Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure.

BACKGROUND: The effect of sodium glucose cotransporter type 2 (SGLT2) inhibitor on left ventricular (LV) longitudinal myocardial function in type 2 diabetes mellitus (T2DM) patients with heart failure (HF) has remained unclear. METHODS: We analyzed data from our previous prospective multicenter study, in which we investigated the effect of the SGLT2 inhibitor dapagliflozin on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e' annular velocities (E/e'). LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), which in turn was determined as the averaged peak longitudinal strain from standard LV apical views. RESULTS: E/e' significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described, while GLS showed significant improvement from 15.5 ± 3.5% to 16.9 ± 4.1% (p < 0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HF with preserved ejection fraction patients was more significant from 17.0 ± 1.9% to 18.7 ± 2.0% (p < 0.001), compared to that in HF with mid-range ejection fraction and HF with reduced ejection fraction patients from 14.4 ± 2.4% to 15.5 ± 1.8% (p = 0.06) and from 8.1 ± 1.5% to 7.8 ± 2.1% (p = 0.44), respectively. It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameters for the change in E/e' after administration of dapagliflozin. CONCLUSION: Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF.

Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure.

BACKGROUND: The objective of this study was to investigate the impact of sodium glucose cotransporter type 2 (SGLT2) inhibitors on left ventricular (LV) diastolic function of type 2 diabetes mellitus (T2DM) patients with heart failure (HF). METHODS: This trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. The physical examinations, blood tests, and echocardiography were performed at baseline and 6 months after administration of dapagliflozin. The primary endpoint was defined as a change in mitral inflow E and mitral e' annular velocities (E/e') between baseline and 6 months after the administration of dapagliflozin. The secondary end points consisted of a change in brain natriuretic peptide (BNP), LV mass index (LVMI) and left atrial volume index (LAVI). RESULTS: E/e' significantly decreased from 9.3 to 8.5 cm/s (p = 0.020) 6 months after administration of dapagliflozin. LAVI and LVMI significantly decreased from 31 to 26 mL/m2 (p = 0.001), and from 75.0 to 67.0 g/m2 (p < 0.001), respectively, 6 months after administration of dapagliflozin. No significant change was observed in BNP (from 27.9 to 28.9 pg/mL; p = 0.132) 6 months after administration of dapagliflozin, except for a significant decrease from 168.8 to 114.3 pg/mL (p = 0.012) in patients with BNP ≥ 100 pg/mL. CONCLUSION: This prospective multicenter trial showed the beneficial effect of SGLT2 inhibitors on LV diastolic functional parameters for T2DM patients with HF. Our findings may thus offer a new insight into the management of T2DM patients. Trial registration UMIN000019789, Registered 28 September 2014, Date of registration: 11/14/2015, Date of enrolment of the first participant to the trial: 6/15/2016, Date of enrolment of the last participant to the trial: 12/9/2017.

Cardiac tamponade in pregnancy during the treatment of severe pre-eclampsia: report of a case.

We present a case of cardiac tamponade that occurred during the course of treatment for severe pre-eclampsia. A 37-year-old woman who underwent cesarean section for severe pre-eclampsia developed cardiac tamponade after delivery. While percutaneous pericardiocentesis temporarily improved her condition, pericardial effusion, dyspnea and tachycardia reappeared 5 days after delivery. A continuous drainage tube placed in the pericardial cavity for 5 days was required to maintain maternal cardiac function. Her clinical course was uneventful after continuous drainage and she was discharged 20 days after delivery. No such causes of symptomatic pericardial effusion were detected in the present case. Physicians should be aware of this complication when dyspnea is accompanied by tachycardia and enlargement of the cardiac silhouette with hypolucent lungs on chest X-ray. Immediate pericardiocentesis is also required to prevent life-threatening cardiac tamponade in such cases.

Usefulness of Clinical Frailty Scale for Comprehensive Geriatric Assessment of Older Heart Failure Patients.

