A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats.

To date, there is no established treatment for heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase-IV (DPP-IV) inhibitors reportedly have improved not only diabetes mellitus but also heart failure with systolic dysfunction in experimental models. We investigated the effects of a DPP-IV inhibitor on HFpEF in rats. Dahl salt-sensitive rats were fed either high-salt (high-salt diet (HSD): 8% NaCl) or low-salt diets (0.3% NaCl) from 6.5 weeks of age. They were then treated with or without a DPP-IV inhibitor, vildagliptin (10 mg/kg/day, orally), from 11 weeks of age for 9 weeks and analyzed at the age of 20 weeks. HSD rats mimicked the pathophysiology of HFpEF. There were no differences in heart rate, blood pressure, left ventricular (LV) systolic function, or the extent of LV hypertrophy between HSD rats with or without vildagliptin. However, vildagliptin decreased LV end-diastolic pressure, the most reliable hemodynamic parameter of HFpEF in HSD rats. Vildagliptin also decreased the LV distensibility index, a sensitive marker of LV diastolic function in HSD rats. Vildagliptin decreased the expression of collagen genes in HSD hearts and attenuated LV interstitial fibrosis (HSD with vehicle and vildagliptin, 2.9% vs. 1.9%; P < 0.05). Furthermore, vildagliptin administration reduced both plasma renin activity and aldosterone concentrations in HSD rats. A DPP-IV inhibitor, vildagliptin, improved the severity of LV fibrosis, and thus, diastolic dysfunction of HFpEF in Dahl salt-sensitive hypertensive rats. DPP-IV inhibitors are promising medicines for treatment of HFpEF in patients with diabetes mellitus.

AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs.

PURPOSE: Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective. METHOD: To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6 weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14 days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group). RESULTS: In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-ß1 expression and increases in AKT phosphorylation. CONCLUSIONS: IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.

Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts.

PURPOSE: Although nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) scavenge free radicals, their short half-life and considerable side effects such as systemic hypotension and bradycardia have limited their clinical application. Since a radical-containing nanoparticle (RNP) delivers nitroxyl radicals with a prolonged half-life specific to ischemic hearts, we investigated whether RNPs reduce infarct size without the occurrence of substantial side effects and whether nitric oxide (NO) contributes to the cardioprotective effects of RNPs. METHODS: The left anterior descending coronary arteries of dogs were occluded for 90 min, followed by reperfusion for 6 h. Either RNPs, micelles (not containing TEMPO) (control), or 4-hydroxy-TEMPO (TEMPOL) was injected into a systemic vein for 5 min before reperfusion. We evaluated the infarct size, myocardial apoptosis, plasma NO levels in coronary venous blood, and the RNP spectra using an electron paramagnetic resonance assay. RESULTS: RNPs reduced infarct size compared with the control group and TEMPOL group (19.5 ± 3.3 vs. 42.2 ± 3.7 vs. 30.2 ± 3.4%). RNPs also reduced myocardial apoptosis compared with the control and TEMPOL group. Coronary venous NO levels increased in the RNP group. CONCLUSIONS: In conclusion, the administration of 2,2,6,6-tetramethylpiperidine-1-oxyl as a RNP exerted cardioprotective effects against ischemia and reperfusion injury in canine hearts without exerting unfavorable hemodynamic effects. RNPs may represent a promising new therapy for patients with acute myocardial infarction.

Endogenously released adenosine causes pulmonary vasodilation during the acute phase of pulmonary embolization in dogs.

BACKGROUND: Endogenous adenosine levels increase under stress in various organs. Exogenously administered adenosine is a well-known pulmonary vasodilator. However, the physiology and therapeutic potential of endogenous adenosine during alteration in pulmonary hemodynamics such as pulmonary embolism is not elucidated. We hypothesized that the adenosine level increases following an acute elevation of pulmonary resistance, resulting in pulmonary vasodilation. METHODS: We induced acute pulmonary embolization by injecting plastic beads in anesthetized dogs. Plasma adenosine levels, defined as the product of plasma adenosine concentration and simultaneous cardiac output, were assessed from blood samples from the superior vena cava, main pulmonary artery (MPA), and ascending aorta 1 and 10 min following injection. Hemodynamics were assessed with (n = 3) and without (n = 8) administration of the adenosine receptor blocker, 8-(p-sulfophenyl)theophylline (8SPT). RESULTS: Mean pulmonary arterial pressure (PAP) increased from 11 ±â€¯1 mmHg, peaking at 28 ±â€¯4 mmHg at 52 ±â€¯13 s after injection. During this period, total pulmonary resistance (TPR) elevated from 11 ±â€¯1 to 33 ±â€¯6 Wood unit. Plasma adenosine levels increased in the MPA from 14.5 ±â€¯2 to 38.8 ±â€¯7 nmol/min 1 min after injection. TPR showed greater elevation under 8SPT treatment, to 96 ±â€¯12 Wood unit at PAP peak. CONCLUSIONS: Endogenously released adenosine after acute pulmonary embolization is one of the initial pulmonary vasodilators. The immediate surge in plasma adenosine levels in the MPA could lead to a hypothesis that adenosine is released by the right heart in response to pressure overload.

Unraveling the RV Ejection Doppler Envelope: Insight Into Pulmonary Artery Hemodynamics and Disease Severity.

OBJECTIVES: The purpose of this study was to characterize the profiles of right ventricular outflow tract (RVOT) Doppler flow velocity envelopes in patients with pulmonary arterial hypertension (PAH) and to establish whether changes in the RVOT flow profile related to patient outcome. BACKGROUND: The RVOT systolic flow profile is frequently abnormal, with findings of a mid-systolic flow deceleration and notching, previously proposed as an indicator of elevated pulmonary vascular resistance (PVR). METHODS: We reviewed RVOT systolic flow profiles recorded by pulsed-wave Doppler from 159 consecutive patients with PAH and measured deceleration time (DT) of mid-systolic deceleration slope (mid-systolic DT) and the peak velocity of pre- and post-notching flow. Concurrent right-heart catheterization was available in all (41 of 41) incident patients and in 39 of 118 established patients. Outcomes, defined as time to all-cause mortality or need for lung transplantation, were assessed during 3 years of follow-up. RESULTS: Notched envelopes were identified in 150 of 159 patients. The presence of a notched pattern and a decrease in the mid-systolic DT were associated with higher PA pressures; higher PVR; and, at a threshold of a mid-systolic DT of <120 ms, worse outcome. Those patients with a shorter DT were further subdivided based on the post-notch systolic flow velocity. In these patients, a decline in the post-notch flow velocity to <62% of the pre-notch flow velocity defined a cohort with a marked reduction in systolic function and the worst outcome. CONCLUSIONS: In PAH, the notched profile of RVOT Doppler flow velocity envelope appears to integrate indicators of pulmonary vascular load and RV function and serves as a marker for adverse outcomes.