Cardiac sympathetic nerve activity trends after renal denervation in heart failure with preserved ejection fraction.

This case report describes the application of ultrasound renal denervation (uRDN) using the Paradise System in a patient with heart failure with preserved ejection fraction. Initially, the cardiac sympathetic nerve activity of the patient exhibited a late heart/mediastinum (H/M) ratio of 2.00 and a washout rate of 66.0% by cardiac iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy. Subsequently, the patient underwent transfemoral uRDN targeting the left, right upper, and right lower renal arteries. At the 6 month follow-up, no significant change was observed in 123I-MIBG findings; however, the estimated stressed blood volume (eSBV) decreased from 1722 to 1029 mL/70 kg. At 18 months, 123I-MIBG findings improved, with the late H/M ratio reaching 2.76 and the washout rate decreasing to 43.1%. This case report highlights the potential of uRDN in reducing eSBV within 6 months and subsequently improving cardiac sympathetic nerve activity at the 18 month follow-up.

Heterogeneous reduction in regional wall stress after aortic valve replacement for aortic regurgitation: a distinct feature from aortic stenosis.

Geometric changes caused by volume reduction early after aortic valve replacement (AVR) for aortic regurgitation (AR) may not be uniform, resulting in varying regional end-systolic wall stress (ESS). This study compared changes in regional ESS between AR and aortic stenosis (AS) patients in the early phase following AVR. Computer-tomographic left ventricular (LV) angiography was performed for 10 patients with AR and 13 with AS before and three months after AVR. Regional ESS at the base, middle, and apex levels, each subdivided into four segments, was calculated based on the Janz equation: ESS = end-systolic LV pressure × local cross-sectional area of LV cavity/that of LV wall. Following AVR, median LV end-diastolic volume index fell from 106 to 69 ml/m2 (P = 0.001) in AR and 60 to 46 ml/m2 (P = 0.01) in AS patients. Global ESS also declined in both (AR, 186 to 124 kdyne/cm2, P = 0.02; AS, 187 to 108 kdyne/cm2, P < 0.001, respectively). Regional ESS was reduced in all segments in AS patients, accompanied by left ventricular ejection fraction (LVEF) improvement (71-80%, P = 0.02). In contrast, regional ESS in AR patients was heterogeneously reduced, as regional ESS fell significantly in the antero-septal wall but was unchanged in the infero-lateral wall, and LVEF remained unchanged (65 to 62%, P = 0.42). In the early postoperative phase after AVR, the loading condition of the regional LV wall in AR patients was characterized by a heterogeneous reduction in regional ESS in contrast to a uniform decline in AS patients.

Early Detection of Worsening Heart Failure in Patients at Home Using a New Telemonitoring System of Respiratory Stability.

BACKGROUND: Early detection of worsening heart failure (HF) with a telemonitoring system crucially depends on monitoring parameters. The present study aimed to examine whether a serial follow up of all-night respiratory stability time (RST) built into a telemonitoring system could faithfully reflect ongoing deterioration in HF patients at home and detect early signs of worsening HF in a multicenter, prospective study.Methods and Results: Seventeen subjects with New York Heart Association class II or III were followed up for a mean of 9 months using a newly developed telemonitoring system equipped with non-attached sensor technologies and automatic RST analysis. Signals from the home sensor were transferred to a cloud server, where all-night RSTs were calculated every morning and traced by the monitoring center. During the follow up, 9 episodes of admission due to worsening HF and 1 episode of sudden death were preceded by progressive declines of RST. The receiver operating characteristic curve demonstrated that the progressive or sustained reduction of RST below 20 s during 28 days before hospital admission achieved the highest sensitivity of 90.0% and specificity of 81.7% to subsequent hospitalization, with an area under the curve of 0.85. CONCLUSIONS: RST could serve as a sensitive and specific indicator of worsening HF and allow the detection of an early sign of clinical deterioration in the telemedical management of HF.

The Impact of Deep Y Descent on Hemodynamics in Patients With Heart Failure and Preserved Left Ventricular Systolic Function.

