Functional Effects of Endogenous Bradykinin in Congestive Heart Failure

AbstractObjectives. The purpose of this study was to determine the level and functional effects of endogenous bradykinin in congestive heart failure (CHF).Background. There is experimental evidence that bradykinin is increased in several cardiac disease states. However, it is unknown whether plasma levels of bradykinin are elevated in CHF. Further, the cardiac and vascular responses to bradykinin in CHF are unclear.Methods. The circulating levels of bradykinin and the effects of endogenous bradykinin were assessed in eight instrumented, conscious dogs both before and after pacing-induced CHF.Results. Before CHF, the plasma bradykinin level was 53.1 ± 12.4 pg/ml. Blocking endogenous bradykinin with HOE-140 (0.3 mg/kg), a specific bradykinin B2-receptor antagonist, produced no significant alterations in heart rate, left ventricular (LV) end-systolic pressure (Pes), total systemic resistance (TSR), the time constant of LV relaxation (tau) or the maximal rate of LV filling (dV/dtmax). However, coronary blood flow was significantly reduced (p < 0.05). LV contractile performance measured by the slopes of pressure–volume relations was unaffected. After induction of CHF, the plasma bradykinin level increased to 234.2 ± 19.4 pg/ml (p < 0.05). Blocking endogenous bradykinin with HOE-140 reduced coronary blood flow and produced significant increases in Pesand TSR, prolonged tau, decreased dV/dtmaxand elevated minimal LV pressure and mean left atrial pressure. Furthermore, the slopes of pressure–volume relations (p < 0.05) were decreased, indicating depressed contractility with HOE-140 after CHF.Conclusions. Before CHF, endogenous bradykinin results in coronary dilation but has no effect on systemic arterial vasodilation or cardiac performance. After CHF, endogenous bradykinin is significantly increased and, acting through B2-receptors, produces coronary and arterial vasodilation and improves LV relaxation and contractile performance. Thus, endogenous bradykinin may play an important role in preserving cardiovascular function in CHF

Prognostic Value of Left Ventricular Diastolic Dysfunction in Patients Undergoing Cardiac Catheterization for Coronary Artery Disease

We hypothesized that left ventricular (LV) diastolic dysfunction assessed by cardiac catheterization may be associated with increased risk for cardiovascular events. To test the hypothesis, we assessed diastolic function by cardiac catheterization (relaxation time constant (Tau) and end-diastolic pressure (EDP)) as well as Doppler echocardiography (early diastolic mitral annular velocity (e′) and a ratio of early diastolic mitral inflow to annular velocities (E/e′)) in 222 consecutive patients undergoing cardiac catheterization for coronary artery disease (CAD). During a followup of 1364 ± 628 days, 5 cardiac deaths and 20 unscheduled cardiovascular hospitalizations were observed. Among LV diastolic function indices, Tau > 48 ms and e′ < 5.8 cm/s were each significantly associated with lower rate of survival free of cardiovascular hospitalization. Even after adjustment for potential confounders (traditional cardiovascular risk factors, the severity of CAD, and cardiovascular medications), the predictive value of Tau > 48 ms and e′ < 5.8 cm/s remained significant. No predictive value was observed in EDP, E/e′, or LV ejection fraction. In conclusion, LV diastolic dysfunction, particularly impaired LV relaxation assessed by both cardiac catheterization and Doppler echocardiography, is independently associated with increased risk for cardiac death or cardiovascular hospitalization in patients with known or suspected CAD

Dietary Salt Intake is a Significant Determinant of Impaired Kidney Function in the General Population

Background/Aims: Kidney dysfunction is an important risk factor for cardiovascular disease and end-stage renal disease. This study investigated whether dietary salt intake predicts deterioration of kidney function in the general population. Methods: In all, 12 126 subjects with a normal estimated glomerular filtration rate (eGFR ≥60 mL/min per 1.73m2) attending an annual check-up were enrolled in the study and were followed-up for a median of 1754 days; the endpoint was the development of impaired kidney function (eGFR &#x3c; 60 mL/min per 1.73m2). Individual salt intake was estimated using spot urine analysis. Results: At baseline, mean (± SD) salt intake and eGFR were 10.6 ± 3.4 g/day and 80.8 ± 12.9 mL/min per 1.73m2, respectively. During the follow-up period, 1384 subjects (25.2 per 1000 person-years) developed impaired kidney function. Multivariate Cox hazard regression analysis revealed salt intake as a significant predictor of the new onset of kidney impairment (hazard ratio 1.045; 95% confidence interval 1.025–1.065). Subjects were divided into two groups based on salt intake; the incidence of impaired kidney function was higher in the group with high than low salt intake (P &#x3c; 0.001, log-rank test). Multivariate Cox hazard regression analysis indicated a 29% increased risk of developing impaired kidney function in the high-salt group. Multivariate linear regression analysis showed a significant correlation between salt intake and yearly decline in eGFR (β = 0.060, P &#x3c; 0.001). Conclusion: Salt intake is associated with the development of impaired kidney function in the general population, independent of its effects on blood pressure. Salt restriction may help prevent the development of impaired kidney function

