Tomoki Kameyama

Importance of abnormal lung perfusion in excessive exercise ventilation in chronic heart failure

Abstract Whether excessive ventilatory response to exercise is related to the maldistribution of pulmonary blood flow was examined in 23 patients with chronic heart failure and nine age-matched normal subjects. With the use of technetium 99m macroaggregated albumin, the resting distribution of pulmonary blood flow was assessed by the scintigraphic counts ratio of upper to lower lung fields. The ventilatory response to exercise was assessed by the slope of the relationship between minute ventilation and carbon dioxide production during exercise. Eight patients (group A) had slope less than 33, the upper limit of the normal range, and 15 patients had slope of 33 or greater (group B). In group B pulmonary blood flow was distributed more to the upper lung, which made the counts ratio (60%) higher than in normal subjects (34%) or in patients in group A (38%). There was no significant difference in pulmonary flow distribution between normal subjects and patients in group A. In group B tidal volume did not increase during exercise as much as it did in normal subjects and in patients in group A; therefore, the respiratory pattern was rapid and shallow. Although the ratio of physiologic dead space to tidal volume fell by 20% during exercise in normal subjects and by 23% in patients in group A, it failed to decrease in patients in group B (−1%), which indicates a relative increase in dead space respiration during exercise. These data indicate that decreased lung compliance and regional ventilation-perfusion mismatch caused by pulmonary vascular and parenchymal abnormalities would play an important role in the excessive exercise ventilation in chronic heart failure.

Ventricular load optimization by unloading therapy in patients with heart failure

The effects of unloading a depressed heart were assessed in terms of optimal coupling between the ventricle and arterial system. To assess the effects of preload on ventricular load coupling, preload was reduced with a lower body negative pressure of -20 mm Hg. Nitroprusside was used to evaluate the effects of afterload on the coupling under the condition that preload reduction was comparable to that with lower body negative pressure. In 13 patients with heart failure (ejection fraction 32 +/- 3%, mean +/- SE), direct arterial pressure was simultaneously recorded with the left ventricular echocardiogram as the pressure was elevated by phenylephrine. Left ventricular contractile properties were defined by the slope (Ees) of the end-systolic pressure-volume relation. The effective arterial elastance (Ea) was expressed by the slope of the end-systolic pressure-stroke volume relation. Left ventricular external work, end-systolic potential energy and work efficiency, defined as external work per pressure volume area (external work + potential energy), were determined. Baseline ventricular load coupling in these patients was characterized by an increase in the ratio of arterial elastance to ventricular elastance (Ea/Ees) (1.96 +/- 0.31). This ratio decreased significantly, to 1.45 +/- 0.22, with nitroprusside, and increased to 2.37 +/- 0.34 with lower body negative pressure. Therefore, end-systolic potential energy was decreased by nitroprusside but was unaltered by lower body negative pressure while external work was comparably decreased by both manipulations, indicating that work efficiency was significantly augmented with nitroprusside but declined with lower body negative pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Energy conversion efficiency in human left ventricle.

BackgroundLeft ventricular mechanical efficiency is one of the most important measures of left ventricular pump performance. Several clinical studies, however, have shown that mechanical efficiency does not fall substantially as the heart fails. To clarify the insensitivity of mechanical efficiency to the change in pump performance, we analyzed human left ventricular mechanical efficiency, applying the concept of left ventricular systolic pressure-volume area (PVA). Methods and ResultsPVA correlates linearly with myocardial oxygen consumption per beat (MVo2): MVo2 = a· PVA+b, and represents the total mechanical energy of contraction. We determined MVo2-PVA relation and external work in 11 patients with different contractile states. We also calculated the energy transfer from MVo2 to PVA (PVA/MVo2 efficiency), that from PVA to external work (work efficiency), and mechanical efficiency (external work/MVo2). Left ventricular pressure-volume loops were constructed by plotting the instantaneous left ventricular pressure against the left ventricular volume at baseline and during pressure loading. The contractile properties of the ventricle were defined by the slope of the end-systolic pressure-volume relation (Ees). Pressure elevation raised external work by 41.4%, PVA by 71.2%, and MVo2 by 54.5%. These changes were associated with a decrease in work efficiency and an increase in PVA/MVo2 efficiency. The opposite directional changes in these two efficiencies rendered the mechanical efficiency constant. The slope, a, of the relation between MVo2 and PVA was relatively constant (2.46±0.33) over the range of 0.8–8.8 mm Hg/ml of Ees, but the oxygen axis intercept, b, tended to decrease with the reduction in Ees. PVA/MVo2 efficiency correlated inversely (r = −0.66, p <0.05) with Ees, whereas work efficiency correlated linearly with Ees (r = 0.91, p<0.01). ConclusionsMechanical efficiency is not appreciably affected by changes in loading and inotropic conditions as long as the left ventricular contractility is not severely depressed.