Background: Influence of right ventricular diastolic function on the hemodynamics of heart failure (HF). We aimed to clarify the hemodynamic features of deep Y descent in the right atrial pressure waveform in patients with HF and preserved left ventricular systolic function. Methods: In total, 114 consecutive inpatients with HF who had preserved left ventricular systolic function (left ventricular ejection fraction ≥ 50%) and right heart catheterization were retrospectively enrolled in this study. The patients were divided into two groups according to right atrial pressure waveform, and those with Y descent deeper than X descent in the right atrial pressure waveform were assigned to the deep Y descent group. We enrolled another seven patients (two men, five women; mean age, 87 ± 6) with HF and preserved ejection fraction, and implanted a pacemaker to validate the results of this study. Results: The patients with deep Y descent had a higher rate of atrial fibrillation, higher right atrial pressure and mean pulmonary arterial pressure, and lower stroke volume and cardiac index than those with normal Y descent (76 vs. 7% p < 0.001, median 8 vs. 5 mmHg p = 0.001, median 24 vs. 21 mmHg p = 0.036, median 33 vs. 43 ml/m2 p < 0.001, median 2.2 vs. 2.7 L/m2, p < 0.001). Multiple linear regression revealed a negative correlation between stroke volume index and pulmonary vascular resistance index (wood unit*m2) only in the patients with deep Y descent (estimated regression coefficient: -1.281, p = 0.022). A positive correlation was also observed between cardiac index and heart rate in this group (r = 0.321, p = 0.038). In the other seven patients, increasing the heart rate (from median 60 to 80/min, p = 0.001) significantly reduced the level of BNP (from median 419 to 335 pg/ml, p = 0.005). Conclusions: The hemodynamics of patients with HF with deep Y descent and preserved left ventricular systolic function resembled right ventricular restrictive physiology. Optimizing the heart rate may improve hemodynamics in these patients.

Naive Bayes Prediction of the Development of Cardiac Events in Heart Failure With Preserved Ejection Fraction in an Outpatient Clinic　- Beyond B-Type Natriuretic Peptide.

BACKGROUND: The heterogeneity of B-type natriuretic peptide (BNP) levels among individuals with heart failure and preserved ejection fraction (HFpEF) makes predicting the development of cardiac events difficult. This study aimed at creating high-performance Naive Bayes (NB) classifiers, beyond BNP, to predict the development of cardiac events over a 3-year period in individual outpatients with HFpEF.Methods and Results:We retrospectively enrolled 234 outpatients with HFpEF who were followed up for 3 years. Parameters with a coefficient of association ≥0.1 for cardiac events were applied as features of classifiers. We used the step forward method to find a high-performance model with the maximum area under the receiver operating characteristics curve (AUC). A 10-fold cross-validation method was used to validate the generalization performance of the classifiers. The mean kappa statistics, AUC, sensitivity, specificity, and accuracy were evaluated and compared between classifiers learning multiple factors and only the BNP. Kappa statistics, AUC, and sensitivity were significantly higher for NB classifiers learning 13 features than for those learning only BNP (0.69±0.14 vs. 0.54±0.12 P=0.024, 0.94±0.03 vs. 0.84±0.05 P<0.001, 85±8% vs. 64±20% P=0.006, respectively). The specificity and accuracy were similar. CONCLUSIONS: We created high-performance NB classifiers for predicting the development of cardiac events in individual outpatients with HFpEF. Our NB classifiers may be useful for providing precision medicine for these patients.

Four-quadrant visualization of systemic circulatory equilibrium: right ventricular failure after left ventricular assist device implantation.

