Substrate stiffness induces nuclear localization of myosin regulatory light chain to suppress apoptosis.

Stiffness of the extracellular matrix regulates various biological responses, but the response mechanisms are poorly understood. Here, we found that the nuclear diphosphorylated myosin regulatory light chain (2P-MRLC) is a critical mechanomediator that suppresses apoptosis in response to substrate stiffness. Stiff substrates promoted the nuclear localization of 2P-MRLC. Zipper-interacting protein kinase [ZIPK; also known as death-associated protein kinase 3 (DAPK3)], a kinase for MRLC, was localized in the nucleus in response to stiff substrates and promoted the nuclear localization of 2P-MRLC. Moreover, actin fiber formation induced by substrate stiffness promoted the nuclear localization of 2P-MRLC via ZIPK. 2P-MRLC in response to substrate stiffness suppressed the expression of MAF bZIP transcription factor B (MafB) and repressed apoptosis. These findings reveal a newly identified role of MRLC in mechanotransduction.

Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents. METHODS: This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents. RESULTS: Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup. CONCLUSION: The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015.

Rationale and design of the EMPYREAN study.

AIMS: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. METHODS AND RESULTS: This ongoing study is a prospective, randomized, open-label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low-frequency (0.04-0.15 Hz)/high-frequency (0.15-0.4 Hz) ratio from baseline to 24 weeks. CONCLUSIONS: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

Total management of chronic obstructive pulmonary disease (COPD) as an independent risk factor for cardiovascular disease.

Patients with cardiovascular disease (CVD) often have multiple comorbid conditions that may interact with each other, confound the choice of treatments, and reduce mortality. Chronic obstructive pulmonary disease (COPD) is one of the most important comorbidities of CVD, which causes serious consequences in patients with ischemic heart disease, stroke, arrhythmia, and heart failure. COPD shares common risk factors such as tobacco smoking and aging with CVD, is associated with less physical activity, and produces systemic inflammation and oxidative stress. Overall, patients with COPD have a 2-3-fold increased risk of CVD as compared to age-matched controls when adjusted for tobacco smoking. Chronic heart failure (HF) is a frequent and important comorbidity which has a significant impact on prognosis in COPD, and vice versa. HF overlaps in symptoms and signs and has a common comorbidity with COPD, so that diagnosis of COPD is difficult in patients with HF. The combination of HF and COPD presents many therapeutic challenges including beta-blockers (BBs) and beta-agonists. Inhaled long-acting bronchodilators including beta2-agonists and anticholinergics for COPD would not worsen HF. Diuretics are relatively safe, and angiotensin-converting enzyme inhibitors are preferred to treat HF accompanied with COPD. BBs are only relatively contraindicated in asthma, but not in COPD. Low doses of cardioselective BBs should be aggressively initiated in clinically stable patients with HF accompanied with COPD combined with close monitoring for signs of airway obstruction and gradually up-titrated to the maximum tolerated dose. Encouraging appropriate and aggressive treatment for both HF and COPD should be recommended to improve quality of life and mortality in HF patients with COPD.

The relationship between the COPD Assessment Test score and airflow limitation in Japan in patients aged over 40 years with a smoking history.