Background: Comprehensive geriatric assessment (CGA) is a multidisciplinary diagnostic process to identify the physical, psychological, and social functions of patients with frailty. The Clinical Frailty Scale (CFS) might aid in effectively identifying older patients with heart failure (HF) and frailty who would then reap maximum benefits from the CGA. Methods and Results: A single-centre prospective cohort study that enrolled consecutive hospitalised patients (age ≥75 years) with HF was conducted. The Barthel index (BI), Mini Mental State Examination (MMSE), the Charlson comorbidity index (CCI), and the COntrolling NUTritional (CONUT) for CGA was used. Among 190 enrolled patients (mean age, 85.4 years; 47.9% male), all-cause mortality (primary endpoint) occurred in 45 patients and HF-related rehospitalization (secondary endpoint) in 59 patients within 1 year. The cumulative incidence of all-cause mortality was significantly higher in the high CFS group (low 6.3%, high 30.5%, P<0.001). However, the cumulative incidence of HF-related rehospitalization was not significantly different (low 26.3%, high 32.0%, P=0.304). The multivariable analysis revealed that the CFS group was independently associated with the risk of all-cause mortality. CFS showed a strong correlation with the BI and moderate correlation with the MMSE. Conclusions: The CFS was associated with all-cause mortality within 1 year and was correlated with frailty domains of CGA.

Integrated backscatter-intravascular ultrasound and modification of plaque during excimer laser coronary angioplasty.

This study aims to test the hypothesis that the effect of excimer laser coronary angioplasty (ELCA) not only vaporizes thrombi and their underlying coronary plaque, it also changes their quality. We performed a series of cross-sectional analyses in 52 lesions in 51 patients before and after ELCA with integrated backscatter-intravascular ultrasound (IB-IVUS). The constituent parts of the plaque can be assessed by IB-IVUS (i.e., calcified, fibrous, lipid) according to integrated backscatter values. Minimum lumen diameter, lumen volume and vessel volume expanded after ELCA, while plaque volume did not significantly decrease. There was also a decrease of 'lipid' component (35.4-30.3%, P < 0.001) and an increase of IB-IVUS-derived 'fibrous' part (34.5-38.3%, P < 0.001). These results may help in understanding plaque change after ELCA. Excimer laser coronary angioplasty seems to contribute to the modification of coronary plaque composition in addition to debulking it.

Cardiac angiosarcoma in the right ventricle treated by surgical resection.

Cardiac angiosarcoma is a rare malignant neoplasm, the gold standard treatment is surgical resection. Our patient, an 81-year old Japanese woman, was admitted to hospital after chest pain over a month-long period. Transthoracic echocardiography (TTE) showed a heterogeneous and irregular mass-like lesion measuring approximately 45 mm and arising from the right ventricular free wall. Transesophageal echocardiography showed the lesion had a mobile portion. Considering the possibility of malignancy and a high risk of embolism and obstruction, we performed surgical resection of the tumour. Histological and immunohistochemical findings led to diagnosis of cardiac angiosarcoma. One year after surgery, TTE and CT showed no evidence of recurrence of angiosarcoma.

Impact of Dapagliflozin on the Left Ventricular Diastolic Function in Diabetic Patients with Heart Failure Complicating Cardiovascular Risk Factors.

Objective Our aim was to investigate the impact of the sodium glucose cotransporter type 2 (SGLT2) inhibitor on the left ventricular (LV) diastolic function in type 2 diabetes mellitus (T2DM) patients with chronic heart failure (HF) complicating cardiovascular risk factors. Methods We analyzed data from our previous prospective multicenter study, in which we investigated the effect of dapagliflozin on the LV diastolic function of T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least 1 antidiabetic drug other than SGLT2 inhibitors started treatment with dapagliflozin. Echocardiography was performed at baseline and six months after the administration of dapagliflozin. Cardiovascular risk factors other than T2DM were age, gender, hypertension, dyslipidemia, history of cardiovascular events and overweight. Results The LV diastolic function, defined as the ratio of the mitral inflow E to the mitral e' annular velocities (E/e'), significantly decreased from 9.3 to 8.5 by six months after the administration of dapagliflozin (p=0.020) as previously reported. A multivariate logistic regression analysis showed that dyslipidemia was the only independent determinant of improvement in the E/e' after the administration of dapagliflozin among cardiovascular risk factors. Furthermore, the relative change in the E/e' from baseline to six months after the administration of dapagliflozin for HF patients with preserved ejection fraction (HFpEF) and dyslipidemia was significantly larger than that for HFpEF patients without dyslipidemia (-15.2% vs. 29.6%, p=0.014), but no such finding was observed in non-HFpEF patients. Conclusion SGLT2 inhibitors may exert a more beneficial effect on the LV diastolic function for T2DM patients with stable HF, especially those with complicating dyslipidemia, than existing treatments.