Right ventricular failure (RVF) is a serious adverse event after left ventricular assist device (LVAD) implantation but difficult to be characterized. This study aimed to visualize the dynamic circulatory equilibrium of acute RVF after LVAD implantation using a new four-quadrant diagram constructed by 1) cardiac function with central venous pressure (CVP) and cardiac index (CI) axes, 2) arterial vascular resistance with CI and mean blood pressure (mBP) axes, 3) pressure-diuretic function with mBP and net urinary sodium output (net U-Na) axes, and 4) venous compliance with net U-Na and CVP axes. Twenty LVAD patients were stratified into two groups, group S (≤10 days) and group L (>10 days), according to duration of postoperative inotropic support. The preoperative equilibrium loops were small in both groups. In the early postoperative phase, the loop in group S became dramatically enlarged to the left and upward, indicating increased CVP and CI by LVAD support. In group L, however, augmentation of CI was smaller despite similarly increased CVP, and net U-Na was decreased despite increased mBP. In the late postoperative phase, the equilibrium loop in group L recovered as similar to that seen in group S. Thus, acute RVF, as shown in group L, was characterized by the shape of the loop constructed by marked increased CVP, a relatively small increase in CI, and concomitant impairment of pressure natriuresis. In conclusion, the novel four-quadrant presentation of systemic circulatory equilibrium provides clear visualization of RVF after LVAD implantation, thus serving as a useful guide for prompt and optimal management.NEW & NOTEWORTHY Systemic circulatory dynamics are regulated by various negative feedback systems, including cardiac, arterial, venous, and renal functions, as well as autonomic nervous systems. The present novel four-quadrant presentation of their functions allows clear visualization of dynamic organ-to-organ interactions that can lead to a new circulatory equilibrium after therapeutic intervention. This new system physiological framework can serve as a useful guide for prompt and optimal management of circulatory malfunction.

Prediction of aortic valve regurgitation after continuous-flow left ventricular assist device implantation using artificial intelligence trained on acoustic spectra.

Significant aortic regurgitation (AR) is a common complication after continuous-flow left ventricular assist device (LVAD) implantation. Using machine-learning algorithms, this study was designed to examine valuable predictors obtained from LVAD sound and to provide models for identifying AR. During a 2-year follow-up period of 13 patients with Jarvik2000 LVAD, sound signals were serially obtained from the chest wall above the LVAD using an electronic stethoscope for 1 min at 40,000 Hz, and echocardiography was simultaneously performed to confirm the presence of AR. Among the 245 echocardiographic and acoustic data collected, we found 26 episodes of significant AR, which we categorized as "present"; the other 219 episodes were characterized as "none". Wavelet (time-frequency) analysis was applied to the LVAD sound and 19 feature vectors of instantaneous spectral components were extracted. Important variables for predicting AR were searched using an iterative forward selection method. Seventy-five percent of 245 episodes were randomly assigned as training data and the remaining as test data. Supervised machine learning for predicting concomitant AR involved an ensemble classifier and tenfold stratified cross-validation. Of the 19 features, the most useful variables for predicting concomitant AR were the amplitude of the first harmonic, LVAD rotational speed during intermittent low speed (ILS), and the variation in the amplitude during normal rotation and ILS. The predictive accuracy and area under the curve were 91% and 0.73, respectively. Machine learning, trained on the time-frequency acoustic spectra, provides a novel modality for detecting concomitant AR during follow-up after LVAD.

Effect of a reduced donor heart right ventricular distensibility on post-heart transplant haemodynamics.

OBJECTIVES: This study aimed to investigate the characteristics of a reduced right ventricular distensibility after heart transplant. METHODS: This study enrolled 64 adult patients who underwent heart transplant at our institution. The degree of right ventricular distensibility was quantified by calculating the difference between right atrial pressures (RAPs) of X descent and Y descent (X-Y) from the RAP waveform in right heart catheterization. Histologically, the ratio of the interstitial tissue in myocardial biopsy samples was calculated. RESULTS: Of the 64 patients, 35 (55%) had a reduced right ventricular distensibility at 1 week after heart transplant (X-Y > 1 mmHg, RD group), and 29 (45%) had a normal right ventricular distensibility (X-Y ≤ 1 mmHg, ND group). The mean RAP and mean pulmonary capillary wedge pressure 1 week after heart transplant in the RD group were significantly higher than that in the ND group. The mean RAP and mean pulmonary capillary wedge pressure in the RD group gradually normalized 12 weeks postoperation. The ratio of the interstitial tissue of biopsy samples significantly correlated with the X-Y value. The number of patients who required inotropic support >14 days was higher in the RD group than in the ND group. CONCLUSIONS: Reduced donor heart distensibility was a common impairment early after heart transplant. It might result from interstitial oedema in the myocardial tissue of the donor heart. Reduced donor heart distensibility after heart transplant might be associated with early clinical outcomes; however, further investigation is required.

