance in normal canine ventricles under physiologically loaded conditions (contraction-excitation feedback, load and arrhythmias, volume load).

Effect of acute volume load on refractoriness and arrhythmia development in isolated, chronically infarcted canine hearts.

In normal isolated, perfused canine ventricles, increased ventricular volume leads to shortening of refractoriness. To test the hypothesis that myocardium within an infarction zone is more susceptible to volume-induced changes in refractoriness than is normal myocardium, we measured strength-interval curves at low and high end-diastolic volumes at control and infarcted sites in 14 isolated, blood perfused, canine hearts with chronic (greater than 25 days) infarctions. In addition, the effect of volume load on inducing ventricular arrhythmias was studied at one to six sites in 11 hearts. Differences in refractoriness and inducibility at low (22 +/- 5 ml) and high (48 +/- 6 ml) end-diastolic volumes were compared. At control sites, volume load reduced the absolute refractory period from 178 +/- 16.5 to 175 +/- 16.7 msec (p less than 0.05), but no significant change in the relative refractory period occurred. At infarcted sites, the change in refractoriness with volume load was greater, and the absolute refractory period decreased from 171.5 +/- 21 to 160.6 +/- 26.3 msec (p less than 0.01), and the relative refractory period decreased from 180.1 +/- 22.1 to 169.9 +/- 26 msec (p = 0.05). This differential effect of volume load on refractoriness led to an increased dispersion of overall refractoriness at high volume. Infarcted sites showing the largest changes in refractoriness were characterized by patchy scars extending at least to the midmyocardium, whereas sites located within areas of transmural scar, endocardial scar, or rare microfoci of fibrosis showed no increased sensitivity to volume load. Of eight hearts in which no tachyarrhythmias were inducible during programmed electrical stimulation at low volume, four had tachyarrhythmias induced at high volume. Sites of stimulation associated with a conversion from noninducible to inducible tachyarrhythmias showed a larger degree of shortening of refractoriness (change in absolute refractory period: 24.7 +/- 16.5 vs. 3.9 +/- 6.5 msec, p less than 0.05). These data indicate that volume loading may have electrophysiologic significance and that it may be of greater functional importance under pathologic conditions.

Influence of contractile state on curvilinearity of in situ end-systolic pressure-volume relations.

Although in situ end-systolic pressure-volume relations (ESPVRs) are approximately linear throughout a limited load range, they often yield seemingly "negative" volume axis intercepts (V0) and V0 shifts with inotropic interventions. We tested whether or not these findings could stem from in situ ESPVR nonlinearity, and we examined the physiologic meaning and limitations of linearized ESPVR variables frequently used for assessing contractile state. Continuous left ventricular pressures and volumes were obtained by micromanometer and conductance (volume) catheters in six open-chest dogs. Left ventricular loading was varied throughout a wide range by rapid left atrial hemorrhage into a reservoir. Propranolol and verapamil were administered to reduce inotropic state, with heart rate maintained by atrioventricular sequential pacing. ESPVRs were fit to nonlinear [Pes = a(Ves-V'0)2 + b(Ves-V'0)] and linear (Pes = Ees (Ves-V0)] models. Contractile state was assessed by the slope of the ESPVR at V'0 (b, of nonlinear model) and by two other ESPVR model-independent measures: the slope of the dP/dtmax and end-diastolic volume relation, and the slope of the stroke work and end-diastolic volume relation. ESPVR was frequently curvilinear, and a significant correlation existed between the extent of nonlinearity (a) and contractile state. Volume intercepts derived from linear fits to the high load ESPVR range were mostly negative and were dependent on changes in Ees. V0 estimates derived from the low load portion were positive and relatively insensitive to Ees. Thus, in situ ESPVR displays contractility-dependent curvilinearity. The contractility range throughout which ESPVRs are essentially linear is typical for isolated hearts, but the range represents low values for in situ ventricles. Despite curvilinearity, Ees determined in situ throughout limited load ranges can accurately assess inotropic state; however, comparisons between ESPVRs should consider potential nonlinearity, and if possible, they should be made within similar end-systolic pressure ranges.