Loading Sequence Plays an Important Role in Enhanced Load Sensitivity of Left Ventricular Relaxation in Conscious Dogs With Tachycardia-Induced Cardiomyopathy

BACKGROUND Left ventricular relaxation rate in the failing heart depends more on the systolic load than in the normal heart. To elucidate the mechanisms for the enhanced load sensitivity of left ventricular relaxation in heart failure, we examined the relative contributions of changes in end-systolic volume and loading sequence to the left ventricular relaxation rate. METHODS AND RESULTS In seven conscious dogs, the time constant (Td) of left ventricular pressure decay, end-systolic volume, systolic circumferential force, and time to peak force during caval occlusion were compared before and after development of tachycardia-induced heart failure. Rapid ventricular pacing decreased the slope of the end-systolic pressure-volume relation from 4.5 to 2.8 mm Hg/mL (P < .01) and prolonged Td from 33 to 49 ms (P < .01). In normal conditions, caval occlusion reduced end-systolic force (-580 g, P < .01) and end-systolic volume (-7 mL, P < .01) but did not change Td or time to peak force. In heart failure, however, caval occlusion shortened Td (-11 ms, P < .01), with a concomitant decrease in the time to peak force (-30 ms, P < .01), while end-systolic volume and force declined slightly. Consequently, for a comparable reduction in end-systolic force, Td decreased more in heart failure than in normal hearts, suggesting enhanced load sensitivity. Moreover, changes in Td correlated well with those in the time to peak force (r = .79, P < .01) but not with those in end-systolic volume. CONCLUSIONS Loading sequence rather than elastic recoil seems to play the predominant role in the enhanced load sensitivity of left ventricular relaxation in heart failure.

Disparate inotropic and lusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure.

Left ventricular (LV) inotropic and lusitropic responses to a calcium sensitizer, pimobendan, were compared between normal and failing hearts. Heart failure was induced by rapid ventricular pacing in 6 dogs instrumented with a micromanometer and a conductance catheter. The effects of pimobendan were evaluated in the conscious state before and after development of heart failure. Pimobendan dose-dependently increased the slope of the end-systolic pressure-volume (P-V) relation (Ees) in both normal and failing hearts, whereas its magnitude was markedly attenuated in failing hearts. Heart rate (HR) was increased by pimobendan in normal heart but did not change in failing heart. LV relaxation, assessed by peak - dP/dt and the time constant of isovolumic pressure decay (Td), was substantially improved to the same extent in failing and normal hearts. Consequently, Ees and Td exhibited a hyperbolic relation over a wide range of contractility states. In normal heart, pimobendan caused a leftward shift of the diastolic P-V relation while maintaining a similar curve. In failing heart, however, this relation shifted directly downward with a concomitant increase in end-diastolic volume, indicating a reduction in the constraints on LV distention and a resultant increase in preload reserve. Thus, pimobendan accelerated LV isovolumic relaxation and improved distensibility in conscious dogs with tachycardia-induced heart failure despite the marked attenuation of inotropic responses.

Mechanoenergetic studies in isolated mouse hearts.

We tested the feasibility of an isolated, balloon-in-ventricle, isovolumically contracting, crystalloid-perfused mouse heart preparation ( n = 10) for studies of cardiac mechanoenergetics using the end-systolic pressure-volume relation (ESPVR) and myocardial oxygen consumption (V˙o 2)-pressure-volume area (PVA) framework employed in larger species. The intraventricular balloon method was shown to be accurate for measurement of left ventricular volume, especially at relatively higher volumes. The ESPVR demonstrated contractility-dependent curvilinearity. Average slope of the ESPVR was 1,299 ± 369 (SD) mmHg ⋅ g ⋅ ml-1, with a volume intercept of 0.018 ± 0.006 ml. TheV˙o 2-PVA relation was well fitted by a straight line, with average slope andV˙o 2 intercept of 3.57 ± 1.31 × 10-5 ml O2 ⋅ mmHg-1 ⋅ ml-1and 0.92 ± 0.21 × 10-3 ml O2 ⋅ beat-1 ⋅ g-1, respectively. Decreasing perfusate Ca2+ concentration resulted in a decrease in the slope of the ESPVR, a decrease in theV˙o 2 intercept of theV˙o 2-PVA relation, but no significant change in its slope. Hearts from hypothyroid ( n = 8) mice demonstrated similar mechanoenergetic changes. We conclude that delineation of the ESPVR and the V˙o 2-PVA relation is feasible in the mouse heart. Our method should allow an assessment of cardiac mechanoenergetics as sophisticated as that previously possible only in larger hearts.