Different Pathophysiology and Outcomes of Heart Failure With Preserved Ejection Fraction Stratified by K-Means Clustering.

Background: Stratified medicine may enable the development of effective treatments for particular groups of patients with heart failure with preserved ejection fraction (HFpEF); however, the heterogeneity of this syndrome makes it difficult to group patients together by common disease features. The aim of the present study was to find new subgroups of HFpEF using machine learning. Methods: K-means clustering was used to stratify patients with HFpEF. We retrospectively enrolled 350 outpatients with HFpEF. Their clinical characteristics, blood sample test results and hemodynamic parameters assessed by echocardiography, electrocardiography and jugular venous pulse, and clinical outcomes were applied to k-means clustering. The optimal k was detected using Hartigan's rule. Results: HFpEF was stratified into four groups. The characteristic feature in group 1 was left ventricular relaxation abnormality. Compared with group 1, patients in groups 2, 3, and 4 had a high mean mitral E/e' ratio. The estimated glomerular filtration rate was lower in group 2 than in group 3 (median 51 ml/min/1.73 m2 vs. 63 ml/min/1.73 m2 p < 0.05). The prevalence of less-distensible right ventricle and atrial fibrillation was higher, and the deceleration time of mitral inflow was shorter in group 3 than in group 2 (93 vs. 22% p < 0.05, 95 vs. 1% p < 0.05, and median 167 vs. 223 ms p < 0.05, respectively). Group 4 was characterized by older age (median 85 years) and had a high systolic pulmonary arterial pressure (median 37 mmHg), less-distensible right ventricle (89%) and renal dysfunction (median 54 ml/min/1.73 m2). Compared with group 1, group 4 exhibited the highest risk of the cardiac events (hazard ratio [HR]: 19; 95% confidence interval [CI] 8.9-41); group 2 and 3 demonstrated similar rates of cardiac events (group 2 HR: 5.1; 95% CI 2.2-12; group 3 HR: 3.7; 95%CI, 1.3-10). The event-free rates were the lowest in group 4 (p for trend < 0.001). Conclusions: K-means clustering divided HFpEF into 4 groups. Older patients with HFpEF may suffer from complication of RV afterload mismatch and renal dysfunction. Our study may be useful for stratified medicine for HFpEF.

The impact of right ventricular dysfunction on the effectiveness of beta-blockers in heart failure with preserved ejection fraction.

BACKGROUND: Whether beta-blockers improve the clinical outcomes for heart failure with preserved ejection fraction (HFpEF) characterized by variable cardiac pathophysiology remains controversial. This study aimed to clarify cardiac dysfunction affecting the effectiveness of beta-blockers in patients with HFpEF. METHODS: Four hundred and nine patients with HFpEF were enrolled retrospectively, and echocardiography and jugular venous pulse were examined to evaluate their cardiac function. The left ventricular (LV) ejection fraction, mean mitral e', mean mitral E/e' ratio, right ventricular (RV) systolic pressure, tricuspid annular plane systolic excursion, and jugular venous pulse waveform were used as indicators of LV contractility, LV relaxation ability, LV filling pressure, RV afterload, RV contractility, and RV diastolic function, respectively. The dominant 'Y' descent of the jugular venous waveform was detected as an established hemodynamic sign of a less-distensible right ventricle. RESULTS: Two hundred and thirteen patients with HFpEF received beta-blockers. During a mean follow-up period of 33±20 months, 92 patients had cardiovascular events of HFpEF. A less-distensible right ventricle and RV systolic pressure were independent risk factors for cardiovascular events of HFpEF (p=0.016 and p=0.002, respectively). The administration of beta-blockers was not an independent factor, but patients with HFpEF and a distensible right ventricle who received them had fewer events than those who did not (p=0.017). Patients with HFpEF and lower RV systolic pressure (<33mmHg) who received beta-blockers also had fewer events than those who did not (p=0.028). A less-distensible right ventricle or higher RV systolic pressure (≥33mmHg) prevented the beneficial effects of beta-blockers for HFpEF. CONCLUSIONS: Beta-blocker usage was not associated with a reduction in the rate of cardiovascular events of HFpEF, but it may have beneficial effects on HFpEF with preserved RV function. RV function may serve as an indicator to administer beta-blockers to patients with HFpEF.