BACKGROUND: A large number of chronic obstructive pulmonary disease (COPD) patients in Japan remain undiagnosed, primarily due to the underuse of spirometry. Two studies were conducted to see whether the COPD Assessment Test (CAT) in primary care has the potential to identify those patients who need spirometry for a diagnosis of COPD and to determine whether patients with cardiovascular disease had airflow limitation, which could be detected by CAT. MATERIALS AND METHODS: Two multicenter, noninterventional, prospective studies (studies 1 and 2) were conducted across Japan. Patients in both studies were ≥40 years old with a smoking history. Those in study 1 were seen in primary care and had experienced repeated respiratory tract infections, but had no diagnosis of COPD. Patients in study 2 were identified in cardiovascular disease clinics when routinely visiting for their cardiovascular disease. All patients completed the CAT prior to lung-function testing by hand-held spirometry. The presence of airflow limitation was defined as a forced expiratory volume in 1 second (FEV1)/FEV6 ratio<0.73. RESULTS: A total of 3,062 subjects completed the CAT (2,067 in study 1, 995 in study 2); 88.8% were male, and the mean age (±standard deviation) was 61.5±11.6 years. Airflow limitation was found in 400 (19.4%) patients in study 1, and 269 (27.0%) in study 2. The CAT score in patients with airflow limitation was significantly higher than in patients without airflow limitation in both studies: 8.6 (95% confidence interval [CI] 7.9-9.2) versus 7.4 (95% CI 7.1-7.6) in study 1, and 8.3 (95% CI 7.5-9.2) versus 6.4 (95% CI 6.0-6.8) in study 2 (both P<0.001). CONCLUSION: These findings suggest that the CAT has the potential to identify patients with cardiovascular disease or a history of frequent chest infections who need spirometry to diagnose COPD.

Prognostic value of serum parathyroid hormone level in acute decompensated heart failure.

BACKGROUND: Secondary hyperparathyroidism develops as a compensatory response to chronic heart failure (HF) and renal failure. The role of parathyroid hormone (PTH) level in acute decompensated HF remains unclear. The aim of this study was therefore to investigate the relationships among mortality, renal function, and serum PTH level in acute decompensated HF patients. METHODS AND RESULTS: A total of 266 consecutive patients admitted for acute decompensated HF without acute coronary syndrome (78±12 years; 48% male) were enrolled. Demographic, clinical, and laboratory characteristics were obtained on admission.During 1-year follow-up, 65 patients (24%) died. Serum PTH level on admission was within the normal range (10-65 pg/ml) in 108 patients (41%), of whom 39 (15%) had low-normal PTH (10-40 pg/ml). On Kaplan-Meier analysis all-cause mortality was significantly higher in patients with low-normal PTH than in those with high-normal (40-65 pg/ml) or high (>65 pg/ml) PTH (log-rank test). On univariate and multivariate Cox regression analysis, low-normal PTH was significantly associated with increased all-cause mortality (unadjusted HR, 2.88; 95% CI: 1.69-4.91; P<0.001; adjusted HR, 3.84; 95% CI: 1.54-9.57; P=0.004). CONCLUSIONS: In patients with acute decompensated HF resulting in hospitalization, low-normal PTH on admission is associated with increased all-cause mortality, regardless of renal function.

Prevalence of airflow limitation in outpatients with cardiovascular diseases in Japan.

BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) commonly coexist and share common risk factors. The prevalence of COPD in outpatients with a smoking history and CVD in Japan is unknown. The aim of this study was to determine the proportion of Japanese patients with a smoking history being treated for CVD who have concurrent airflow limitation compatible with COPD. A secondary objective was to test whether the usage of lung function tests performed in the clinic influenced the diagnosis rate of COPD in the patients identified with airflow limitation. METHODS: In a multicenter observational prospective study conducted at 17 centers across Japan, the prevalence of airflow limitation compatible with COPD (defined as forced expiratory volume (FEV)1/FEV6 <0.73, by handheld spirometry) was investigated in cardiac outpatients ≥40 years old with a smoking history who routinely visited the clinic for their CVD. Each patient completed the COPD Assessment Test prior to spirometry testing. RESULTS: Data were available for 995 patients with a mean age of 66.6±10.0 years, of whom 95.5% were male. The prevalence of airflow limitation compatible with COPD was 27.0% (n=269), and 87.7% of those patients (n=236) did not have a prior diagnosis of COPD. The prevalence of previously diagnosed airflow limitation was higher in sites with higher usage of lung function testing (14.0%, 15.2% respectively) compared against sites where it is performed seldom (11.1%), but was still low. CONCLUSION: The prevalence of airflow limitation in this study indicates that a quarter of outpatients with CVD have COPD, almost all of whom are undiagnosed. This suggests that it is important to look routinely for COPD in CVD outpatients.

