Shuji Joho

α1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

An alpha1-adrenergic receptor (alpha1-AR) antagonist increased heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to alpha1-AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main alpha1-AR subtypes in the heart, alpha 1A (Adra1a) and alpha 1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and beta-AR stimulation, and beta-ARs were desensitized. Thus, alpha1-AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that alpha1-signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of alpha1-antagonists in clinical trials are due to loss of alpha1-signaling in myocytes, emphasizing concern about clinical use of alpha1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.

Short term effect of adaptive servo-ventilation on muscle sympathetic nerve activity in patients with heart failure.

Chronic heart failure (HF) is characterized by sympathetic overactivation and periodic breathing. We examined whether adaptive servo-ventilation (ASV) exerts a sympathoinhibitory effect in patients with HF via normalizing respiratory pattern. Muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, respiratory pattern and oxygen saturation were examined in 29 HF patients without obstructive sleep apnea (age, 61±15years; ejection fraction, 0.32±0.09; obstructive apnea index, <5/h) before (10 min), during (30 min) and after (10 min) the application of ASV. Periodic breathing was defined as a repeated oscillation of tidal volume with regularly recurring hyperpnea and hypopnea with a variation in tidal volume of greater than 25%. The severity of respiratory instability was determined using the coefficient of variation of tidal volume (CV-TV). Of 29 patients with HF, 11 had periodic breathing and 18 did not. There was a modest positive correlation between MSNA and CV-TV (n=29, p<0.05). ASV reduced respiratory rate, CV-TV and MSNA only in the group with periodic breathing (p<0.01). Change in MSNA significantly correlated with changes in respiratory rate, CV-TV and presence of periodic breathing. However, multivariate analyses revealed that respiratory rate and CV-TV were independent predictors of change in MSNA. ASV reduces MSNA by slowing respiratory rates and stabilizing respiratory patterns in patients with HF.

Impact of sleeping position on central sleep apnea/Cheyne-Stokes respiration in patients with heart failure.

BACKGROUND The present study determines the influence of sleeping position on central sleep apnea (CSA) in patients with heart failure (HF). METHODS The apnea/hypopnea index (AHI) during different body positions while asleep was examined by cardiorespiratory polygraphy in 71 patients with HF (ejection fraction <45%). RESULTS Twenty-five of the patients having predominantly CSA (central apnea index 10/h) with a lower obstructive apnea index (<5/h) were assigned to groups with positional (lateral to supine ratio of AHI <50%, n=12) or non-positional (ratio > or = 50%, n=13) CSA. In the non-positional group the BNP level was higher, the ejection fraction was lower and the trans-tricuspid pressure gradient was higher than in the positional group. Multiple regression analysis revealed more advanced age (p=0.006), log(10)BNP (p=0.017) and lung-to-finger circulation time (p=0.020) as independent factors of the degree of positional CSA. Intensive treatment for HF changed CSA from non-positional to positional in all eight patients tested. Single night of positional therapy reduced CSA (p<0.05) and BNP level (p=0.07) in seven positional patients. CONCLUSION As cardiac dysfunction progresses, severity of CSA also increases and positional CSA becomes position-independent. Positional therapy could decrease CSA, thereby having a valuable effect on HF.

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.

Altered inotropic and lusitropic responses to heart rate in conscious dogs with tachycardia-induced heart failure

