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.

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.

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.

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.

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.

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.

Prevalence and signal characteristics of late gadolinium enhancement on contrast-enhanced magnetic resonance imaging in patients with takotsubo cardiomyopathy.

BACKGROUND: To determine the prevalence and signal intensity (SI) characteristics of late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) in takotsubo cardiomyopathy (TC). METHODS AND RESULTS: Cine, black-blood T2-weighted and LGE MR images were acquired in 23 patients with TC within 72 h of onset. Wall motion abnormality (WMA), edema and LGE were evaluated with a 16-segment model. The SI characteristics of LGE were analyzed using SI distribution in remote normal segments as reference. Follow-up MRI was performed 3 months later. Retrospective analysis of LGE MRI was also performed in 10 patients with acute myocardial infarction (AMI) to compare the SI characteristics between TC and AMI. In acute phase, WMA and edema were observed in 236 (64%) and 205 (56%) of 368 segments. LGE was observed in 10 (2.7%) of 368 segments and in 5 (22%) of 23 patients. All LGE lesions in TC exhibited transmural enhancement. The contrast-to-noise ratio (CNR) in TC was significantly lower than that of AMI (3.1±0.3 standard deviations (SD) vs. 6.1±1.2 SD, P<0.01), and CNR value of 4 was useful for distinguishing TC from AMI. Both LGE and WMA disappeared within 12 months. CONCLUSIONS: Grey myocardial signal on LGE MRI may be observed in patients with TC. However, the extent of LGE is substantially less than that of WMA and edema, and disappears within 12 months.

Role of haemodialytic therapy on left ventricular mechanical dyssynchrony in patients with end-stage renal disease quantified by speckle-tracking strain imaging.

BACKGROUND: Abnormal myocardial loading can contribute to left ventricular (LV) mechanical dyssynchrony in patients with end-stage renal disease (ESRD). The aims of this study were to characterize and quantify LV function and mechanical dyssynchrony in patients with ESRD, and to elucidate the impact of haemodialytic (HD) therapy on these parameters by speckle-tracking strain imaging. METHODS: Twenty-three patients with ESRD (63 ± 11 years) before (pre-dialysis group) and after HD therapy (post-dialysis group) and 28 normal subjects (control group; 60 ± 10 years) were examined by echocardiography. Global and segmental LV peak systolic strain (PSS) were analysed, and LV mechanical dyssynchrony was assessed by calculating the standard deviation of the segmental time-to-PSS over longitudinal, circumferential or radial regions, respectively. RESULTS: Global PSS and LV ejection fraction in the pre-dialysis group were similar to those in the control group, and were not altered by HD therapy. LV mechanical dyssynchronies in the longitudinal and radial directions, but not in the circumferential direction, were significantly greater in the pre-dialysis group than those in the control group [longitudinal direction: 63 ± 15 (P < 0.05 vs. the control group) vs. 49 ± 15 ms, circumferential direction: 44 ± 24 vs. 41 ± 23 ms, and radial direction: 47 ± 29 (P < 0.05 vs. the control group) vs. 16 ± 18 ms]. HD therapy dramatically improved only the radial LV dyssynchrony in the post-dialysis group (23 ± 24 ms, P < 0.05 vs. the pre-dialysis group). CONCLUSIONS: The presence of ESRD was associated with longitudinal and radial LV dyssynchronies. In addition, HD therapy dramatically improved radial LV dyssynchrony, which strongly indicates that only radial LV dyssynchrony is preload dependent among the three LV systolic directions.

Impact of chronic kidney disease on the presence and severity of aortic stenosis in patients at high risk for coronary artery disease.