Detection of coronary artery disease using coronary flow velocity reserve by transthoracic Doppler echocardiography versus multidetector computed tomography coronary angiography: influence of calcium score.

BACKGROUND: There have been no clinical data specifying the degree of calcium deposition at which coronary flow velocity reserve (CFVR) measurement using transthoracic Doppler echocardiography surpasses 320-row multidetector computed tomographic coronary angiography (CTCA) in detecting obstructive coronary artery disease. METHODS: One hundred seventy patients who underwent invasive coronary angiography, transthoracic Doppler echocardiography, and CTCA were prospectively enrolled. Coronary artery stenosis was defined as percentage diameter stenosis ≥ 50% on invasive coronary angiography. CFVR < 2.0 and narrowing ≥ 50% measured with CTCA were the thresholds indicating the presence of coronary artery stenosis. The degree of coronary artery calcification was also assessed using the Agatston calcium score method by computed tomography. RESULTS: The majority of patients (89%) were classified as having either high or intermediate pretest probability of coronary artery disease. Significant coronary artery stenoses by invasive coronary angiography were found in 71 patients and 104 vessels. Although the overall diagnostic performance of CTCA was comparable with that of CFVR measurement for detecting coronary artery stenosis, only the diagnostic performance of CTCA was negatively affected by the extent of a patient's coronary artery calcification. Receiver operating characteristic curve analysis indicated that only CFVR measurement is diagnostically accurate when calcium scores are >319 in the patient-based assessment, 189 for the left anterior descending coronary artery, 98 for the left circumflex coronary artery and 282 for the right coronary artery. CONCLUSIONS: Transthoracic Doppler echocardiography and 320-row multidetector CTCA successfully diagnosed significant coronary artery stenosis with high feasibility and accuracy. However, only the diagnostic performance of CTCA was negatively affected by the extent of a patient's coronary artery calcification, and therefore the diagnostic performance of CFVR measurement for detecting coronary artery stenosis surpassed that of CTCA when the calcium score exceeded specified cutoff values.

Changes in plasma levels of B-type natriuretic peptide with acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Elevated plasma B-type natriuretic peptide (BNP) levels and their association with heart failure have been reported in subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). PURPOSE: To examine and compare plasma BNP levels and diastolic and systolic dysfunction in subjects with AECOPD and stable chronic obstructive pulmonary disease (COPD). METHODS: In all, 87 unselected consecutive hospitalizations due to AECOPD in 61 subjects and a total of 190 consecutive subjects with stable COPD were recruited. Plasma BNP levels were compared cross-sectionally and longitudinally. Transthoracic echocardiographic examinations were also performed in the hospitalized subjects. RESULTS: In the hospitalized subjects, the median plasma BNP level (interquartile range) was 55.4 (26.9-129.3) pg/mL and was higher than that of patients with stable COPD: 18.3 (10.0-45.3) for Global Initiative for Chronic Obstructive Lung Disease grade I; 25.8 (11.0-53.7) for grade II; 22.1 (9.1-52.6) for grade III; and 17.2 (9.6-22.9) pg/mL for grade I V, all P<0.001. In 15 subjects studied prospectively, the median plasma BNP level was 19.4 (9.8-32.2) pg/mL before AECOPD, 72.7 (27.7-146.3) pg/mL during AECOPD, and 14.6 (12.9-39.0) pg/mL after AECOPD (P<0.0033 and P<0.0013, respectively). Median plasma BNP levels during AECOPD were significantly higher in ten unsuccessfully discharged subjects 260.5 (59.4-555.0) than in 48 successfully discharged subjects 48.5 (24.2-104.0) pg/mL (P=0.0066). Only 5.6% of AECOPD subjects were associated with systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <50%; a further 7.4% were considered to have impaired relaxation defined as an E/A wave velocity ratio <0.8 and a deceleration time of E >240 ms. BNP levels were weakly correlated with the E/peak early diastolic velocity of the mitral annulus (Ea) ratio (Spearman's rank correlation coefficient =0.353, P=0.018), but they were not correlated with the LVEF (Spearman's rank correlation coefficient =-0.221, P=0.108). CONCLUSION: A modest elevation of plasma BNP is observed during AECOPD. It appears that AECOPD may have an impact on plasma BNP levels that is not attributable to heart failure.