Vitamin C restores the contractile response to dobutamine and improves myocardial efficiency in patients with heart failure after anterior myocardial infarction.

BACKGROUND: Excessive oxidative stress is considered one of the mechanisms of a decrease in contractile force without concomitant reduction in oxygen cost in failing myocardium. We hypothesized that the antioxidant vitamin C may help reverse hyporesponsiveness to beta-adrenergic stimulation and improve myocardial efficiency in patients with heart failure (HF) after myocardial infarction (MI). METHODS AND RESULTS: Nineteen patients with mild to moderate HF due to previous MI (mean left ventricular [LV] ejection fraction 39%) were instrumented with conductance and coronary sinus thermodilution catheters. Left ventricular contractility, expressed as E(es), the slope of end-systolic pressure-volume relationship, and mechanical efficiency, expressed as the ratio of LV stroke work (SW) to myocardial oxygen consumption (MVO2), were measured in response to the intravenous infusion of dobutamine (4 microg/kg per min) before (Dob) and during (Dob + Vit C) the infusion of vitamin C (2.0-g bolus injection and subsequent 50-mg/min infusion through the jugular vein) (vitamin C group, n = 10). The infusion of vitamin C augmented the E(es) response to dobutamine by 20% +/- 8% (Dob 2.1 +/- 0.3, Dob + Vit C 2.5 +/- 0.4 mm Hg/mL, P < .01) and the SW/MVO2 response by 21% +/- 5% (Dob 36% +/- 3%, Dob + Vit C 43% +/- 4%, P < .01). In the control group (n = 9), E(es) and SW/MVO2 were measured in response to dobutamine before (Dob) and during (Dob + vehicle) the infusion of saline. No difference in E(es) or SW/MVO2 was observed between Dob and Dob + vehicle (E(es): Dob 2.1 +/- 0.2, Dob + vehicle 2.1 +/- 0.2 mm Hg/mL per square meter, P = nonsignificant) (SW/MVO2: Dob 35% +/- 4%, Dob + vehicle 33% +/- 4%, P = nonsignificant). CONCLUSION: The administration of the antioxidant vitamin C enhances the contractile response to dobutamine and improves myocardial efficiency in patients with HF.

Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress.

BACKGROUND: A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis. METHODS AND RESULTS: To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered mouse models that have an attenuated hypertrophic response to 8 weeks of pressure overload. End-systolic wall stress (sigma(es)) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of sigma(es) in pressure-overloaded wild-type mice (287+/-39 versus sham, 254+/-34 g/cm2), whereas the blunted hypertrophic response in the transgenic mice was inadequate to normalize sigma(es) (415+/-81 g/cm2, P<0.05). Remarkably, despite inadequate normalization of sigma(es), cardiac function as measured by serial echocardiography showed little deterioration in either of the pressure-overloaded genetic models with blunted hypertrophy. In contrast, wild-type mice with similar pressure overload showed a significant increase in chamber dimensions and progressive deterioration in cardiac function. Analysis of downstream signaling pathways in the late stages of pressure overload suggests that phosphoinositide 3-kinase may play a pivotal role in the transition from hypertrophy to heart failure. CONCLUSIONS: These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized.

Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction.