OBJECTIVE: We evaluated the impact of chronic kidney disease (CKD) on the presence and severity of aortic stenosis (AS) in patients at high risk for coronary artery disease (CAD). METHODS: One hundred and twenty consecutive patients who underwent invasive coronary angiography were enrolled. Aortic valve area (AVA) was calculated by the continuity equation using transthoracic echocardiography, and was normalized by body surface area (AVA index). RESULTS: Among all 120 patients, 78% had CAD, 55% had CKD (stage 3: 81%; stage 4: 19%), and 34% had AS (AVA < 2.0 cm²). Patients with AS were older, more often female, and had a higher frequency of CKD than those without AS, but the prevalence of CAD and most other coexisting conventional risk factors was similar between patients with and without AS. Multivariate linear regression analysis indicated that only CKD and CAD were independent determinants of AVA index with standardized coefficients of -0.37 and -0.28, respectively. When patients were divided into 3 groups (group 1: absence of CKD and CAD, n = 16; group 2: presence of either CKD or CAD, n = 51; and group 3: presence of both CKD and CAD, n = 53), group 3 had the smallest AVA index (1.19 ± 0.30*# cm²/m², *p < 0.05 vs. group 1: 1.65 ± 0.32 cm²/m², and #p < 0.05 vs. group 2: 1.43 ± 0.29* cm²/m²) and the highest peak velocity across the aortic valve (1.53 ± 0.41*# m/sec; *p < 0.05 vs. group 1: 1.28 ± 0.29 m/sec, and #p < 0.05 vs. group 2: 1.35 ± 0.27 m/sec). CONCLUSION: CKD, even pre-stage 5 CKD, has a more powerful impact on the presence and severity of AS than other conventional risk factors for atherosclerosis in patients at high risk for CAD.

Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice.

Tenascin-C (TN-C) is an extracellular matrix glycoprotein with high bioactivity. It is expressed at low levels in normal adult heart, but upregulated under pathological conditions, such as myocardial infarction (MI). Recently, we (Ref. 34) reported that MI patients with high serum levels of TN-C have a greater incidence of maladaptive cardiac remodeling and a worse prognosis. We hypothesized that TN-C may aggravate left ventricular remodeling. To examine the effects of TN-C, MI was induced by ligating coronary arteries of TN-C knockout (KO) mice under anesthesia and comparing them with sibling wild-type (WT) mice. In WT+MI mice, TN-C expression was upregulated at day 1, peaked at day 5, downregulated and disappeared by day 28, and the molecule was localized in the border zone between intact myocardium and infarct lesions. The morphometrically determined infarct size and survival rate on day 28 were comparable between the WT+MI and KO+MI groups. Echocardiography and hemodynamic analyses demonstrated left ventricular end-diastolic diameter, myocardial stiffness, and left ventricular end-diastolic pressure to be significantly increased in both WT+MI and KO+MI mice compared with sham-operated mice. However, end-diastolic pressure and dimension and myocardial stiffness of KO+MI were lower than those of the WT+MI mice. Histological examination revealed normal tissue healing, but interstitial fibrosis in the residual myocardium in peri-infarcted areas was significantly less pronounced in KO+MI mice than in WT+MI mice. TN-C may thus accelerate adverse ventricular remodeling, cardiac failure, and fibrosis in the residual myocardium after MI.

Overexpression of myosin phosphatase reduces Ca(2+) sensitivity of contraction and impairs cardiac function.

BACKGROUND: Phosphorylation of the regulatory light chain of myosin (MLC) has roles in cardiac function. In vitro, myosin phosphatase target subunit 2 (MYPT2) is a strongly suspected regulatory subunit of cardiac myosin phosphatase (MP), but there is no in-vivo evidence regarding the functions of MYPT2 in the heart. METHODS AND RESULTS: Transgenic mice (Tg) overexpressing MYPT2 were generated using the alpha-MHC promoter. Tg hearts showed an increased expression of MYPT2 and concomitant increase of the endogenous catalytic subunit of type 1 phosphatase (PP1cdelta), resulting in an increase of the MP holoenzyme. The level of phosphorylation of ventricular MLC was reduced. The pCa-tension relationship, using beta-escin permeabilized fibers, revealed decreased Ca(2+) sensitization of contraction in the Tg heart. LV enlargement with associated impairment of function was observed in the Tg heart and ultrastructural examination showed cardiomyocyte degeneration. CONCLUSIONS: Overexpression of MYPT2 and the increase in PP1cdelta resulted in an increase of the MP holoenzyme and a decrease in the level of MLC phosphorylation. The latter induced Ca(2+) desensitization of contraction and decreased LV contractility, resulting in LV enlargement. Thus, MYPT2 is truly the regulatory subunit of cardiac MP in-vivo and plays a significant role in modulating cardiac function. (Circ J 2010; 74: 120 - 128).