Myocardial perfusion reserve is impaired in patients with chronic obstructive pulmonary disease: a comparison to current smokers.

AIMS: Recent studies have demonstrated that chronic obstructive pulmonary disease (COPD) is associated with cardiovascular disease (CVD). However, the association between COPD and coronary microcirculatory dysfunction is unknown. We sought to assess whether myocardial perfusion reserve (MPR) is impaired in patients with COPD, even in the absence of regional myocardial ischaemia or infarction, by using quantitative myocardial perfusion cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: We recruited 60 subjects with a normal CMR study: 20 individuals with mild-to-moderate COPD; 20 age-matched control smokers, and 20 age-matched control-never smokers. Individuals with established CVD and diabetes mellitus were excluded. Stress-rest myocardial blood flow (MBF) was quantified in 16 myocardial segments by using a Patlak plot method. There were no significant differences in the rest MBF among COPD patients, control smokers, and control-never smokers. However, the mean MPR was significantly lower in COPD patients than in control smokers and control-never smokers (1.76 ± 0.58, 2.57 ± 1.30, and 3.56 ± 1.27, respectively). Univariate associations with MPR were smoking (r = -0.44, P < 0.001), forced expiratory volume in 1 s (FEV1) (r = 0.30, P = 0.02), haematocrit (r = 0.25, P = 0.04), and C-reactive protein (CRP; r = -0.46, P < 0.001). On multivariable analysis, the levels of CRP, FEV1, and renal dysfunction were independent predictors of the impaired MPR. The presence of COPD was associated with a five-fold increased risk of MPR <1.5 (95% confidence interval, 1.4-19.0; P = 0.01). CONCLUSIONS: The MPR, which was independently associated with systemic inflammation and airflow limitation, was impaired in patients with COPD. The presence of COPD was a powerful predictor of impaired MPR in patients without regional myocardial ischaemia or infarction.

Hemodynamic and pathophysiological characteristics of intradialytic blood pressure elevation in patients with end-stage renal disease.

An increase in systolic blood pressure (SBP) after hemodialysis (intradialytic-HTN) is associated with adverse outcomes in patients on regular hemodialysis. However, the hemodynamic and Doppler echocardiographic characteristics of intradialytic-HTN and its impact on clinical outcomes are unclear. A retrospective analysis of 84 patients (45 men, 70±9 years) stratified into three groups on the basis of SBP response from pre- to post-hemodialysis: GHTN (intradialytic-HTN, SBP increase 10 mm Hg), GDROP<15 mm Hg (SBP drop <15 mm Hg), and GDROP15 mm Hg (SBP drop 15 mm Hg). Hemodynamic and echocardiographic assessments were performed pre- and post-hemodialysis, and patients were followed for 41±17 months. GHTN had higher blood glucose and lower baseline SBP, serum potassium and total cholesterol. Cardiothoracic ratio was smaller, and peak early diastolic mitral annular velocity (E') was lower in GHTN. During hemodialysis, SBP and diastolic blood pressure increased only in GHTN. After hemodialysis, left ventricular (LV) filling pressure (E/E' ratio) decreased only in GDROP15 mm Hg, resulting in a higher E/E' ratio in GHTN than GDROP15 mm Hg. Multivariate logistic regression analysis revealed a positive correlation between blood glucose and intradialytic-HTN, whereas cardiothoracic ratio, pre-hemodialysis SBP and the change in E/E' ratio with hemodialysis were negatively related to intradialytic-HTN. During follow-up, GHTN had more cardiovascular deaths than GDROP15 mm Hg (P=0.03). Multivariate Cox regression analysis showed that lower serum potassium and previous coronary artery disease, but not intradialytic-HTN, were associated with cardiovascular deaths. A higher LV afterload and elevated filling pressures after hemodialysis, indicative of increased cardiovascular stiffening and impaired diastolic filling, may contribute in part to an increased cardiovascular burden in patients with intradialytic-HTN.

