Noninvasive single-beat determination of left ventricular end-systolic elastance in humans.

OBJECTIVES: The goal of this study was to develop and validate a method to estimate left ventricular end-systolic elastance (E(es)) in humans from noninvasive single-beat parameters. BACKGROUND: Left ventricular end-systolic elastance is a major determinant of cardiac systolic function and ventricular-arterial interaction. However, its use in heart failure assessment and management is limited by lack of a simple means to measure it noninvasively. This study presents a new noninvasive method and validates it against invasively measured E(es). METHODS: Left ventricular end-systolic elastance was calculated by a modified single-beat method employing systolic (P(s)) and diastolic (P(d)) arm-cuff pressures, echo-Doppler stroke volume (SV), echo-derived ejection fraction (EF) and an estimated normalized ventricular elastance at arterial end-diastole (E(Nd)): E(es(sb)) = [P(d) - (E(Nd(est)) x P(s) x 0.9)[/(E(Nd(est)) x SV). The E(Nd) was estimated from a group-averaged value adjusted for individual contractile/loading effects; E(es(sb)) estimates were compared with invasively measured values in 43 patients with varying cardiovascular disorders, with additional data recorded after inotropic stimulation (n = 18, dobutamine 5 to 10 microg/kg per min). Investigators performing noninvasive analysis were blinded to the invasive results. RESULTS: Combined baseline and dobutamine-stimulated E(es) ranged 0.4 to 8.4 mm Hg/ml and was well predicted by E(es(sb)) over the full range: E(es) = 0.86 x E(es(sb)) + 0.40 (r = 0.91, SEE = 0.64, p < 0.00001, n = 72). Absolute change in E(es(sb)) before and after dobutamine also correlated well with invasive measures: E(es(sb)): DeltaE(es) = 0.86 x DeltaE(es(sb)) + 0.67 (r = 0.88, p < 0.00001). Repeated measures of E(es(sb)) over two months in a separate group of patients (n = 7) yielded a coefficient of variation of 20.3 +/- 6%. CONCLUSIONS: The E(es) can be reliably estimated from simple noninvasive measurements. This approach should broaden the clinical applicability of this useful parameter for assessing systolic function, therapeutic response and ventricular-arterial interaction.

Enhancement of contrast echocardiography by image variability analysis.

BACKGROUND: Although there have been recent advances in echocardiography, many studies remain suboptimal due to poor image quality and unclear blood-myocardium border. We developed a novel image processing technique, cardiac variability imaging (CVI), based on the variance of pixel intensity values during passage of ultrasound microbubble contrast into the left ventricle chamber, with the aim of enhancing endocardial border delineation and image quality. METHODS AND RESULTS: CVI analysis was performed on simulated data to test and verify the mechanism of image enhancement. Then CVI analysis was applied to echocardiographic images obtained in two different clinical studies, and still images were interpreted by expert reviewers. In the first study (N = 15), using contrast agent EchoGen, the number of observable wall segments in end-diastolic images, for example, was significantly increased by CVI (4.93) as compared to precontrast (3.28) and contrast images (3.36), P < 0.001 for both comparisons to CVI. In the second study (N = 8), using contrast agent Optison, interobserver variability of manually traced end-diastolic volumes was significantly decreased using CVI (22.3 ml) as compared to precontrast (63.4) and contrast images (49.0), P < 0.01 for both comparisons to CVI. CONCLUSION: CVI can substantially enhance endocardial border delineation and improve echocardiographic image quality and image interpretation.

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.

Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block.

BACKGROUND: Left ventricular or biventricular pacing/stimulation can acutely improve systolic function in patients with dilated cardiomyopathy (DCM) and intraventricular conduction delay by resynchronizing contraction. Most heart failure therapies directly enhancing systolic function do so while concomitantly increasing myocardial oxygen consumption (MVO(2)). We hypothesized that pacing/stimulation, in contrast, incurs systolic benefits without raising energy demand. METHODS AND RESULTS: Ten DCM patients with left bundle-branch block (ejection fraction 20+/-3%, QRS duration 179+/-3 ms, mean+/-SEM) underwent cardiac catheterization to measure ventricular and aortic pressure, coronary blood flow, arterial-coronary sinus oxygen difference (DeltaAVO(2)), and MVO(2). Data were measured under sinus rhythm or with left ventricular or biventricular pacing/stimulation at the same heart rate. These results were then contrasted to intravenous dobutamine (n=7) titrated to match systolic changes during LV pacing. Systolic function rose quickly and substantially from LV pacing (18+/-4% rise in arterial pulse pressure, which correlates with cardiac output, and 43+/-6% increase in dP/dt(max); both P<0.01). However, DeltaAVO(2) and MVO(2) declined -4+/-2% and -8+/-6.5%, respectively (both P<0.05). Similar results were obtained with biventricular activation. In contrast, dobutamine raised dP/dt(max) 37+/-6%, accompanied by a 22+/-11% rise in per-beat MVO(2) (P<0.05 versus pacing). CONCLUSIONS: Ventricular resynchronization by left ventricular or biventricular pacing/stimulation in DCM patients with left bundle-branch block acutely enhances systolic function while modestly lowering energy cost. This should prove valuable for treating DCM patients with basal dyssynchrony.