Regional myocardial perfusion reserve determined using myocardial perfusion magnetic resonance imaging showed a direct correlation with coronary flow velocity reserve by Doppler flow wire.

AIMS: Quantitative analysis of rest-stress myocardial perfusion magnetic resonance imaging (MRI) can provide assessments of regional myocardial perfusion reserve (MPR). The purpose of this study was to compare regional MPR determined by myocardial perfusion MRI with coronary flow reserve (CFR) by intracoronary Doppler flow wire. METHODS AND RESULTS: Twenty patients with suspected coronary artery disease (CAD) were studied. Average peak velocity was measured by Doppler flow wire in the resting state and during adenosine triphosphate (ATP) stress in 36 coronary arteries. CFR measurements for each patient were performed in the culprit and one non-culprit non-stenotic artery. First-pass, contrast-enhanced myocardial perfusion MR images were obtained in the resting state and during ATP stress within the week before the Doppler wire procedure. Regional myocardial blood flow (MBF) was quantified in 16 myocardial segments by analysing arterial input and myocardial output using a Patlak plot method. MPR was calculated as stress MBF divided by rest MBF. CFR measured by Doppler flow wire was compared with MPR in the myocardial segments corresponding to vessel territories. The average MPR measured by perfusion MRI was 1.77 +/- 0.62 for the culprit arteries and 3.45 +/- 0.78 for the non-culprit arteries, respectively (P < 0.001). The averaged CFR by Doppler flow wire was 1.72 +/- 0.44 in the culprit arteries and 3.14 +/- 0.74 in the non-culprit arteries, respectively (P < 0.001). For both culprit and non-culprit vessel groups, significant direct correlations were observed between MR assessments of MPR and Doppler assessments of CFR (culprit artery: R = 0.87, Non-culprit artery: R = 0.86) On Bland-Altman analysis, the mean differences between MPR determined by myocardial perfusion MRI and CFR measured by Doppler wire were 0.05 in culprit arteries (95% limit of agreement; -0.65 to 0.56) and 0.36 in non-culprit arteries (95% limit of agreement; -1.24 to 0.44). The sensitivity and specificity of MR measurement of MPR for predicting physiologically significant reduction of Doppler CFR (<2) was 88% (95% CI 61.7-98.5) and 90% (95% CI 68.3-98.8), respectively. CONCLUSION: The current results using Doppler flow wire as a reference method demonstrated that quantitative analysis of stress-rest myocardial perfusion MRI can provide a non-invasive assessment of reduced MPR in patients with CAD.

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.

Incremental prognostic values of serum tenascin-C levels with blood B-type natriuretic peptide testing at discharge in patients with dilated cardiomyopathy and decompensated heart failure.

BACKGROUND: This study investigates the predictive value of serum tenascin-C (TN-C), which is observed at the active sites of ongoing tissue remodeling, for cardiac events of patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: In this trial, 110 consecutive patients hospitalized with heart failure (HF) resulting from DCM underwent assessments of serum TN-C and plasma brain natriuretic peptide (BNP) levels at discharge and were followed up for 22.4 months. Cardiac function and hemodynamics were assessed invasively in 60 of these patients at discharge. There were 19 cardiac events (14 rehospitalizations, 3 deaths from refractory HF, and 2 sudden deaths) during follow-up. The average levels of TN-C and BNP were 73 +/- 38 ng/mL and 279 +/- 414 pg/mL, respectively. The optimal cutoff value for serum TN-C levels predicted cardiac events were >or=78.4 ng/mL, whereas BNP levels were >or=219 pg/mL. Patients with levels higher than this had significantly higher cardiac events and serum TN-C >or=78.4 ng/mL had an incremental predictive power with BNP for cardiac events. Left ventricular end-diastolic volume was significantly larger, and mean pulmonary arterial pressure was elevated in patients with serum TN-C >or=78.4 ng/mL. CONCLUSIONS: The combined index of serum levels for TN-C and BNP at discharge predicts cardiac events from decompensated HF. Additionally, elevated serum TN-C levels reflect left ventricular and pulmonary vascular remodeling in DCM patients.