BACKGROUND: Human atrial natriuretic peptide (hANP) and spontaneous nitric oxide (NO) donor share cyclic guanosine monophosphate (cGMP) as a second messenger, but their effect on myocardium may differ. We compared the effect of hANP and sodium nitroprusside (SNP) on left ventricular (LV) mechano-energetics in heart failure (HF). METHODS: Ten patients with HF due to previous myocardial infarction (LV ejection fraction: 45±3%) were instrumented with conductance and coronary sinus thermodilution catheters. LV contractility (Ees: slope of end-systolic pressure-volume relation) and the ratio of LV stroke work (SW) to myocardial oxygen consumption (SW/MVO2=mechanical efficiency) were measured in response to intravenous infusion of ANP (0.05 µg/kg/min) or SNP (0.3 µg/kg/min) to lower blood pressure by at least 10 mmHg, and changes in plasma cGMP. RESULTS: SNP had no effect on Ees, SW, or MVO2, thus SW/MVO2 remained unchanged (40.54±5.84% to 36.59±5.72%, p=0.25). ANP increased Ees, and decreased MVO2 with preserved SW, resulting in improved SW/MVO2 (40.49±6.35% to 50.30±7.96%, p=0.0073). Infusion of ANP (10.42-34.95 pmol/ml, p=0.0003) increased cGMP levels, whereas infusion of SNP had no effect (10.42-12.23 pmol/ml, p=0.75). CONCLUSIONS: Compared to SNP, the ANP-dependent increase in cGMP may ameliorate myocardial inotropy and energetics in HF.

Depletion of antioxidants is associated with no-reflow phenomenon in acute myocardial infarction.

BACKGROUND: No-reflow phenomenon is observed in approximately one-third of patients after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), and is associated with poor functional and clinical outcomes. On the other hand, the formation of free radicals in vasculature exerts deleterious effects on coronary microcirculation. HYPOTHESIS: We hypothesized that redox state in coronary circulation may play a crucial role in no-reflow phenomenon in AMI. METHODS: Consecutive 26 patients with first AMI who underwent primary PCI < 24 h after onset were enrolled. Before PCI, blood samples were obtained from coronary sinus to measure plasma or serum antioxidative vitamins (vitamin C, vitamin E, and beta-carotene) and antioxidative enzymes (extracellular glutathione peroxidase [GPX], superoxide dismutase, and catalase). After PCI, the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count (CTFC) was measured in the target vessel. Patients with TIMI < or = 2 flow despite an optimal PCI result were designated as no-reflow group (Group NR, n = 6) and the others as reflow group (Group R, n = 20). RESULTS: Levels of vitamin C, vitamin E, and GPX before PCI were significantly lower in Group NR than in Group R. The CTFC correlated inversely with levels of vitamin C, vitamin E, and GPX (p < 0.05). CONCLUSIONS: Depletion of antioxidants is associated with no-reflow phenomenon in AMI. These findings strongly suggest that the redox state in coronary circulation plays an important role in the pathogenesis of no-reflow phenomenon.

Clinically suspected acute myopericarditis with cardiac tamponade associated with peripheral blood eosinophilia presenting in early pregnancy: a case report.

INTRODUCTION: The clinical presentation of eosinophilic myocarditis may vary from asymptomatic to the manifestation of severe symptoms, including cardiac tamponade and arrhythmias. In pregnant patients with this condition, drugs must be used cautiously up to approximately the 4th month of pregnancy because drug use should be limited during the period of fetal organogenesis. CASE PRESENTATION: A 30-year-old Asian woman at 14 weeks of pregnancy with progressive malaise was hospitalized. The electrocardiogram revealed ST elevation and low QRS voltage. Echocardiography revealed massive pericardial effusion and myocardial swelling. A laboratory examination revealed an increase in her white blood cell count, with a predominance of neutrophils. Pericardial drainage was performed for relief of the cardiac tamponade. The pericardial effusion revealed an abundance of eosinophils. Subsequently, the peripheral blood eosinophil count began to rise, and the patient was clinically diagnosed with eosinophilic myopericarditis. The patient's condition improved rapidly following the initiation of prednisolone treatment, and she finally delivered a full-term normal infant. CONCLUSIONS: A patient with clinically suspected myopericarditis in the early stage of pregnancy who improved rapidly with pericardial drainage and prednisolone therapy, and successfully delivered a normal full-term infant; the diagnosis was made in the early stage of the disease, based on the detection of an abundance of eosinophils in the pericardial effusion preceding the subsequent development of peripheral blood eosinophilia.