Pulmonary venous occlusion and death in pulmonary arterial hypertension: survival analyses using radiographic surrogates

BACKGROUND: Recent studies find that a considerable number of patients with pulmonary arterial hypertension (PAH) develop fibrous obstruction of the pulmonary veins. Such obstruction more commonly accompanies connective tissue disorder (CTD)-associated PAH than idiopathic PAH. However, few researchers have gauged the risk of death involving obstruction of the pulmonary veins. METHODS: Thirty-seven patients with PAH were enrolled (18 patients, idiopathic PAH; 19 patients, CTD-associated PAH). The patients were 49 ± 18 years and had a World Health Organization functional class of 3.2 ± 0.6. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were surrogates for obstruction of the pulmonary veins, and were detected by a 16-row multidetector computed tomography scanner. RESULTS: The follow-up period was 714 ± 552 days. Fifteen deaths occurred. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were found in 37.8%, 24.3%, and 16.2% of patients, respectively. Cox proportional hazard analysis revealed an increased risk of death with each radiographic surrogate (mediastinal adenopathy: p < 0.0001, hazard ratio = 13.9; thickening of interlobular septa: p < 0.001, hazard ratio = 12.0; ground-glass attenuation: p = 0.02, hazard ratio = 3.7). The statistical significance of these relationships was independent of the cause of PAH and plasma concentration of brain natriuretic peptide. CONCLUSIONS: The results of this study imply that obstruction of the pulmonary veins is associated with an increased risk of death in patients with PAH

Comparison of Hemorrhagic Risk between Prasugrel and Clopidogrel : a Retrospective Study using Adverse Drug Event Reporting Databases

Background: Prasugrel inhibits platelet aggregation more potently and exerts therapeutic action faster than clopidogrel. In the global phase III trial conducted in Western and South American countries that excluded Asian countries, prasugrel reduced ischemic events but increased hemorrhagic risk compared with clopidogrel in patients with acute coronary syndrome scheduled for percutaneous coronary intervention. In the Japanese phase III trial for similar patients, the efficacy of prasugrel compared with clopidogrel was comparable to the global trial, but the safety could not be confirmed because of an insufficient number of patients. Furthermore, given the strict enrollment criteria, the results of these trials may not be applicable to routine clinical practice. Accordingly, we compared the hemorrhagic risk of prasugrel and clopidogrel in real-world settings by analyzing adverse drug event reports in post-marketing stages provided by the Japanese regulatory authorities and the U.S. Food and Drug Administration (FDA). Methods: We analyzed a total of 3,970 reports for prasugrel (n = 518) or clopidogrel (n = 3,452) between 2014 and 2017 in the Japanese Adverse Drug Event Report (JADER) and a total of 91,914 reports for either prasugrel (n = 5,992) or clopidogrel (n = 85,922) between 2009 and 2019 in the FDA Adverse Event Reporting System (FAERS). Results: In JADER and FAERS, prasugrel was more frequently and significantly associated with hemorrhagic event reports than clopidogrel. After adjustment for known confounders including age, sex, and concomitant medications (aspirin, anticoagulants, and proton pump inhibitors), the hemorrhagic risk of prasugrel compared with clopidogrel remained significant (adjusted reporting odds ratios [95% CI] for total, intracranial, and gastrointestinal hemorrhagic events = 2.42 [1.97-2.96], 2.45 [1.85-3.24], and 2.27 [1.73-2.97] in JADER, and 2.21 [2.09-2.34], 1.21 [1.09-1.33], and 1.41 [1.29-1.54] in FAERS). Conclusions: The hemorrhagic risk was found to be greater with prasugrel than clopidogrel in real-world patients, including Japanese patients

Effects of atrial natriuretic peptide on left ventricular performance in conscious dogs before and after pacinginduced heart failure.