Role of radial strain and displacement imaging to quantify wall motion dyssynchrony in patients with left ventricular mechanical dyssynchrony and chronic right ventricular pressure overload.

Left ventricular (LV) deformation with ventricular septal shift is one of the most distinctive echocardiographic observations in patients with chronic right ventricular (RV) pressure overload (PO). However, little is known about the effects of RVPO on LV performance and regional synchrony. Accordingly, our objective was to test the hypothesis that chronic RVPO affects regional wall motion, synchronicity, and global LV function using a novel speckle-tracking approach to quantify and characterize regional LV wall motion dyssynchrony. Displacement and strain imaging echocardiographic studies were performed in 20 patients with RVPO from pulmonary arterial hypertension or pulmonic stenosis (mean age 53 +/- 16 years, New York Heart Association class 2.6 +/- 0.7, and peak RV systolic pressure 73 +/- 28 mm Hg) and 20 age-matched normal subjects (mean age 47 +/- 16 years). Segmental signals from 6 segments around the mid-LV short axis were defined as dyssynchronous if their changes were opposite to that of the global LV signal at each time frame, and overall LV dyssynchrony was calculated as the percentage of dyssynchrony in all 6 segments within the specified time interval from onset of QRS to the end of isovolumic relaxation. RVPO was associated with a large degree of regional dyssynchrony with paradoxical ventricular septal motion observed by displacement imaging (21 +/- 6%, p <0.05 vs control group), which was closely associated with LV eccentricity index (r = 0.79, p <0.05) and LV myocardial performance index with linear regression (r = 0.76, p <0.05). In contrast, strain imaging showed uniform segmental radial thickening in the RVPO group, which was similar to the control group, and suggests that there was no intrinsic LV contractile dyssynchrony. In conclusion, LV wall motion dyssynchrony assessed by displacement imaging, not intrinsic contractile dyssynchrony by strain imaging, coexists with LV chamber deformation with ventricular septal shift and is closely associated with impairment of LV performance.

Exaggerated hypertensive response to exercise in patients with diastolic heart failure.

Systolic load elevation during exercise prolongs left ventricular (LV) relaxation, compromises filling, and raises end-diastolic pressure, leading to reduced exercise tolerance. The aim of this study was to test the hypothesis that the hypertensive response to exercise is exaggerated in patients with diastolic heart failure (DHF). Echocardiograms and treadmill testing were performed in patients with DHF (n=20) and age-matched hypertension with LV hypertrophy (HTN; n=20). The Minnesota Living with Heart Failure Questionnaire was used to estimate quality of life (QOL). There were no differences in resting blood pressure or echocardiographic parameters between the groups. The maximum exercise time was significantly shorter in the DHF group than in the HTN group (6.0+/-3.0 vs. 12.5+/-2.5 min), and the peak systolic blood pressure during exercise was significantly higher in the DHF group (212+/-18 vs. 189+/-16 mmHg, p<0.05). After 4 weeks of treatment with candesartan, an angiotensin II receptor blocker (8 mg/d), peak systolic blood pressure during exercise decreased to 191+/-13 mmHg, maximum exercise time increased (10.4+/-3.0 min; p<0.05), and QOL improved in patients with DHF, while there was no change in patients with HTN, despite the similar resting blood pressure. In patients with DHF, systolic blood pressure markedly increased during exercise, and this was accompanied by impaired exercise tolerance and a decreased QOL, both of which were partly suppressed by blocking angiotensin II.

Hemodynamic characteristics of patients with diastolic heart failure and hypertension.