Precise analysis of the autofluorescence characteristics of rat colon under UVA and violet light excitation.

PURPOSE: Tissue autofluorescence study is a promising means of endoscopic detection of colonic neoplasia, but the mechanism of autofluorescence eruption has still not been verified. The purpose of this study was to precisely analyze the autofluorescence characteristics of freshly prepared normal rat colon under UVA and violet light excitation. METHODS: Excised rat colons were studied by using multichannel spectrophotometry, spectroscopic imaging, confocal microscopy, combined two-photon excited fluorescence and second-harmonic generation (SHG) microscopy, and fluorescence lifetime imaging microscopy. RESULTS: Spectroscopic analysis of freshly prepared colon sections revealed that the mucosa and the submucosa showed strong autofluorescence under UVA and violet light excitation. The combined images of two-photon and SHG microscopy revealed that the mucosal epithelia are the important source of autofluorescence. Nicotinamide adenine dinucleotide seems to be one of the major substances involved in the autofluorescence of the mucosal layer on 365- nm light excitation. The autofluorescence spectra of the luminal surfaces were identical to those of the mucosa on crosssectional examinations with 365-nm excitation. The main origin of autofluorescence of the luminal surface with 365-nm excitation is the epithelial cells in the mucosa without overlay of submucosal fluorescence. CONCLUSIONS: The mucosal layer is the important source of the autofluorescence observed under excitation with UVA/violet light in multilayered colonic structures. Illumination of 365-nm wavelength light is a suitable means of analyzing the autofluorescence of mucosal epithelia.

Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure.

OBJECTIVES: This study was designed to determine the prognostic importance of left ventricular (LV) myocardial stiffness, a hemodynamic index which is closely related to B-type natriuretic peptide (BNP) concentration in patients with congestive heart failure (CHF). BACKGROUND: While elevated BNP, an abnormality of cardiac neurohormones, is known to be an independent marker of death or re-admission, it remains to be clarified whether there is also a strong predictor directly related to cardiac dysfunction. METHODS: LV performance variables and stress-strain analyses including diastolic myocardial stiffness constant (K(m)) were obtained from 37 patients with initial CHF by the combined simultaneous measurement of echocardiographic and hemodynamic data. Survivors were monitored for a mean of 23 months, with the main endpoint being combined death or first re-admission for CHF. RESULTS: Ten patients (27%) were primary endpoint cases. Both K(m) and plasma BNP levels were higher in the event than in the event-free group. By Cox proportional hazards analysis, K(m)≥4.0 was identified as the only variable with significant and independently incremental predictive power to affect the primary endpoint (adjusted hazard ratio=7.354, 95% confidence interval 1.379-39.232, p=0.02). CONCLUSIONS: In patients with CHF, increased myocardial stiffness may have greater prognostic significance compared to other conventional predictors. Increased myocardial stiffness may be considered to be an important prognostic factor independent of the loading conditions.

Increased myocardial contractility and enhanced exercise function in transgenic mice overexpressing either adenylyl cyclase 5 or 8.