Time-varying spectral analysis of heart rate and left ventricular pressure variability during balloon coronary occlusion in humans: A sympathoexcitatory response to myocardial ischemia

OBJECTIVES We assessed time-varying spectral components of heart rate and left ventricular (LV) pressure variability during coronary angioplasty to elucidate dynamic autonomic responses to transient myocardial ischemia. BACKGROUND Sympathoexcitatory reflexes elicited by acute coronary occlusion are rarely addressed in the clinical settings because of a lack of technique to monitor transient changes in sympathetic activation. METHODS RR interval and LV pressure and volume were serially recorded in 14 patients with effort angina during balloon coronary angioplasty. Wavelet analysis was applied for determination of nonstationary spectral components of RR interval and LV peak pressure variability. RESULTS The wavelet analysis revealed that coronary occlusion provoked low-frequency (LF) fluctuations of RR interval (seven patients) and LV peak pressure (six patients) at 0.06 +/- 0.01 Hz, but not in the remaining patients. Following the balloon inflation, the LF component of RR interval began to increase after the onset of myocardial ischemia, peaked at about 80 s, and then declined in the late phase of inflation. Consequently, the ratio of low to high frequency component rose to be significantly greater in the LF augmentation group than in the no LF augmentation group in the middle phase of coronary occlusion. The patients with no LF augmentation had little evidence of myocardial ischemia as reflected by changes in ST segment and LV systolic function during coronary occlusion. CONCLUSIONS The wavelet analysis of RR interval and LV pressure variability clearly showed a dynamic profile of spectral components in response to transient coronary artery occlusion. The resultant regional myocardial ischemia elicited a profound sympathoexcitatory response followed by a gradual suppression. This method provides a useful tool to gain a new insight into the nonstationary autonomic influence on the cardiovascular system.

Energetically optimal left ventricular pressure for the failing human heart

BACKGROUND An energy-starved failing heart would benefit from more effective transfer of the mechanical energy of ventricular contraction to blood propulsion. However, the energetically optimal loading conditions for the failing heart are difficult to establish. In the present study, we analyzed the optimal left ventricular pressure to achieve maximal mechanical efficiency of the failing heart in humans. METHODS AND RESULTS We determined the relation between left ventricular pressure-volume area and myocardial oxygen consumption per beat (VO2), stoke work, and mechanical efficiency (stroke work/VO2) in 13 patients with different contractile states. We also calculated the optimal end-systolic pressure that would theoretically maximize mechanical efficiency for a given end-diastolic volume and contractility. Left ventricular pressure-volume loops were constructed by plotting the instantaneous left ventricular pressure against the left ventricular volume at baseline and during pressure loading. The contractile properties of the ventricle were defined by the slope of the end-systolic pressure-volume relation. In patients with less compromised ventricular function, the operating end-systolic pressure was close to the optimal pressure, achieving nearly maximal mechanical efficiency. As the heart deteriorated, however, the optimal end-systolic pressure became significantly lower than normal, whereas the actual pressure remained within the normal range. This discrepancy resulted in worsening of ventriculoarterial coupling and decreased mechanical efficiency compared with theoretically maximal efficiency. CONCLUSIONS Homeostatic mechanisms to maintain arterial blood pressure within the normal range cause the failing heart to deviate from energetically optimal conditions.

Ventriculoarterial coupling during exercise in normal human subjects.

To examine the relative roles of ventricular contractility and loading conditions for cardiovascular adjustment during exercise, 10 normal human subjects were studied using a framework of ventriculoarterial coupling. Anaerobic threshold was evaluated to determine the work rates of aerobic and anaerobic exercise. Ventricular contractile properties were quantified by the slope of the end-systolic pressure-volume relationship (ventricular elastance) and arterial system properties were expressed by the end-systolic pressure-stroke volume relationship (arterial elastance). During aerobic exercise, left ventricular end-diastolic volume and stroke volume were increased by 14 and 33%, with plasma norepinephrine levels being doubled. Arterial elastance was reduced by 30%, but ventricular elastance did not change significantly. During anaerobic exercise, ventricular end-diastolic volume returned to the resting value, while stroke volume remained increased by 31%. In contrast to aerobic exercise, ventricular elastance rose substantially by 89% in association with about a 10 times increase in plasma norepinephrine. Arterial elastance remained the same as in aerobic exercise. Thus, the increase in stroke volume was primarily mediated by changes in loading conditions during aerobic exercise and by enhanced contractility during anaerobic exercise.

Acute hemodynamic effects of a new inotropic agent (OPC-8212) in patients with congestive heart failure

The acute effects of OPC-8212, a newly synthesized orally effective inotropic agent, were assessed clinically. Eleven patients with moderate congestive heart failure received a single mean dose of 6.5 mg/kg body weight of the drug. Eight hours after administration, the cardiac and stroke work indexes increased by 11% (p less than 0.01) and 20% (p less than 0.005), respectively, with concomitant decreases in the diastolic pulmonary artery (25%, p less than 0.005) and right atrial pressures (33%, p less than 0.01). There were no significant changes in blood pressure or heart rate. The contractile state of the left ventricle was also assessed by the shift of the Starling curve. To construct the function curve, lower body negative pressure was used to regulate the venous return to the heart. An inotropic effect of the agent was confirmed by the shift of this function curve upward and to the left, even when an augmentation of the cardiac output was masked by the marked reduction in preload. The hemodynamic and clinical effects of OPC-8212 were encouraging and the drug appears to be promising for the treatment of congestive heart failure.