Diastolic heart failure (DHF) has different underlying pathophysiologic mechanisms. We sought to compare hemodynamic characteristics in DHF patients with or without hypertension. A conductance catheter with microtip-manometer was used to measure left ventricular (LV) function and hemodynamics in 28 DHF patients. After baseline measurements, nitroglycerin was infused to alter the loading condition and the measurements were repeated. At baseline, end-systolic pressure was higher and the time constant of LV relaxation (tau) was longer in hypertensive DHF patients. Patients in hypertensive DHF had lower LV-arterial coupling ratio than those in non-hypertensive DHF. The peak of loading sequence was in early systole in non-hypertensive DHF patients and in late systole in hypertensive DHF patients. Nitroglycerin decreased LV end-systolic pressure and end-diastolic volume in both groups. In non-hypertensive DHF, nitroglycerin significantly reduced stroke volume and shortened tau (59+/-11 vs. 54+/-10 ms, p<0.05) without any changes in the time to peak LV force, effective arterial elastance (E(a)), or LV-arterial coupling ratio. In contrast, in hypertensive DHF patients, nitroglycerin significantly reduced E(a) and shortened the time to peak LV force, resulting in an improved LV-arterial coupling ratio, preserved stroke volume and shortened tau (75+/-14 vs. 62+/-13 ms, p<0.05). In conclusion, LV relaxation was more prolonged in hypertensive DHF patients than non-hypertensive DHF patients, partly because of the different loading sequence. Changing the loading condition by nitroglycerin improved LV systolic and diastolic function in hypertensive DHF patients.

Patients with a hypertensive response to exercise have impaired left ventricular diastolic function.

An exaggerated increase in systolic blood pressure prolongs myocardial relaxation and increases left ventricular (LV) chamber stiffness, resulting in an increase in LV filling pressure. We hypothesize that patients with a marked hypertensive response to exercise (HRE) have LV diastolic dysfunction leading to exercise intolerance, even in the absence of resting hypertension. We recruited 129 subjects (age 63+/-9 years, 64% male) with a preserved ejection fraction and a negative stress test. HRE was evaluated at the end of a 6-min exercise test using the modified Bruce protocol. Patients were categorized into three groups: a group without HRE and without resting hypertension (control group; n=30), a group with HRE but without resting hypertension (HRE group; n=25), and a group with both HRE and resting hypertension (HTN group; n=74). Conventional Doppler and tissue Doppler imaging were performed at rest. After 6-min exercise tests, systolic blood pressure increased in the HRE and HTN groups, compared with the control group (226+/-17 mmHg, 226+/-17 mmHg, and 180+/-15 mmHg, respectively, p<0.001). There were no significant differences in LV ejection fraction, LV end-diastolic diameter, and early mitral inflow velocity among the three groups. However, early diastolic mitral annular velocity (E') was significantly lower and the ratio of early diastolic mitral inflow velocity (E) to E' (E/E') was significantly higher in patients of the HRE and HTN groups compared to controls (E': 5.9+/-1.6 cm/s, 5.9+/-1.7 cm/s, 8.0+/-1.9 cm/s, respectively, p<0.05). In conclusion, irrespective of the presence of resting hypertension, patients with hypertensive response to exercise had impaired LV longitudinal diastolic function and exercise intolerance.

Impact of heart rate on mechanical dyssynchrony and left ventricular contractility in patients with heart failure and normal QRS duration.

AIMS: The quantification of mechanical dyssynchrony has important diagnostic value and may help to determine optimal therapy in heart failure (HF). We hypothesized that mechanical dyssynchrony may be augmented at increased heart rates in patients with HF and normal QRS duration. METHODS AND RESULTS: From online segmental conductance catheter signals, we derived indices to quantify temporal and spatial aspects of mechanical dyssynchrony during systole in 20 control subjects, 20 HF patients with normal QRS duration, and 12 HF patients with complete left bundle branch block (CLBBB). Data were collected at baseline, and then following a 40 bpm increase in heart rate induced by right atrial pacing. Mechanical dyssynchrony in HF patients with normal QRS duration or CLBBB was higher than that found in control subjects. In HF patients with normal QRS duration, mechanical dyssynchrony increased from 37.4+/-4.8% at baseline to 43.2+/-4.4% with increased heart rate (p<0.01), the resultant degree of mechanical dyssynchrony was similar to that at baseline in the HF patients with CLBBB. Increased heart rate did not affect dyssynchrony in the control patients. CONCLUSION: Mechanical dyssynchrony was augmented as heart rate increased by right atrial pacing in patients with HF and normal QRS duration.