Isosorbide dinitrate, with or without hydralazine, does not reduce wave reflections, left ventricular hypertrophy, or myocardial fibrosis in patients with heart failure with preserved ejection fraction

Background-Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. Methods and Results-We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mmHg/mL per second; P=0.003) and forward wave amplitude (P-f, mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mmHg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51], P=0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). Conclusions-ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction

Sublingual nitroglycerin in patients with heart failure and preserved ejection fraction: impact on central and regional carotid and radial input impedance and hemodynamics

Background: The systolic blood pressure lowering effect of sublingual nitroglycerin (NTG) administration is generally thought to primarily arise from its action on wave reflection, although recent invasive data indicate that at least part of the blood pressure reduction can be ascribed to an effect on left ventricular dynamics. Methods: Carotid and radial pressure waveforms and aortic, carotid and radial flow were measured in 19 HFpEF patients using applanation tonometry and pulsed Doppler ultrasound, respectively. Signals were time-aligned and global systemic as well as regional impedance and wave reflection analysis was applied. Results: NTG lowered carotid systolic (130.8±26 at baseline vs. 110.4±18.4mmHg after NTG, P<0.01) and mean (92.5±18.4 vs.85.4±14.3) blood pressure. Global systemic effects included a decrease in systemic vascular resistance (1.00±0.32 vs. 0.88±0.28 mmHg.ml-1.s, P<0.05), characteristic impedance (0.133±0.089 vs. 0.089±0.034 mmHg.ml-1.s, P<0.05) and an increase in total arterial compliance (1.20±0.58 vs. 1.52±0.53 ml.mmHg-1, P<0.01).NTG had a major impact on the amplitude of the forward pressure wave (58±24.3 vs. 40.6±13.3 mmHg, P<0.01), with no significant change in reflection magnitude. Regional analysis demonstrated a large effect of NTG on carotid input impedance, lowering impedance over the entire frequency spectrum, with radial artery input impedance did not demonstrate any significant changes (despite large effects on pressure and flow waveform morphology). Conclusions: Our data in HFpEF confirm the absence of impact of NTG on reflection magnitude, and demonstrate large effects of NTG on the input impedance of the cerebral vascular district, with little effect on the distal forearm circulation

Potential Antileptospiral Constituents from Phyllanthus amarus

Background: Phyllanthus amarus (PA) is a well-known herb for its medicinal properties and widely used worldwide. PA has a significant role in Indian Ayurveda system of medicine for treating various ailments such as gonorrhea, menorrhagia, and other genital infections. Objectives: The aim of the study is to investigate antileptospiral activity and isolate the potential antileptospiral constituents of the methanol extract of PA (MPA). Materials and Methods: The primary pharmacological tests for leptospirosis were investigated by test tube dilution technique and microdilution technique. To examine the morphogenesis of experimental leptospirosis by morphologic and histological methods, albino mice were inoculated intraperitoneally with Leptospira interrogans sero group Icterohaemorrhagiae strains. Results: The activity-guided repeated fractionation for MPA through silica gel column chromatography yielded three compounds that exhibited antioxidant and in vitro, in vivo, and in silico antileptospiral activities. Based on diverse physicochemical and spectroscopic analyses (viz., 13C NMR,1H NMR, ultraviolet UV], IR, and mass spectroscopy), the potential constituents were elucidated as 5-(3-(3,4-dimethoxybenzyl)-4-methoxy-2-(methoxymethyl)butyl)4,7- dimethoxybenzod] 1,3] dioxole(C1), 1-(3-( 3,4- dimethoxybenzyl)- 4-methoxy- 2-(methoxymethyl) butyl)- 2,3,4,5tetramethoxybenzene(C2), and 4-(3-(3,4dimethoxybenzyl)-4-methoxy-2-(methoxymethyl)butyl)-3,6-dimethox ybenzene-1,2-diol (C3). The histopathological examinations of both kidney and liver showed promising activity with C3 at 75 and 100 mu g/mL, respectively. Conclusion: The in vitro, in vivo, and in silico studies revealed that benzo methoxy class of compounds has great potential as antileptospiral agents

MRI assessment of diastolic and systolic intraventricular pressure gradients in heart failure

Background: Non-invasive assessment of left ventricular (LV) diastolic function is an important goal to better understand physiologic abnormalities in heart failure. The spatiotemporal pattern of LV blood flow velocities during early filling can be used to estimate intraventricular pressure gradients driving early filling. MRI can provide accurate flow velocity information in the LV, but this method has not been exploited to assess diastolic function in heart failure (HF). Aim: To assess differences in intraventricular pressure gradients in heart failure and preserved ejection fraction (HFPEF) and heart failure with reduced ejection fraction (HFREF), compared to subjects without HF. Methods: We studied 23 subjects without HF, 13 subjects with HFREF and 14 subjects with HFPEF. Intraventricular flow during diastole was measured using 2D in-plane phase-contrast MRI. We solved the Eulier equations to compute intraventricular pressure gradients during LV early filling (figure) and during ejection. Results: Whereas the initial velocity of wave propagation (was not significantly different between the groups, the terminal diastolic propagation velocity during early diastolic filling was significantly slower (P=0.004) in HFREF (5.2 m/s; 95%CI=3.9-6.8) than in patients with HFPEF (9.5; 95%CI=6.6-13.6) or subjects without HF (8.9; 95%CI=7.3-10.7). In contrast, HFPEF was associated with a greater amplitude of the reversal of the base-to-apex intraventricular pressure gradient during early filling (β=-0.34; P=0.04), which was driven by the inertial component. Conclusions: HFPEF and HFREF are associated with distinct patterns of intraventricular pressure gradient abnormalities during early diastolic filling. Our findings support fundamental differences in the nature of diastolic dysfunction in these 2 conditions