Comparison of ventricular pressure relaxation assessments in human heart failure: quantitative influence on load and drug sensitivity analysis.

OBJECTIVES: We contrasted various methods for assessing ventricular pressure decay time constants to test whether sensitivity to slight data instability or disparities between model-assumed and real decay are systematically altered by cardiac failure. We hypothesized that such discrepancies could result in apparent increased relaxation sensitivity to load and drug stimulation. BACKGROUND: Deviation of relaxation behavior from model-assumed waveforms may be worsened by failure, enhancing instability and apparent load and drug sensitivity of commonly used indexes. METHODS: Pressure-volume relations were measured in patients with normal (n = 14), hypertrophic (hypertrophic cardiomyopathy [HCM], n = 15) and dilated-myopathic (dilated cardiomyopathy [DCM], n = 37) hearts before and during preload reduction or inotropic stimulation. Relaxation parameters (monoexponential [ME] model assuming zero-T(in) or non-zero-T(D), T(F) asymptote:, hybrid logistic-T(L), linear-T(LR), and pressure halftime-T(1/2)) were contrasted regarding sensitivity to slight data range manipulation and loading or drug changes. RESULTS: In DCM, T(D) and T(F) prolonged 15% to 25% (p < 0.0001) by deletion of only 1-2 data points, whereas this had minimal effect on controls or HCM. This stemmed from systematic deviation of relaxation from an ME decay in DCM. T(1/2) and T(in) were highly sensitive to pure pressure offsets, whereas T(L) was most stable to both manipulations in all hearts. As a result, T(D) and T(F) appeared to be much more sensitive to systolic load in DCM than T(1/2) or T(L) and disproportionately sensitive to increased cyclic adenosine monophosphate (cAMP). CONCLUSIONS: Relaxation consistently deviates from an ME decay in DCM resulting in instability and amplified relaxation systolic load or drug dependence of ME-based indexes in failing versus control (or HCM) hearts. The hybrid-logistic method improves quantitative analyses by providing more consistent data fits with all three heart types.

Parametric model derivation of transfer function for noninvasive estimation of aortic pressure by radial tonometry.

Aortic pressure can be estimated noninvasively by applying a transfer function (TF) to radial tonometry signals. This study compares the performance of prior approaches, based on Fourier transform and inverted aortic-to-radial model, with direct radial-to-aortic autoregressive exogenous (ARX) model. Simultaneous invasive aortic pressure and radial tonometry pressure were recorded during rest in 39 patients in the supine position. Individual radial-aortic TF's were estimated from 20 patients, and the average TF was used to predict aortic pressures in the remaining 19 patients. The direct average TF yielded accurate aortic systolic pressure estimation (error 0.4 +/- 2.9 mmHg) and good reproduction of the aortic pressure waveform (root mean squared error 2.2 +/- 0.9 mmHg). The inverted reverse TF (aortic radial) yielded comparable results, while the Fourier-based TF had worse performance. Individual direct TF provided improved predictive accuracy only for indexes which are based on higher frequency components of the waveform (augmentation index, systolic time period). An ARX average TF can be used to accurately estimate central aortic pressure waveform parameters from noninvasive radial pulse tracings, and its performance is superior to previous techniques.

Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals.