Right Atrial Pressure Waveform Predicts Right Ventricular Failure After Left Ventricular Assist Device Implantation.

BACKGROUND: Right ventricular failure (RVF) is one of the major adverse events after left ventricular assist device (LVAD) implantation. Right ventricle (RV) distensibility plays a key role in the preload reserve capability and in RV ejection through the Frank-Starling mechanism. However, there are no studies focusing on the relationship between RVF and RV distensibility. METHODS: Between 2013 and 2017, 115 consecutive patients underwent continuous-flow LVAD implantation at Osaka University Hospital. Of these, 71 who recorded preoperative right atrial pressure waveform were included. We assessed RV distensibility and the incidence and risk factors for RVF, which was defined as the requirement for a right ventricular assist device or 14 or more consecutive days of inotropic support required postoperatively, or both. A distensible RV was interpreted if the right atrial pressure waveform showed a dominant "Y" descent that was equal to or deeper than the "X" descent. RESULTS: Thirty-two patients (45%) had RVF after LVAD implantation. Among the patients with RVF, 4 required right ventricular assist device support and all of them had a less distensible RV. Multivariate analysis revealed that a less distensible RV (odds ratio 10.5, 95% confidence interval, 1.75 to 63.5, P = .003) and an elevated level of central venous pressure/pulmonary capillary wedge pressure (odds ratio 2.02, 95% confidence interval, 1.20 to 3.40, P = .002) were independent risk factors for RVF after LVAD implantation. CONCLUSIONS: Less distensible RV and elevated central venous pressure/pulmonary capillary wedge pressure level were significant risks for RVF after LVAD implantation. This result suggested that analysis of not only the hemodynamic numbers but also the pattern of waveforms are important to assess risk for RVF in LVAD candidates.

Prominent 'Y' descent is an ominous sign of a poorer prognosis in heart failure with preserved ejection fraction.

AIMS: The heterogeneity of heart failure with preserved ejection fraction (HFpEF) represents different pathophysiological paths by which individual patients develop heart failure. The deterioration mechanisms are considered to be mainly left ventricular diastolic dysfunction, right ventricular (RV) systolic function, and RV afterload. It is unclear whether RV distensibility affects the deterioration of HFpEF. Our study aimed to clarify whether impaired RV distensibility is associated with the deterioration of HFpEF. METHODS AND RESULTS: We retrospectively enrolled 322 patients with HFpEF and examined their echocardiography results, electrocardiograms, phonocardiograms, and jugular venous pulse waves. Using signal-processing techniques, the prominent 'Y' descent of the jugular venous waveform was detected as an established haemodynamic sign of a less-distensible right ventricle. We defined cardiovascular events of HFpEF as follows: sudden death, death from heart failure, or hospitalization for HFpEF. During a mean follow-up period of 33 ± 20 months, 73 patients had cardiovascular events of HFpEF. The prevalence of a less-distensible right ventricle and the variables of RV systolic pressure were independent risk factors for cardiovascular events (hazard ratio, 2.046, P = 0.005, and hazard ratio, 1.032 per 1 mmHg, P = 0.002, respectively). The event-free rate of HFpEF was the lowest for HFpEF with a less-distensible right ventricle and elevated RV systolic pressure (≥35 mmHg) (P for trend <0.001). CONCLUSIONS: A less-distensible right ventricle and elevated RV systolic pressure were found to be closely associated with the deterioration of HFpEF. Assessment of a less-distensible right ventricle may help to stratify patients and improve therapeutic strategies for HFpEF.

Blood Oxygen, Sleep Disordered Breathing, and Respiratory Instability in Patients With Chronic Heart Failure　- PROST Subanalysis.