OBJECTIVES The effects of increasing heart rate on left ventricular contraction and relaxation were examined in conscious dogs with tachycardia-induced heart failure under autonomically blocked conditions. BACKGROUND Previous studies using isolated myocardium have shown attenuated positive inotropic responses to stimulation frequency in heart failure. However, these responses have not been well examined in intact preparations in the presence of heart failure with autonomic system blockade, where the intrinsic ventricular responses to increasing heart rate could be revealed. METHODS Seven dogs were instrumented with a micromanometer and a conductance volume catheter. After autonomic blockade to eliminate neural reflexes, left ventricular contractile properties were quantified by the slope of the end-systolic pressure-volume relation (ventricular elastance), and left ventricular relaxation was assessed by the time constant of isovolumetric ventricular pressure decay. RESULTS Increasing the heart rate by 60 beats/min enhanced ventricular elastance by 71 +/- 18% (mean +/- SD) and decreased end-systolic volume by 6 +/- 5% in normal hearts. In failing hearts, ventricular elastance increased by only 21 +/- 20%, and end-systolic volume did not change appreciably. Although the reduction in left ventricular end-diastolic and minimal pressures by tachycardia was smaller in the failing heart, ventricular relaxation rate remained unaltered both in the normal heart and in the failing heart. CONCLUSIONS Under conscious but autonomically blocked conditions, effects of increasing heart rate on the failing left ventricle are characterized by a predominant attenuation of the inotropic response rather than of the lusitropic response.

Modulation of left ventricular diastolic distensibility by collateral flow recruitment during balloon coronary occlusion

OBJECTIVES The goals of this study were to elucidate the scaffolding effect of blood-filled coronary vasculature and to determine the functional role of recruited collateral flow in modulating left ventricular (LV) distensibility during balloon coronary occlusion (BCO). BACKGROUND Although LV distensibility is an important factor affecting acute dilation after myocardial infarction, the response of LV diastolic pressure-volume (P-V) relations to coronary occlusion is inconsistent in humans. METHODS Micromanometer and conductance derived LV P-V loops were serially obtained from 16 patients undergoing percutaneous transluminal coronary angioplasty. Coronary collateral flow recruitment was angiographically evaluated by contralateral and ipsilateral contrast injection during BCO. RESULTS In the group with poor collateral flow (grades 0-I; n = 8), BCO resulted in a downward and rightward shift of the diastolic P-V relations, where end-diastolic volume (EDV) increased by 13% (p < 0.05) without appreciable change in end-diastolic pressure (EDP; 18 +/- 6 to 18 +/- 8 mm Hg). In contrast, BCO in the group with good collateral flow (grades II-III; n = 8) shifted the diastolic P-V relations upward to the right with a concomitant increase in minimal pressure (min-P; 6 +/- 4 to 10 +/- 5 mm Hg, p < 0.05), EDP (15 +/- 7 to 21 +/- 9 mm Hg, p < 0.05) and EDV (+/- 10%, p < 0.05). Reactive hyperemia after balloon deflation caused a rapid and parallel upward shift of the diastolic P-V relations with a marked increase in min-P and EDP, especially in the group with poor collateral flow, before any improvement in LV contraction or relaxation abnormalities. CONCLUSIONS Grades of coronary filling, either retrograde or anterograde, abruptly modulate LV distensibility through the rapid scaffolding effect of coronary vascular turgor.

Slow and deep respiration suppresses steady-state sympathetic nerve activity in patients with chronic heart failure: from modeling to clinical application

Influences of slow and deep respiration on steady-state sympathetic nerve activity remain controversial in humans and could vary depending on disease conditions and basal sympathetic nerve activity. To elucidate the respiratory modulation of steady-state sympathetic nerve activity, we modeled the dynamic nature of the relationship between lung inflation and muscle sympathetic nerve activity (MSNA) in 11 heart failure patients with exaggerated sympathetic outflow at rest. An autoregressive exogenous input model was utilized to simulate entire responses of MSNA to variable respiratory patterns. In another 18 patients, we determined the influence of increasing tidal volume and slowing respiratory frequency on MSNA; 10 patients underwent a 15-min device-guided slow respiration and the remaining 8 had no respiratory modification. The model predicted that a 1-liter, step increase of lung volume decreased MSNA dynamically; its nadir (-33 ± 22%) occurred at 2.4 s; and steady-state decrease (-15 ± 5%), at 6 s. Actually, in patients with the device-guided slow and deep respiration, respiratory frequency effectively fell from 16.4 ± 3.9 to 6.7 ± 2.8/min (P < 0.0001) with a concomitant increase in tidal volume from 499 ± 206 to 1,177 ± 497 ml (P < 0.001). Consequently, steady-state MSNA was decreased by 31% (P < 0.005). In patients without respiratory modulation, there were no significant changes in respiratory frequency, tidal volume, and steady-state MSNA. Thus slow and deep respiration suppresses steady-state sympathetic nerve activity in patients with high levels of resting sympathetic tone as in heart failure.

