Abstract Activation of the sympathetic nervous system is observed in pulmonary arterial hypertension patients. This study investigates whether inhibiting the conversion of dopamine into noradrenaline by dopamine β ‐hydroxylase (D β H) inhibition with BIA 21‐5337 improved right ventricular (RV) function or remodeling in pressure overload‐induced RV failure. RV failure was induced in male Wistar rats by pulmonary trunk banding (PTB). Two weeks after the procedure, PTB rats were randomized to vehicle ( n = 8) or BIA 21‐5337 ( n = 11) treatment. An additional PTB group treated with ivabradine ( n = 11) was included to control for the potential heart rate‐reducing effects of BIA 21‐5337. A sham group ( n = 6) received vehicle treatment. After 5 weeks of treatment, RV function was assessed by echocardiography, magnetic resonance imaging, and invasive pressure–volume measurements before rats were euthanized. RV myocardium was analyzed to evaluate RV remodeling. PTB caused a fourfold increase in RV afterload which led to RV dysfunction, remodeling, and failure. Treatment with BIA 21‐5337 reduced adrenal gland D β H activity and 24‐h urinary noradrenaline levels confirming relevant physiological response to the treatment. At end‐of‐study, there were no differences in RV function or RV remodeling between BIA 21‐5337 and vehicle‐treated rats. In conclusion, treatment with BIA 21‐5337 did not have any beneficial—nor adverse—effects on the development of RV failure after PTB despite reduced adrenal gland D β H activity.
BACKGROUND: Surgical removal of thromboembolic material by pulmonary endarterectomy (PEA) leads within months to the improvement of right ventricular (RV) function in the majority of patients with chronic thromboembolic pulmonary hypertension. However, RV mass does not always normalize. It is unknown whether incomplete reversal of RV remodeling results from extracellular matrix expansion (diffuse interstitial fibrosis) or cellular hypertrophy, and whether residual RV remodeling relates to altered diastolic function. METHODS: We prospectively included 25 patients with chronic thromboembolic pulmonary hypertension treated with PEA. Structured follow-up measurements were performed before, and 6 and 18 months after PEA. With single beat pressure-volume loop analyses, we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV–arterial coupling (Ees/Ea), and RV end-diastolic elastance (stiffness, Eed). The extracellular volume fraction of the RV free wall was measured by cardiac magnetic resonance imaging and used to separate the myocardium into cellular and matrix volume. Circulating collagen biomarkers were analyzed to determine the contribution of collagen metabolism. RESULTS: RV mass significantly decreased from 43±15 to 27±11g/m 2 (−15.9 g/m 2 [95% CI, −21.4 to –10.5]; P <0.0001) 6 months after PEA but did not normalize (28±9 versus 22±6 g/m 2 in healthy controls [95% CI, 2.1 to 9.8]; P <0.01). On the contrary, Eed normalized after PEA. Extracellular volume fraction in the right ventricular free wall increased after PEA from 31.0±3.8 to 33.6±3.5% (3.6% [95% CI, 1.2–6.1]; P =0.013) as a result of a larger reduction in cellular volume than in matrix volume ( P interaction =0.0013). Levels of MMP-1 (matrix metalloproteinase-1), TIMP-1 (tissue inhibitor of metalloproteinase-1), and TGF-β (transforming growth factor-β) were elevated at baseline and remained elevated post-PEA. CONCLUSIONS: Although cellular hypertrophy regresses and diastolic stiffness normalizes after PEA, a relative increase in extracellular volume remains. Incomplete regression of diffuse RV interstitial fibrosis after PEA is accompanied by elevated levels of circulating collagen biomarkers, suggestive of active collagen turnover.
Adults with congenital heart disease represent a rapidly growing patient group. Dysfunction of the right ventricle is often present, and right heart failure constitutes the main cause of death. Heart failure therapies used in acquired left heart failure are often initiated in adults with right heart failure due to congenital heart disease, but the right ventricle differs substantially from the left ventricle, and the clinical evidence for this treatment strategy is lacking. In this review, we identified existing clinical studies evaluating the effects of ACE inhibitors, angiotensin II receptor blockers and aldosterone antagonists in adults with congenital heart disease by a systematic literature search. From 13 identified studies no clear evidence of beneficial effects was found, but the design of the studies limits the validity of the results. The studies in general include low numbers of patients, have short follow-up periods and evaluate surrogate endpoints instead of hard clinical endpoints. Specific evaluation of symptomatic patients with a systemic right ventricle indicates that these patients may benefit from RAAS inhibitory treatments, but this requires further investigation. To conclude, existing studies do not support the use of RAAS inhibitory treatments in right heart failure due to congenital heart disease but contain important limitations. Hence, there is a need for new well-designed trials including higher numbers of patients and validated endpoints to optimize and guide future treatment of this patient group.
OBJECTIVE High-heat cooking of food induces the formation of advanced glycation end products (AGEs), which are thought to impair glucose metabolism in type 2 diabetic patients. High intake of fructose might additionally affect endogenous formation of AGEs. This parallel intervention study investigated whether the addition of fructose or cooking methods influencing the AGE content of food affect insulin sensitivity in overweight individuals. RESEARCH DESIGN AND METHODS Seventy-four overweight women were randomized to follow either a high- or low-AGE diet for 4 weeks, together with consumption of either fructose or glucose drinks. Glucose and insulin concentrations-after fasting and 2 h after an oral glucose tolerance test-were measured before and after the intervention. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity index were calculated. Dietary and urinary AGE concentrations were measured (liquid chromatography tandem mass spectrometry) to estimate AGE intake and excretion. RESULTS When adjusted for changes in anthropometric measures during the intervention, the low-AGE diet decreased urinary AGEs, fasting insulin concentrations, and HOMA-IR, compared with the high-AGE diet. Addition of fructose did not affect any outcomes. CONCLUSIONS Diets with high AGE content may increase the development of insulin resistance. AGEs can be reduced by modulation of cooking methods but is unaffected by moderate fructose intake.
Abstract: Right heart failure may be the ultimate cause of death in patients with acute or chronic pulmonary hypertension (PH). As PH is often secondary to other cardiovascular diseases, the treatment goal is to target the underlying disease. We do however know, that right heart failure is an independent risk factor, and therefore, treatments that improve right heart function may improve morbidity and mortality in patients with PH. There are no therapies that directly target and support the failing right heart and translation from therapies that improve left heart failure have been unsuccessful, with the exception of mineralocorticoid receptor antagonists. To understand the underlying pathophysiology of right heart failure and to aid in the development of new treatments we need solid animal models that mimic the pathophysiology of human disease. There are several available animal models of acute and chronic PH. They range from flow induced to pressure overload induced right heart failure and have been introduced in both small and large animals. When initiating new pre-clinical or basic research studies it is key to choose the right animal model to ensure successful translation to the clinical setting. Selecting the right animal model for the right study is hence important, but may be difficult due to the plethora of different models and local availability. In this review we provide an overview of the available animal models of acute and chronic right heart failure and discuss the strengths and limitations of the different models.