Quantifying longitudinal right ventricular dysfunction in patients with old myocardial infarction by using speckle-tracking strain echocardiography.

BACKGROUND: We investigated longitudinal right ventricular (RV) function assessed using speckle-tracking strain echocardiography in patient with myocardial infarction (MI), and identified the contributing factors for RV dysfunction. METHODS: We retrospectively studied 71 patients with old MI (the OMI group) and 45 normal subjects (the Control group) who underwent a transthoracic echocardiography. Global and free wall RV peak systolic strains (PSSs) in the longitudinal direction were measured by using speckle-tracking strain echocardiography. Left ventricular (LV) PSSs were measured in the longitudinal, radial and circumferential directions. Cardiac hemodynamics including peak systolic pulmonary artery pressure was also assessed non-invasively. Plasma brain natriuretic peptide (BNP) levels were measured in all patients. RESULTS: In the OMI group, 73% of the patients had a normal estimated peak systolic pulmonary artery pressure of less than 35 mmHg. Global and free wall RV PSS were impaired in the OMI group compared with the Control group, and these RV systolic indices were significantly associated with heart rate, logarithmic transformed plasma BNP, greater than 1 year after onset of MI, Doppler-derived estimated pulmonary vascular resistance, LV systolic indices, LV mass index, infarcted segments within a territory of the left circumflex artery and residual total occlusion in the culprit right coronary artery. Multivariable linear regression analysis indicated that reduced longitudinal LV PSS in the 4-chamber view and BNP levels ≥500 pg/ml were independently associated with reduced global and free wall RV PSS. Moreover, when patients were divided into 3 groups according to plasma BNP levels (BNP <100 pg/ml; n = 31, 100 ≤BNP <500 pg/ml; n = 24, and BNP ≥500 pg/ml; n = 16), only patients with BNP ≥500 pg/ml had a strong correlation between RV PSS and longitudinal LV PSS in the 4-chamber view (r = 0.78 for global RV PSS and r = 0.71 for free wall RV PSS, p <0.05). CONCLUSION: Longitudinal RV systolic strain depends significantly on longitudinal LV systolic strain especially in patients with high plasma BNP levels, but not on estimated peak systolic pulmonary artery pressure. These results indicate that process of RV myocardial dysfunction following MI may be governed by neurohormonal activation which causing ventricular remodeling rather than increased RV afterload.

Echocardiographic estimation of pulmonary capillary wedge pressure using the combination of diastolic annular and mitral inflow velocities.

BACKGROUND: We aimed to identify the clinical utility of a simple echocardiographic approach for estimating the pulmonary capillary wedge pressure (PCWP) on the basis of the combined assessment of mitral inflow and tissue Doppler mitral annular velocities. METHODS: We retrospectively enrolled 165 patients who underwent both echocardiographic examination and right heart catheterization, and determined the diagnostic accuracy of echocardiography-derived parameters for estimating PCWP >18 mmHg. RESULTS: Eighty-three patients had preserved left ventricular (LV) ejection fraction ≥50% (the PEF group) and 82 patients had reduced LVEF <50% (the REF group). The PEF group had higher peak early mitral annular velocity (E') compared with the REF group. Eight patients in the PEF group but none in the REF group had normal LV diastolic function, represented as E' >8 cm/s, and all of these patients had normal inflow pattern. The mean PCWP had the strongest correlation with the ratio of the peak early mitral inflow velocity (E) to the peak late diastolic mitral inflow velocity during atrial contraction (E/A) in both groups, followed by the left atrial diameter and E/E' in both patient groups. Receiver operating characteristic (ROC) analysis demonstrated that the combination of abnormal E' ≤8 and elevated E/A had high diagnostic accuracy compared with E/E' in both patient groups with different cutoff values of E/A (1.81 in the PEF group and 1.16 in the REF group) for predicting mean PCWP >18 mmHg. CONCLUSION: After excluding patients with normal diastolic function using E', conventional E/A is a reliable marker for predicting high PCWP and is superior to E/E'.