OBJECTIVE: ss-adrenergic receptors (ssARs) are powerful regulators of cardiac function in vivo, activating heterotrimeric G proteins and the effector molecule adenylyl cyclase (AC). Interestingly, cardiac-specific overexpression of different AC isoforms leads to variable changes in cardiac function. Whether AC overexpression affects intrinsic cardiac contractility in an isoform-specific fashion determining a change in exercise capacity is currently unknown. METHODS: To address this issue, we performed load-independent measurements of cardiac systolic and diastolic function by pressure-volume (PV) loop analysis in intact wild-type mice (WT) and transgenic mice overexpressing the AC isoforms 5 or 8. RESULTS: Here we show that cardiac overexpression of either AC5 or AC8 transgenic mice determined an increase in intrinsic cardiac contractility. Interestingly, AC8 transgenic mice displayed a significantly greater increase in cardiac contractility and improved active phase of relaxation. Despite these differences detected by PV loop analysis, both AC5 and AC8 mice showed a marked increase in exercise capacity on treadmill testing. CONCLUSIONS: Our results demonstrate that load-independent measurements of cardiac function are needed to compare different groups of genetically-modified mouse models and to detect subtle AC isoform-specific changes in cardiac performance.

Sumatriptan provokes coronary artery spasm in patients with variant angina: possible involvement of serotonin 1B receptor.

BACKGROUND: Serotonin (5HT) can induce coronary artery spasm (CAS) in patients with variant angina (VA). We have previously reported that 5HT(1B) and 5HT(2A) receptors gene were expressed in human coronary arterial smooth muscle cells and that isolated coronary artery from a patient with VA showed the supersensitivity to sumatriptan (SMT), a 5HT(1B/1D) receptor agonist. The aim of the present study was to determine whether SMT can provoke CAS directly or indirectly through platelet aggregation in patients with VA. METHODS: We evaluated the effects of intracoronary infusion of graded concentrations of SMT on coronary arteries in 9 patients, including 5 documented VA and 4 participants with atypical chest pain as control. RESULTS: SMT provoked CAS in all patients with VA. SMT could not induce CAS in control. SMT (10(-4) M) caused significant contractions (%diameter of baseline; median [interquartile range], 0 [0-18.4]% in VA, as compared with control (proximal segments; 92.6 [77.9-118.9]%, p<0.05 vs. VA, distal segments; 92.9 [65.3-158.5]%, p<0.01 vs. VA). In control, minor dilation occurred at SMT concentration up to 10(-5) M. SMT could induce in vitro platelet aggregation neither in healthy subjects nor in patients with VA. CONCLUSIONS: These findings suggest that activation of 5HT(1B) receptor by SMT can induce CAS directly in patients with VA without platelet activation. This is the first report directly demonstrating the effect of 5HT(1B) receptor activation on human coronary arteries in vivo.

Inhibition of endogenous nitric oxide synthase augments contractile response to adenylyl cyclase stimulation without altering mechanical efficiency in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Increased nitric oxide (NO) in the failing heart attenuates the myocardial contractile response to beta-adrenergic receptor stimulation. However, the physiological effects of NO on the beta-adrenergic post-receptor signaling system are unknown. The objective of the present study was to examine the effects of cardiac NO synthase (NOS) inhibition on left ventricular (LV) hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation in human heart failure. METHODS AND RESULTS: The study group comprised 13 patients with heart failure because of idiopathic cardiomyopathy (IDC). Emax was examined as an index of LV contractility, LV external work (EW), pressure-volume area (PVA), myocardial oxygen consumption (MVO2), and mechanical efficiency (EW/MVO2) with the use of conductance and coronary sinus thermodilution catheters before and during colforsin daropate infusion, and during concurrent infusion of colforsin daropate with the NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA; 200 micromol). Colforsin daropate increased Emax by 53% and EW by 18%, and reduced PVA by 14%, without altering MVO2 or mechanical efficiency. The combination of colforsin daropate with L-NMMA further increased Emax by 26% and reduced PVA by 9%, without altering MVO2 or mechanical efficiency. CONCLUSIONS: These findings suggest endogenous NO may modulate beta-adrenergic post-receptor pathways and preserve myocardial efficiency in patients with IDC.

JNK1 is required to preserve cardiac function in the early response to pressure overload.