Background: Respiratory stability index (RSI), a semi-quantitative measure of respiratory instability, was found to reflect congestive and other clinical status of acutely decompensated heart failure in the PROST study. Given that the association between RSI and another important factors affecting respiration, such as peripheral oxygen saturation (SpO2), and the influence of oxygen inhalation on this association were undetermined, and that the association between common sleep-disordered breathing (SDB) parameters and RSI was unknown, we performed a subanalysis using PROST data. Methods and Results: Correlation analyses were performed to evaluate the relationships between RSI, SpO2, and other SDB parameters (3% oxygen desaturation index [3%ODI], respiratory disturbance index [RDI]) using Spearman's rank correlation. RSI and overnight mean SpO2 were not significantly correlated either after admission (n=38) or before discharge (n=36; r=0.27, P=0.10 and r=0.05, P=0.76, respectively). This correlation was also not affected by presence or absence of oxygen inhalation. 3%ODI, RDI and RSI were significantly and inversely correlated both after admission and before discharge. Conclusions: RSI and blood oxygen level were not significantly correlated irrespective of oxygen inhalation, while the SDB parameters were significantly correlated, suggesting that RSI reflects lung congestion independently of blood oxygen concentration and, thus, can be a useful indicator of the non-invasive assessment of lung congestion.

Multicenter, Prospective Study on Respiratory Stability During Recovery From Deterioration of Chronic Heart Failure.

BACKGROUND: The respiratory instability frequently observed in advanced heart failure (HF) is likely to mirror the clinical status of worsening HF. The present multicenter study was conducted to examine whether the noble respiratory stability index (RSI), a quantitative measure of respiratory instability, reflects the recovery process from HF decompensation. Methods and Results: Thirty-six of 44 patients hospitalized for worsening HF completed all-night measurements of RSI both at deterioration and recovery phases. Based on the signs, symptoms, and laboratory data during hospitalization, the Central Adjudication Committee identified 22 convalescent patients and 14 patients with less extent of recovery in a blinded manner without any information on RSI or other respiratory variables. The all-night RSI in the convalescent patients was increased from 27.8±18.4 to 34.6±15.8 (P<0.05). There was no significant improvement of RSI, however, in the remaining patients with little clinical improvement. Of the clinical and laboratory variables, on stepwise linear regression modeling, body weight, peripheral edema, and lung congestion were closely related to the RSI of recovered patients and accounted for 56% of the changes in RSI (coefficient of determination, R2=0.56). CONCLUSIONS: All-night RSI, a quantitative measure of respiratory instability, could faithfully reflect congestive signs and clinical status of HF during the recovery process from acute decompensation.

Independent prognostic importance of respiratory instability and sympathetic nerve activity in patients with chronic heart failure.

BACKGROUND: Respiratory instability in chronic heart failure (CHF) is characterized by irregularly rapid respiration or non-periodic breathing rather than by Cheyne-Stokes respiration. We developed a new quantitative measure of respiratory instability (RSI) and examined its independent prognostic impact upon CHF. METHODS: In 87 patients with stable CHF, respiratory flow and muscle sympathetic nerve activity (MSNA) were simultaneously recorded. RSI was calculated from the frequency distribution of respiratory spectral components and very low frequency components. RESULTS: During a mean follow-up of 85±38 months, 24 patients died. Sixteen patients who died of cardiac causes had a lower RSI (16±6 vs. 30±21, p<0.01), a lower specific activity scale (4.3±1.4 Mets vs. 5.7±1.4 Mets, p<0.005), a higher MSNA burst area (16±5% vs. 11±4%, p<0.001), and a higher brain natriuretic peptide (BNP) level (514±559pg/ml vs. 234±311pg/ml, p<0.05) than 71 patients who did not die of cardiac causes. Multivariate analysis revealed that RSI (p=0.015), followed by MSNA burst area (p=0.033), was an independent predictor of subsequent all-cause deaths and that RSI (p=0.026), MSNA burst area (p=0.001), and BNP (p=0.048) were independent predictors of cardiac deaths. Patients at very high risk of fatal outcome could be identified by an RSI<20. CONCLUSIONS: The daytime respiratory instability quantified by a new measure of RSI has prognostic importance independent of sympathetic nerve activation in patients with clinically stable CHF. An RSI of <20 identifies patients at very high risk for subsequent all-cause and cardiovascular death.