Ventricular function and dyssynchrony quantified by speckle-tracking echocardiography in patients with acute and chronic right ventricular pressure overload.

BACKGROUND: The aim of this study was to noninvasively investigate right ventricular and left ventricular (LV) adaptation to right ventricular pressure overload in patients with acute pulmonary thromboembolism (APTE) and chronic pulmonary artery hypertension (CPAH). METHODS: Thirty-seven patients with APTE, 36 patients with CPAH, and 33 controls were retrospectively enrolled. Myocardial deformation and wall motion were analyzed using speckle-tracking strain and displacement imaging echocardiography in the right and left ventricles. The standard deviation of the heart rate-corrected intervals from QRS onset to peak systolic strain and peak systolic displacement (PSD) for the six segments was used to quantify right ventricular and LV mechanical dyssynchrony (peak systolic strain dyssynchrony and PSD dyssynchrony). The myocardial performance index in both ventricles was also evaluated. RESULTS: The APTE and CPAH groups had reduced ventricular performance (LV myocardial performance index, 0.40 ± 0.10, 0.66 ± 0.18 [P < .05 vs controls], and 0.58 ± 0.19 [P < .05 vs controls] in the control, APTE, and CPAH groups, respectively) and large mechanical dyssynchrony (LV longitudinal PSD dyssynchrony, 58 ± 41 msec, 119 ± 49 msec [P < .05 vs controls], and 83 ± 37 msec [P < .05 vs controls and the APTE group] in the control, APTE, and CPAH groups, respectively) in both ventricles. Multiple regression analysis indicated that LV longitudinal PSD dyssynchrony in the APTE group and the LV eccentricity index in the CPAH group were independent determinants of LV myocardial performance index. CONCLUSIONS: Pathophysiologic mechanisms that regulate ventricular performance vary depending on whether the ventricles are exposed to acute or chronic right ventricular pressure overload.

Improving drug adherence using fixed combinations caused beneficial treatment outcomes and decreased health-care costs in patients with hypertension.

We enrolled 196 patients with hypertension who were already being treated with free-drug combinations of angiotensin-II receptor blocker (ARB) and amlodipine. The free-drug combinations of ARB and amlodipine were replaced with the same dose of the fixed-dose combinations. The average home blood pressure (BP) in all patients receiving fixed-dose combinations was significantly lower than those receiving free-drug combinations (131 ± 10/75 ± 8 vs. 136 ± 11/77 ± 9 mm Hg, P < .01) accompanied with increasing drug adherence. After lowering BP by fixed-dose combinations, the costs for medications decreased by 31% over the 3 months.

Interrelationship between haemodynamic state and serum intact parathyroid hormone levels in patients with chronic heart failure.

OBJECTIVE: To assess the impact of serum intact parathyroid hormone (PTH) levels on haemodynamic state and their relations by comparing plasma B-type natriuretic peptide (BNP) levels. DESIGN: Cross-sectional study in molecular epidemiology. SETTING: Mie University Hospital, Tsu, Japan. PATIENTS: Consecutive 105 patients with chronic heart failure (CHF). MAIN OUTCOME MEASURES: Serum intact PTH and plasma BNP levels were assessed simultaneously with right heart catheterisation. RESULTS: Although serum intact PTH levels (46±25 pg/ml) were within the normal range (<65 pg/ml) in 87% of patients, log-transformed intact PTH levels significantly correlated with pulmonary capillary wedge pressure (PCWP: 15±9 mm Hg, r=0.55, p<0.05) and heart rate (73±14/min, r=0.40, p<0.05), whereas log-transformed intact PTH levels were inversely correlated with stroke volume index (SVI: 38±11 ml/m(2), r=-0.52, p<0.05) and cardiac index (2.6±0.7 l/min/m(2), r=-0.41, p<0.05) in all patients. PCWP and SVI were independent determinants of log-transformed intact PTH levels (ß=0.40 and -0.37, p<0.05, respectively) after adjusting for variables associated with PTH. Conversely, after adjusting for variables associated with CHF, log-transformed intact PTH levels were an independent determinant of PCWP, SVI, heart rate and cardiac index (ß=0.38, -0.33, 0.32, and -0.25, p<0.05, respectively), and might be defined as a superior determinant of SVI and cardiac index compared with log-transformed BNP levels using stepwise multivariate regression analyses. CONCLUSIONS: Increased PCWP and decreased SVI independently contribute to elevated intact PTH in patients with CHF.