Cardiac sympathetic denervationmodulates the sympathoexcitatoryresponse to acute myocardial ischemia

Abstract Objectives This study was designed to elucidate the influence of cardiac sympathetic denervation on the sympathoexcitatory response to acute myocardial ischemia during balloon coronary occlusion (BCO) in humans. Background Alterations of cardiac sympathetic nerve function could modulate sympathetic reflexes originating from the ischemic area. Methods In 23 patients with angina pectoris, we quantified the baseline cardiac sympathetic denervation of the ischemia-related area by iodine-123 metaiodobenzylguanidine (123I-MIBG), and transient changes in sympathetic activity during BCO by wavelet analysis of RR interval variability. Results Balloon coronary occlusion resulted in a transient augmentation of low-frequency (LF: 0.04 to 0.14 Hz) spectral components of RR interval variability in 4 of 12 patients with cardiac denervation and in 8 of 11 patients without denervation (p Conclusions These findings suggest that if the provoked ischemia is not severe, cardiac sympathetic denervation could prevent ischemia-induced sympathoexcitation.

Renal insufficiency coexisting with heart failure is related to elevated sympathetic nerve activity

We investigated whether coexisting renal insufficiency (RI) is associated with elevated sympathetic activity in patients with heart failure (HF). Resting muscle sympathetic nerve activity (MSNA) was determined in 101 patients with HF (ejection fraction<0.45) and 8 patients with RI but without HF (RI group). Diagnosis of RI was made of glomerular filtration rates <60ml/min/1.73m(2) estimated using the simplified Modification of Diet in Renal Disease equation. Of 101 patients, 45 had RI (HFRI group) and 56 did not (HF group). HFRI group was older (p<0.05) and given loop diuretics more frequently (p<0.05), and had a lower specific activity scale (p<0.05) than HF group. HFRI group exhibited significantly greater MSNA indices than either HF group or RI group (burst rate, p<0.05; burst incidence, p<0.01). Univariate analysis showed that RI, age, specific activity scale level and dose of furosemide were significant predictors of increased burst incidence of MSNA in patients with HF. Notably, multivariate analysis revealed that RI was the only independent factor for increased MSNA indices. These findings suggest that coexisting RI is associated with elevated sympathetic activity in patients with HF.

A health-related quality of life questionnaire in symptomatic patients with heart failure : Validity and reliability of a Japanese version of the MRF28

BACKGROUND Major characteristics of symptomatic patients with heart failure are exercise intolerance, poor prognosis, and poor quality of life (QOL). However, most QOL questionnaires are applicable for patients with mild to moderate heart failure, and are not sufficiently sensitive to discriminate between patients with NYHA classes III and IV. Therefore, it is necessary to prepare a questionnaire focused on patients with severe heart failure. OBJECTIVES We developed a Japanese version of the Maugeri Foundation Respiratory Failure (MRF28) questionnaire and assessed validity and reliability of MRF28 in heart failure patients. METHODS The MRF28 questionnaire was evaluated in 124 patients with heart failure (NYHA classes: I, 24; II, 31; III, 52; IV, 17). Reliability was evaluated by internal consistency and test-retest reliability. Validity was determined by correlation with World Health Organization Quality of Life (WHOQOL) questionnaire and physiological parameters. RESULTS The MRF28 showed high internal consistency and reproducibility. The total score and subscores were all increased with the progress of heart failure. The total score could differentiate patients among NYHA II, III, and IV, but could not between NYHA I and II. However, all subscores and total score changed consistently with changes in symptoms of heart failure. CONCLUSION MRF28 is a valid and reliable disease-specific questionnaire for assessing QOL in symptomatic patients with heart failure. Thus, this questionnaire may be useful for a QOL evaluation of patients with moderate to severe heart failure.