ABSTRACT Atrial natriuretic peptide (ANP) has potent vasodilatory and natriuretic actions and may have therapeutic benefit in congestive heart failure (CHF). These benefits may be offset by a negative inotropic effect of ANP seen in isolated preparations. However, ANP&apos;s integrated effect on left ventricular (LV) contraction and relaxation, independent of loading conditions, both under normal conditions and after CHF, is not known. We studied six conscious dogs, instrumented to measure LV and left atrial pressures and to determine LV volume from three dimensions. ANP produced significant (P Ͻ .05) decreases in LV end-systolic pressure (101.2 Ϯ 11.8 versus 91.7 Ϯ 11.2 mm Hg, P Ͻ .05) in normal dogs and in dogs with CHF (93.1 Ϯ 6.4 versus 87.1 Ϯ 4.4 mm Hg, P Ͻ .05). ANP also caused significant reductions of the slope of end-systolic pressure-end-systolic volume relation both before (7.0 Ϯ 1.5 versus 6.3 Ϯ 1.5 mm Hg/ml) and after CHF (4.8 Ϯ 1.3 versus 4.4 Ϯ 1.2 mm Hg/ml, P Ͻ .05). Both before and after CHF, ANP slowed LV relaxation at matched end-systolic pressure. Before CHF, steady-state stroke volume and peak LV filling rate (dV/dt max ) were reduced. However, after CHF, the fall in end-systolic pressure more than offset the load-independent LV depression, as stroke volume, the rate LV relaxation, and dV/dt max were increased and minimum LV pressure reduced. ANP has negative effects on LV contractility and relaxation both before and after CHF. However, after CHF, afterload reduction with ANP overcomes its negative effects, resulting in net improvement of LV ejection and relaxation. Thus, the direct cardiodepressant effects of ANP should not limit its usefulness in CHF. Atrial natriuretic peptide (ANP) is a vasodilatory and natriuretic peptide secreted mainly by atrial myocytes ANP produces vasodilation and natriuresis in both the normal circulation and in CHF Materials and Methods Instrumentation. Six healthy, adult, heartworm-negative mongrel dogs (weight, 25-36 kg) were instrumented under anesthesia after induction with xylazine (2 mg/kg i.m.) and sodium thiopental (

Lack of Inertia Force of Late Systolic Aortic Flow Is a Cause of Left Ventricular Isolated Diastolic Dysfunction in Patients With Coronary Artery Disease

ObjectivesWe investigated whether a lack of inertia force of late systolic aortic flow and/or apical asynergy provoke early diastolic dysfunction in patients with coronary artery disease (CAD).BackgroundLeft ventricular (LV) isolated diastolic dysfunction is a well-recognized cause of heart failure.MethodsWe evaluated LV apical wall motion and obtained left ventricular ejection fraction (LVEF) by left ventriculography in 101 patients who underwent cardiac catheterization to assess CAD. We also computed the LV relaxation time constant (Tp) and the inertia force of late systolic aortic flow from the LV pressure (P)–first derivative of left ventricular pressure (dP/dt) relation. Using color Doppler echocardiography, we measured the propagation velocity of LV early diastolic filling flow (Vp). Patients with LVEF ≥50% (preserved systolic function [PSF], n = 83) were divided into 2 subgroups: patients with inertia force (n = 53) and without inertia force (n = 30). No patient with systolic dysfunction (SDF) (LVEF <50%) had inertia force (n = 18).ResultsThe Tp was significantly longer in patients with SDF (85.7 ± 21.0 ms) and with PSF without inertia force (81.1 ± 23.6 ms) than in those with PSF with inertia force (66.3 ± 12.8 ms) (p< 0.001). The Vp was significantly less in the former 2 groups than in the last group. In patients with PSF, LV apical wall motion abnormality was less frequently observed in those with inertia force than in those without (p < 0.0001).ConclusionsAn absence of inertia force in patients with PSF is one of the causes of isolated diastolic dysfunction in patients with CAD. Normal LV apical wall motion is substantial enough to give inertia to late systolic aortic flow

Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure : a sub analysis of the CANDLE trial

Background: Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Methods: Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. Results: The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89–1.08) in the canagliflozin group and 1.07 (95% CI 0.97–1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82–1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e′) showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e′ < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66–1.04). Conclusions: In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction

Assessment of pulse rate variability by the method of pulse frequency demodulation

BACKGROUND: Due to its easy applicability, pulse wave has been proposed as a surrogate of electrocardiogram (ECG) for the analysis of heart rate variability (HRV). However, its smoother waveform precludes accurate measurement of pulse-to-pulse interval by fiducial-point algorithms. Here we report a pulse frequency demodulation (PFDM) technique as a method for extracting instantaneous pulse rate function directly from pulse wave signal and its usefulness for assessing pulse rate variability (PRV). METHODS: Simulated pulse wave signals with known pulse interval functions and actual pulse wave signals obtained from 30 subjects with a trans-dermal pulse wave device were analyzed by PFDM. The results were compared with heart rate and HRV assessed from simultaneously recorded ECG. RESULTS: Analysis of simulated data revealed that the PFDM faithfully demodulates source interval function with preserving the frequency characteristics of the function, even when the intervals fluctuate rapidly over a wide range and when the signals include fluctuations in pulse height and baseline. Analysis of actual data revealed that individual means of low and high frequency components of PRV showed good agreement with those of HRV (intraclass correlation coefficient, 0.997 and 0.981, respectively). CONCLUSION: The PFDM of pulse wave signal provides a reliable assessment of PRV. Given the popularity of pulse wave equipments, PFDM may open new ways to the studies of long-term assessment of cardiovascular variability and dynamics