Short-term effects of low-dose tolvaptan on hemodynamic parameters in patients with chronic heart failure.

BACKGROUND: We evaluated the short-term effects of low-dose tolvaptan treatment on hemodynamic parameters in patients with chronic heart failure (HF). METHODS: We studied 22 patients (69 ± 10 years) with chronic HF and excess fluid retention despite receiving appropriate medical therapy, including loop and/or thiazide diuretics. The therapeutic effects of low-dose (7.5mg) once-daily tolvaptan on hemodynamics associated with changes in fluid balance and neurohumoral activations were investigated after a seven day treatment period. RESULTS: After the treatment period, body weight decreased (-2.7 ± 2.3 kg) associated with increases in daily urine output. Whereas plasma arginine-vasopressin levels, serum aldosterone concentration, and plasma renin activity mildly increased, plasma levels of B-type natriuretic peptide and atrial natriuretic peptide significantly decreased after tolvaptan treatment. Serum electrolytes were not adversely affected by tolvaptan treatment. Although cardiac index and systemic vascular resistance index remained unchanged, mean pulmonary artery wedge pressure (22 ± 7 mmHg vs. 17 ± 7 mmHg, p<0.05), mean right atrial pressure (12 ± 5 mmHg vs. 9 ± 5 mmHg, p<0.05), mean pulmonary artery pressure (32 ± 9 mmHg vs. 25 ± 7 mmHg, p<0.05), and pulmonary vascular resistance index (332 ± 207 dynes/cm(-5)/m(2) vs. 245 ± 110 dynes/cm(-5)/m(2), p<0.05) significantly decreased after tolvaptan treatment. The extent of the reduction in pulmonary vascular resistance index after tolvaptan treatment strongly correlated with baseline values. CONCLUSIONS: Short-term treatment with low-dose tolvaptan improved hemodynamic parameters and correlated with significant fluid removal in patients with chronic HF.

Impaired myocardial perfusion reserve in patients with fatty liver disease assessed by quantitative myocardial perfusion magnetic resonance imaging.

BACKGROUND: The purpose of this study was to determine whether the presence of fatty liver is associated with an alteration in myocardial perfusion reserve (MPR). METHODS AND RESULTS: A retrospective analysis of 65 asymptomatic subjects who underwent both plain abdominal computed tomography and cardiac magnetic resonance imaging (MRI), and who had normal left ventricular wall motion, no regional myocardial ischemia and no myocardial scar on MRI was performed. Stress and rest myocardial perfusion MRI were analyzed by Patlak plot method to quantify myocardial blood flow (MBF) and MPR in 16 myocardial segments. Fatty liver was detected in 18 (28%) of the 65 subjects. No significant difference was found in rest-MBF between subjects with and without fatty liver (1.2 ± 0.75 vs. 1.1 ± 0.67 ml·min(-1)·g(-1), P=0.59). However, MPR was significantly lower in subjects with fatty liver than the non-fatty liver subjects (2.3 ± 0.74 vs. 3.3 ± 1.4, P<0.001). Subjects with fatty liver had a higher prevalence of MPR <2.5 (78% vs. 38%, P<0.005) and higher triglyceride levels (206 ± 61 vs. 92 ± 37 mg/dl, P<0.001). Multivariate analysis revealed the presence of fatty liver as a significant predictor of reduced MPR with an odds ratio of 8.2 (P<0.01). CONCLUSIONS: Nonalcoholic fatty liver disease is related to reduced MPR, suggesting impaired coronary microcirculation.