OBJECTIVES: We tested the hypothesis that acute intravenous verapamil acutely enhances aerobic exercise performance in healthy older individuals in association with a combined reduction of ventricular systolic and arterial vascular stiffnesses. BACKGROUND: Age-related vascular stiffening coupled with systolic ventricular stiffening may limit cardiovascular reserve and, thus, exercise performance in aged individuals. METHODS: Nineteen healthy volunteers with mean age 70 +/- 10 years underwent maximal-effort upright ergometry tests on two separate days after receiving either 0.15 mg/kg i.v. verapamil or 0.5 N saline in a double-blind, randomized, crossover study. RESULTS: Baseline vascular stiffness, indexed by arterial pulse-wave velocity (Doppler) and augmentation index (carotid tonometry) declined with verapamil (-5.9 +/- 2.1% and -31.7 +/- 12.8%, respectively, both p < 0.05). Preload-adjusted maximal ventricular power, a surrogate for ventricular end-systolic stiffness, also declined by -9.5 +/- 3.6%. Peripheral resistance and peak filling rate were unchanged. With verapamil, exercise duration prior to the anaerobic threshold (AT) increased by nearly 50% (260 +/- 129 to 387 +/- 176 s) with a corresponding 13.4 +/- 4.7% rise in oxygen consumption (VO2) at that time (both p < 0.01). Total exercise duration prolonged by +6 +/- 2.7% (p < 0.05) with no change in maximal VO2. Baseline cardiodepression from verapamil reversed by peak exercise with net increases in stroke volume and cardiac output (p < 0.05). CONCLUSIONS: Acute intravenous verapamil reduces ventriculovascular stiffening and improves aerobic exercise performance in healthy aged individuals. This highlights a role for heart-arterial coupling in modulating exertional capacity in the elderly, suggesting a potentially therapeutic target for aged individuals with exertional limitations.

Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay.

BACKGROUND: Ventricular pacing can improve hemodynamics in heart failure patients, but direct effects on left ventricular (LV) function from varying pacing site and atrioventricular (AV) delay remain unknown. We hypothesized that the magnitude and location of basal intraventricular conduction delay critically influences pacing responses and that single-site pacing in the delay-activated region yields similar or better responses to biventricular pacing. METHODS AND RESULTS: Aortic and LV pressures were measured in 18 heart failure patients (mean+/-SD: LV ejection fraction, 19+/-7%; LV end-diastolic pressure, 25+/-8 mm Hg; QRS duration, 157+/-36 ms). Data under normal sinus rhythm were compared with ventricular pacing (VDD) at varying sites and AV delays (randomized order). Right ventricular (RV) apical or midseptal pacing had negligible contractile/systolic effects. However, LV free-wall pacing raised dP/dtmax by 23.7+/-19.0% and pulse-pressure by 18.0+/-18.4% (P<0.01). Biventricular pacing yielded less change (+12.8+/-9.3% in dP/dtmax, P<0.05 versus LV). Pressure-volume analysis performed in 11 patients consistently revealed minimal changes with RV pacing but increased stroke work and lower end-systolic volumes with LV pacing. Optimal AV intervals averaged 125+/-49 ms, and within this range, AV delay had less influence on LV function than pacing site. Basal QRS duration positively correlated with %DeltadP/dtmax (P<0.005), but pacing efficacy was not associated with QRS narrowing. Conduction delay pattern generally predicted pacing sites with most effect. CONCLUSIONS: VDD pacing acutely enhances contractile function in heart failure patients with intraventricular conduction delay. Single-site pacing at the site of greatest delay achieves similar or greater benefits to biventricular pacing in such patients. These data clarify pacing-effect mechanisms and should help in candidate identification for future studies.

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.

Optimal preload adjustment of maximal ventricular power index varies with cardiac chamber size.

BACKGROUND: Maximal left ventricular power (PWRmax) can index contractile function and reserve; however, its marked preload dependence mandates load adjustment to yield a more cardiac-specific measurement. Prior studies have used varying methods, but supporting data have generally been lacking. We hypothesized that the optimal approach for preload adjustment varies with ventricular volume (particularly end-systolic volume) and is significantly different for dilated hearts with reduced left ventricular function compared with small to normal-sized hearts with normal systolic function. METHODS: Left ventricular pressure-volume relations were measured by the conductance catheter method in 36 patients, with preload altered by inferior vena cava obstruction. Patients with normal ventricles (n = 16), hypertrophy or mitral stenosis (n = 12), and dilated cardiomyopathy (n = 8) were divided into three groups based on resting end-diastolic volume: group 1, 66.3 +/- 12; group 2, 118.1 +/- 20; and group 3, 218.2 +/- 48 ml. PWRmax was the maximal product of simultaneous left ventricular pressure and rate of volume change. PWRmax end-diastolic volume (EDV) data were fit to a power function, PWRmax = alphaEDVbeta (where alpha is a scaling factor and beta is the power coefficient), and the preload sensitivity of beta and PWRmax/EDVbeta ratios (beta = 1, 2, or best fit) were compared. RESULTS: Beta varied directly with chamber size: 0 = 0.004 x (EDV + 0.56), r = 0.65, p < 0.0001. However, it was equally well approximated by 1.0 in groups 1 and 2 (ESV <75 ml, EF >40%), whereas beta = 2 was more appropriate in group 3. CONCLUSION: PWRmax/EDV provides adequate preload independence in all but dilated hearts with reduced LV function, whereas PWRmax/EDV2 is required in the latter. These data should help clinical application of a noninvasive PWRmax index for assessing chamber contractility and contractile reserve in human beings.

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.