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.

Effects of tolvaptan on volume overload in Japanese patients with heart failure: results of a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

PURPOSE: Tolvaptan may reduce the signs of volume overload in heart failure (HF) patients who experience volume overload despite using conventional diuretics. In this study, we evaluated the dose-response effects of tolvaptan on weight loss, urine volume and electrolyte excretion in furosemide-treated Japanese HF patients exhibiting volume overload. METHODS: In the study, 117 HF patients with volume overload on stable doses of furosemide (≥ 40 mg/day) were treated with tolvaptan (15, 30 or 45 mg) or placebo once-daily for 7 days. RESULTS: The decrease in body weight from baseline to the day after the final dose with 15, 30 or 45 mg tolvaptan (-1.62 ± 1.55, -1.35 ± 1.54 and -1.85 ± 1.10 kg, respectively), was significantly greater compared with that in the placebo group (-0.53 ± 0.96 kg) (p < 0.05). However, the decrease in body weight with tolvaptan was not significantly dose-dependent. Signs of volume overload improved at all doses of tolvaptan. Tolvaptan elicited a dose-dependent increase in urine volume and a decrease in urine osmolality, but did not affect urinary sodium or potassium excretion. Adverse reactions associated with diuresis were most frequently observed at the higher doses of tolvaptan. CONCLUSIONS: Once-daily tolvaptan (15, 30 or 45 mg) was effective and tolerable as an add-on treatment to furosemide therapy in Japanese HF patients with volume overload.

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.

Circadian changes in autonomic function in conscious rats with heart failure: effects of amiodarone on sympathetic surge.

Cardiovascular events are characterized by circadian periodicity with a peak prevalence during the awakening period, which suggests a morning surge in sympathetic activity. We developed an experimental system to determine circadian changes in heart rate (HR), blood pressure (BP), locomotor activity (Loc), respiratory rate and autonomic function in conscious, unrestrained rats. The effects of amiodarone on circadian variation of these variables were determined in rats with myocardial infarction and subsequent congestive heart failure (CHF). We continuously recorded BP, HR and Loc for 24h in rats with CHF (n=16) or after a sham operation (Sham; n=7). To determine circadian changes in sympathovagal balance, digitized BP and HR data throughout 24h were analyzed based on maximum entropy. The study was repeated after 3 weeks of oral amiodarone (50mg/kg/day) or saline administration. Baseline HR, mean BP, and Loc were higher in the dark period than in the light period (all p<0.05) in both CHF and Sham rats, which is consistent with the circadian periodicity of nocturnal animals. Low-frequency components of diastolic BP variability (LFdp), an index of sympathetic tone, were significantly higher during the awakening period (16:00-20:00) than during the sleeping period (08:00-14:00), a finding analogous to the sympathetic morning surge in men. Amiodarone suppressed this transient increase in LFdp power during the awakening period. Our experimental system could detect sympathetic surge in conscious rats. Amiodarone suppressed the sympathetic surge, which could explain, at least in part, beneficial effects of amiodarone in patients with CHF.

Development of a ubiquitous healthcare monitoring system combined with non-conscious and ambulatory physiological measurements and its application to medical care.

The demand for ubiquitous healthcare monitoring has been increasingly raised for prevention of lifestyle-related diseases, acute life support or chronic therapies for inpatients and/or outpatients having chronic disorder and home medical care. From these view points, we developed a non-conscious healthcare monitoring system without any attachment of biological sensors and operations of devices, and an ambulatory postural changes and activities monitoring system. Furthermore in this study, in order to investigate those applicability to the ubiquitous healthcare monitoring, we have developed a new healthcare monitoring system combined with the non-conscious and the ambulatory measurements developed by us. In patients with chronic cardiovascular disease or stroke, the daily health conditions such as pulse, respiration, activities and so on, could be continuously measured in the hospital, the rehabilitation room and subject's own home, using the present system. The results demonstrated that the system appears useful for the ubiquitous healthcare monitoring not only at medical facility, but also during daily living at home.