Peter H. Pak

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.

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.

Validation of Carotid Artery Tonometry as a Means of Estimating Augmentation Index of Ascending Aortic Pressure

Our objective was to validate a carotid artery tonometry-derived augmentation index as a means to estimate augmentation index (AI) of ascending aortic pressure under various physiological conditions. A total of 66 patients (50 men, 16 women; mean age, 55 years; range, 21 to 78 years; 44 in Taiwan and 22 in the United States) undergoing diagnostic catheterization were studied. Arterial pressure contours were obtained simultaneously from the right common carotid artery by applanation tonometry with an external micromanometer-tipped probe and from the ascending aorta by a micromanometer-tipped catheter at baseline (n = 62), after handgrip (n = 36), or after sublingual nitroglycerin administration (n = 17). The AI (expressed as percentage values) was calculated as the ratio of amplitude of the pressure wave above its systolic shoulder to the total pulse pressure. The carotid AI was consistently lower than the aortic AI, but the two were highly correlated at baseline and after both handgrip and nitroglycerin. Mean +/- SD and correlation coefficients were baseline (14 +/- 16, 28(+) +/- 17, .77), handgrip (18 +/- 19, 32(+) +/- 15, .86), and nitroglycerin (7 +/- 12, 18(+) +/- 13, .52). In addition, after adjusting for age, sex, height, blood pressure, heart rate, and study site, the changes of both AIs from baseline values with handgrip or nitroglycerin were highly associated such that the aortic AI could be approximated from the carotid AI with appropriate regression equations. The high correlations and predictable changes after interventions between the central AI and those estimated from noninvasive carotid tonometry suggest that this technique may have wide applicability for many cardiovascular studies.

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.

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.

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.

Contribution of External Forces to Left Ventricular Diastolic Pressure: Implications for the Clinical Use of the Starling Law

