Myo-inositol trispyrophosphate prevents right ventricular failure and improves survival in monocrotaline-induced pulmonary hypertension in the rat.

BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, and eventually to RV failure. Hypoxia can trigger both pulmonary vasculopathy and RV failure. Therefore, we tested if myo-inositol trispyrophosphate (ITPP), which facilitates oxygen dissociation from haemoglobin, can relieve pulmonary vasculopathy and RV hypoxia, and eventually prevent RV failure and mortality in the rat model of monocrotaline-induced PH. EXPERIMENTAL APPROACH: Rats were injected with monocrotaline (PH) or saline (control) and received ITPP or placebo for 5 weeks. Serial echocardiograms were obtained to monitor the disease, pressure-volume loops were recorded and evaluated, myocardial pO2 was measured using a fluorescent probe, and histological and molecular analyses were conducted at the conclusion of the experiment. KEY RESULTS AND CONCLUSIONS: ITPP reduced PH-related mortality. It had no effect on progressive increase in pulmonary vascular resistance, yet significantly relieved intramyocardial RV hypoxia, which was associated with improvement of RV function and reduction of RV wall stress. ITPP also tended to prevent increased hypoxia inducible factor-1α expression in RV cardiac myocytes but did not affect RV capillary density. IMPLICATIONS: Our study suggests that strategies aimed at increasing oxygen delivery to hypoxic RV in PH could potentially be used as adjuncts to other therapies that target pulmonary vessels, thus increasing the ability of the RV to withstand increased afterload and reducing mortality. ITPP may be one such potential therapy.

Methods of Protection of Electrochemical Sensors against Biofouling in Cell Culture Applications.

In this work, we evaluated more than 10 antifouling layers presenting different modes of action for application in electrochemical sensors. These layers included porous materials, permselective membranes, hydrogels, silicate sol-gels, proteins, and sp3 hybridized carbon. To evaluate the protective effects of the antifouling modification as well as its impact on the catalyst, we adsorbed a redox mediator on the electrode surface. Five of the tested coatings allowed us to preserve the electrochemical properties of the tested mediator. Later studies showed that sol-gel silicate layer, poly-l-lactic acid, and poly(l-lysine)-g-poly(ethylene glycol) were the only ones capable of sustaining the catalyst's performance during prolonged incubation in a cell culture medium. The highest signal deterioration was observed, as expected during the first few hours of incubation in a cell culture environment. Tested layers exhibited different dynamics of the protective effect. The poly-l-lactic acid layer presented lower changes in the first hours of the study but suffered complete signal deterioration after 72 h. Whereas the signal intensity of the silicate layer was lowered by half after just 3 h but was still visible after 6 weeks of constant incubation of the electrode in the cell culture.

Role of Oxygen Starvation in Right Ventricular Decompensation and Failure in Pulmonary Arterial Hypertension.

Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.

Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate.

Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO2) in PH are lacking. We hypothesized that RV hypoxia occurs in monocrotaline-induced PH in rats and that myo-inositol trispyrophosphate (ITPP), facilitating oxygen dissociation from hemoglobin, can relieve it. Rats received monocrotaline (PH) or saline (control) and 24 days later echocardiograms, pressure-volume loops were obtained and myocardial pO2 was measured using a fluorescent probe. In PH mean pulmonary artery pressure more than doubled (35 ± 5 vs. 15 ± 2 in control), RV was hypertrophied, though its contractility was augmented. RV and LV pO2 was 32 ± 5 and 15 ± 8 mmHg, respectively, in control rats. In PH RV pO2 was reduced to 18 ± 9 mmHg, while LV pO2 was unchanged. RV pO2 correlated with RV diastolic wall stress (negatively) and LV systolic pressure (positively). Acute ITPP administration did not affect RV or LV pO2 in control animals, but increased RV pO2 to 26 ± 5 mmHg without affecting LV pO2 in PH. RV oxygen balance is impaired in PH and as such can be an important target for PH therapy. ITPP may be one of such potential therapies.

Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?

Cardiac arrhythmias are a major source of mortality and morbidity. Unfortunately, their treatment remains suboptimal. Major classes of antiarrhythmic drugs pose a significant risk of proarrhythmia, and their side effects often outweigh their benefits. Therefore, implantable devices remain the only truly effective antiarrhythmic therapy, and new strategies of antiarrhythmic treatment are required. Ivabradine is a selective heart rate-reducing agent, an inhibitor of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, currently approved for treatment of coronary artery disease and chronic heart failure. In this review, we focus on the clinical and basic science evidence for the antiarrhythmic and proarrhythmic effects of ivabradine. We attempt to dissect the mechanisms behind the effects of ivabradine and indicate the focus of future studies.