Cardiac stress consistently activates c-Jun NH(2)-terminal kinase (JNK) pathways, however the role of different members of the JNK family is unclear. In this study, we applied pressure overload (TAC) in mice with selective deletion of the three JNK genes (Jnk1(-/-), Jnk2(-/-), and Jnk3(-/-)). Following TAC, all three JNK knockout mouse lines developed cardiac hypertrophy similar to wild-type mice (WT), but only JNK1(-/-) mice displayed a significant reduction in fractional shortening after 3 and 7 days of pressure overload, associated with a significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and marked inflammatory infiltrate. After the acute deterioration stage, JNK1(-/-) mice underwent a slow recovery followed by a steady progression of cardiac dysfunction, becoming indistinguishable from WT after 12 weeks of TAC. These data suggest that JNK1 plays a protective role in response to pressure overload, preventing the early deterioration in cardiac function following an acute increase in afterload.

Myocardial stiffness is an important determinant of the plasma brain natriuretic peptide concentration in patients with both diastolic and systolic heart failure.

AIMS: Plasma brain natriuretic peptide (BNP) concentration increases in proportion to heart failure (HF) severity. Although plasma BNP decreases to a certain level by optimal treatment, there is significant heterogeneity in the baseline value among individuals. The underlying mechanism of the steady-state plasma BNP levels remains still controversial. We investigated the hypothesis that myocardial stiffness (K(m)) is a major determinant of the plasma BNP level. METHODS AND RESULTS: In 19 patients with diastolic HF [DHF; left ventricular ejection fraction (LVEF) > or =4 5%], 18 with systolic HF (SHF; LVEF < 45%), and 12 controls, left ventricular (LV) performance variables and the results of the stress-strain analyses were obtained by the combined simultaneous measurement of echocardiographic and haemodynamic data, and compared with the plasma BNP level. In DHF, a significant correlation was observed between plasma BNP and fractional shortening (P = 0.010), pulmonary capillary wedge pressure (P = 0.030), end-diastolic pressure (P = 0.006), time constant of the LV isovolumic-pressure decline (P = 0.049), end-diastolic stress (P = 0.012), and K(m) (P = 0.004), respectively. In SHF, a significant correlation was observed between plasma BNP and end-diastolic stress (P = 0.036), chamber stiffness (P = 0.048), and K(m) (P = 0.003), respectively. CONCLUSION: In stable conditions, K(m) may be the most important determinant of the plasma BNP production in patients with both DHF and SHF.

Pathophysiological characteristics and responsiveness to neurohormonal antagonism in idiopathic dilated cardiomyopathy patients with antihepatitis C virus antibody.

A high prevalence of hepatitis C virus (HCV) infection has been reported among idiopathic dilated cardiomyopathy (DCM) patients. We examined the prevalence of DCM patients with HCV antibody, and the pathophysiological characteristics and responsiveness to neurohormonal antagonism in DCM with HCV. HCV antibodies were determined in 540 patients with cardiac diseases. In 117 DCM patients, clinicopathologic data were evaluated before and 1 year after angiotensin converting enzyme inhibitor and/or beta-blocker (ACE-inhibitor/BB) administration and their prognosis was followed-up for a mean of 72 +/- 41 months. HCV antibodies were found in 12 of 135 DCM patients (8.9%) and in 37 of 405 patients without DCM (9.1%) (P = NS). At baseline, contrary to DCM without HCV, DCM with HCV was associated (P < 0.05) with greater left ventricular (LV) end-diastolic and end-systolic dimension, LV mass, and myocardial diameter in endomyocardial biopsy, and lower % fractional shortening. By multivariate analysis, HCV infection was independently associated with larger LV end-systolic dimension among DCM patients (P = 0.005). The advanced LV dilatation and hypertrophy in DCM with HCV decreased more in response to the ACE-inhibitor/BB therapy compared to DCM without HCV. There were no differences between DCM patients with and without HCV in survival and cardiac event-free rates. In summary, although HCV infection appears not to be the specific cause of DCM, HCV may enhance ventricular remodeling leading to heart failure among DCM patients. Nevertheless, the advanced ventricular remodeling with HCV was adequately reversed by neurohormonal antagonism, and did not lead to an unfavorable outcome.