The Starling law of the heart states that the more the left ventricle fills with blood, the more volume it ejects. This dependence of cardiac output on filling volume was first recognized nearly a century ago [1] and remains at the core of the clinical evaluation and treatment of cardiac disorders. To apply this concept to the individual patient, the clinician must assess left ventricular filling, which is most often estimated using the pressure within the ventricle or the pulmonary capillary wedge pressure. However, these pressures do not solely reflect the blood volume within the left ventricle but are also influenced by extraventricular forces arising from the filling of the right heart and the constraining effects of the pericardium [2-8]. Altering these external forces can change left ventricular diastolic pressures, even when left-heart filling volume and, thus, cardiac output are unchanged [9-12]. Previous clinical and animal studies have established that altering extraventricular forces can change left ventricular diastolic pressures [9-12]. However, the quantitative importance of external contributions to the resting ventricular diastolic pressure remains controversial. In normal hearts, extraventricular forces are thought to have a small effect [13]; in chronically dilated hearts, the influence of these forces is thought to be reduced by simultaneous pericardial enlargement [14, 15]. Previous clinical studies probing external forces have been limited by the use of pharmacologic manipulations to alter these forces: These manipulations typically also lower left-heart volumes and arterial pressures, thereby complicating any interpretation of results [8-12, 16]. An alternative is to use mechanical interventions that suddenly lower external forces before they change left ventricular filling. For example, Slinker and colleagues [17] inhibited filling of the right heart within a single beat to evaluate ventricular interaction in normal animals. This is not feasible in humans, but an alternative method that can achieve similar effects is rapid obstruction of inferior vena caval inflow using a balloon catheter [18-20]. In the first few beats after balloon inflation, right atrial pressures often decrease almost to zero, although blood inflow to the left heart does not immediately diminish. This results in a sudden decrease in left ventricular diastolic pressures with minimal change in filling volumes [20]. As obstruction of venous inflow is sustained, filling of the left ventricle eventually decreases. The initial decrease in diastolic pressure, however, principally reflects the withdrawal of extraventricular forces. We used this maneuver to test the hypothesis that a considerable proportion of resting diastolic filling pressure stems from factors extrinsic to the left heart. We also tested whether this proportion would be diminished by chronic cardiac disease that would be expected to dilate the pericardium. Our results show that 30% to 40% of measured diastolic pressures result from forces external to the left ventricle and that this percentage is only slightly changed by cardiac disease. Methods Patients We studied 29 patients. Twelve had normal ventricular function confirmed by echocardiography, ventriculography, or both; an ejection fraction of at least 60%; and end-diastolic pressure of 20 mm Hg or less. All patients had been referred for diagnostic cardiac catheterization to evaluate atypical chest pain. Six patients had chronic idiopathic dilated cardiomyopathy with exertional dyspnea; ejection fraction of 40% or less; chamber dilation (short-axis diastolic dimension 6 cm); and a normal coronary angiogram. Five patients presented with dyspnea, pulmonary congestion, or both but had histories of hypertension and ventricular hypertrophy. Lastly, six patients had high-grade proximal coronary stenoses and recent histories of unstable or accelerated angina pectoris. No patients had had a myocardial infarction. The studies were done at the Johns Hopkins Medical Institutions, Baltimore, Maryland (n = 19); Veterans General Hospital, Taipei, Taiwan (n = 5); and the Instituto di Coracao, Sao Paolo, Brazil (n = 5). All patients provided informed consent, and the study protocol was approved by the human investigation committee of each institution. Procedure The method used to measure left ventricular pressure and volume with an intracardiac conductance catheter has been previously reported [18-20]. Each patient first had standard right- and left-heart catheterization. A multielectrode conductance (volume) catheter was then advanced to the left ventricular apex. A low-amplitude, high-frequency current was applied to electrodes located at the left ventricular base and apex, and resistances were measured at multiple intervening electrodes. This yielded a time-varying signal proportional to intracavitary chamber volume. A micromanometer (PC-330A, Millar, Inc., Houston, Texas) placed within the lumen of the catheter provided a simultaneous high-fidelity measurement of ventricular pressure. A custom-designed, large-balloon occlusion catheter (SP-09168, Cordis, Miami, Florida) was placed in the right atrium. Balloon inflation using 10 to 20 mL carbon dioxide and withdrawal of the catheter toward the proximal inferior vena cava produced rapid reversible decrease of cardiac filling. Pressure-volume data were measured continuously at steady state and immediately after the onset and continuation of inferior vena caval balloon occlusion. Occlusion was sustained for 10 to 15 seconds and then released. The conductance catheter volume signal was calibrated to the contrast left ventriculogram (single plane, right anterior oblique projection) by matching end-diastolic and end-systolic volumes. Ventriculogram volumes were estimated from the frames of maximal and minimal area, respectively. The corresponding catheter signal volumes were obtained as the averaged volumes during phases of isovolumetric contraction and relaxation. Data Analysis Left ventricular pressure-volume data from five consecutive end-expiratory cardiac cycles were averaged to yield a single pressure-volume loop (plot of instantaneous left ventricular volume on x-axis compared with simultaneous left ventricular pressure on y-axis). From these data, the stable resting diastolic pressure-volume curve [20], end-diastolic and end-systolic volumes, stroke volume and cardiac output, and ejection fraction were measured [19, 20]. The isovolumetric relaxation time constant, which indexes the rate of ventricular pressure decay, was also derived from these data [21]. Figure 1 shows an example of the left ventricular pressure-volume data used to assess the relative contributions of the intrinsic (due to properties of the left ventricle itself) and extrinsic components of resting left ventricular diastolic pressure. Figure 1A shows resting pressure-volume loops. During each cardiac cycle, data moved counterclockwise around the loop. Shortly after the obstruction of inferior vena caval inflow, left ventricular diastolic pressures decreased with little change in chamber volumes (Figure 1B). This downward shift of the diastolic pressure-volume relation primarily reflects the sudden decrease in external forces mediated by the extent of right ventricular filling. Continued obstruction of inferior vena caval inflow eventually decreased left ventricular volumes, shifting the pressure-volume loops leftward beat by beat (Figure 1C) and reducing systolic pressures and stroke volume (height and width of loops). This response is the manifestation of the Starling law. Note that after the initial near-parallel decrease of the left ventricular diastolic pressure-volume relation, the remaining diastolic data of subsequent beats occurred along a more or less single curve (Figure 1C). This relation was called the diastolic pressure-volume relation and reflects the intrinsic diastolic properties of the left ventricle. Figure 1. Measurement of the contribution of external forces to resting left ventricular diastolic pressures. The initial downward shift of diastolic pressure-volume data was taken as a measure of the contribution of external forces to resting diastolic pressure (Figure 1D). This downward shift was measured as the difference in pressure between initial resting beats and the diastolic pressure-volume relation at a common volume just before atrial contraction. At this point, relaxation of the left ventricle was more than 99% complete as judged by the isovolumetric relaxation time constant, and rapid filling and atrial contraction had minimal influence on diastolic pressures. Statistical Analysis Data are presented as means SD. Hemodynamic comparisons between patients with diseased and normal hearts were done using a multiple-comparisons analysis of variance. Data obtained before and after occlusion of the inferior vena cava were compared using a paired Student t-test. Results Clinical and Hemodynamic Characteristics of Patients Table 1 shows the clinical and major hemodynamic characteristics of the four groups of patients. Mean age was similar among all groups. Left ventricular end-diastolic pressure was significantly higher in each of the groups with disease than in the controls and averaged almost 20 mm Hg. Only patients with dilated cardiomyopathy had increased chamber volumes and decreased ejection fractions. Cardiac output and heart rate were reduced in the group with ischemia, probably because of concomitant -blocker therapy. Table 1. Clinical and Major Hemodynamic Characteristics of Study Patients* Contribution of External Forces to Resting Left Ventricular Diastolic Pressure Figure 2 shows the relation between left ventricular diastolic pressure obtained under resting conditions (LVPd) and the component of this pressure that is caused by forces external to the left ventricle (Delta Pd). Data from all groups of patients are combined into a single plot; each group is identified

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%...

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.

Endomyocardial gene expression during development of pacing tachycardia-induced heart failure in the dog.

Selective and specific changes in gene expression characterize the end-stage failing heart. However, the pattern and relation of these changes to evolving systolic and diastolic dysfunction during development of heart failure remains undefined. In the present study, we assessed steady-state levels of mRNAs encoding a group of cardiac proteins during the early development of left ventricular dysfunction in dogs with pacing-induced cardiomyopathy. Corresponding hemodynamic assessments were made in the conscious state in the same animals and at the same time points at baseline, after 1 week of ventricular pacing, and at the onset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was undetectable in 7 of 12 hearts at baseline but was expressed in all hearts at 1 week (P < .01 by chi 2 test), and it increased markedly with progression to failure (P = .05). Creatine kinase-B mRNA also rose markedly with heart failure (P < .01). Levels of mRNA encoding beta-myosin heavy chain, mitochondrial creatine kinase, phospholamban, and sarcoplasmic reticulum Ca(2+)-ATPase did not significantly change from baseline, despite development of heart failure. Additional analysis to determine if these mRNA changes were related to the severity of diastolic or systolic dysfunction revealed that phospholamban mRNA decreased in hearts with larger net increases in end-diastolic pressure (+19.2 +/- 1.9 mm Hg) compared with those hearts in which it did not change (+4.0 +/- 4.9, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)