Current pathophysiological concepts and management of pulmonary hypertension

Pulmonary hypertension (PH), increasingly recognized as a major health burden, remains underdiagnosed due mainly to the unspecific symptoms. Pulmonary arterial hypertension (PAH) has been extensively investigated. Pathophysiological knowledge derives mostly from experimental models. Paradoxically, common non-PAH PH forms remain largely unexplored. Drugs targeting lung vascular tonus became available during the last two decades, notwithstanding the disease progresses in many patients. The aim of this review is to summarize recent advances in epidemiology, pathophysiology and management with particular focus on associated myocardial and systemic compromise and experimental therapeutic possibilities. PAH, currently viewed as a panvasculopathy, is due to a crosstalk between endothelial and smooth muscle cells, inflammatory activation and altered subcellular pathways. Cardiac cachexia and right ventricular compromise are fundamental determinants of PH prognosis. Combined vasodilator therapy is already mainstay for refractory cases, but drugs directed at these new pathophysiological pathways may constitute a significant advance

Activation profile of pro-inflammatory cytokines in acute cardiac overload

INTRODUCTION:Pro-inflammatory cytokines have been implicated in ventricular remodeling during heart failure progression. In the present study, we investigated the effects of acute volume and RV pressure overload on biventricular hemodynamics and myocardial gene expression of IL-6 and TNF-alpha.METHODS:Male Wistar rats (n = 45) instrumented with RV and LV tip micromanometers were randomly assigned to one of three protocols: i) acute RV pressure overload (PrOv) induced by pulmonary trunk banding in order to double RV peak systolic pressure, for 120 or 360 min; ii) acute volume overload (VolOv) induced by dextran40 infusion (5 ml/h), for 120 or 360 min; iii) Sham. Free wall samples from the RV and LV were collected for mRNA quantification.RESULTS:In the RV, acute overload induced IL-6 and TNF-alpha gene expression, higher in VolOv (IL-6: + 669.7 +/- 263.4%; TNF-alpha: + 5149.9 +/- 1099.0%; 360 min) than in PrOv (IL-6: + 64.9 +/- 44.2%; TNF-alpha: + 628.1 +/- 229.3%; 360 min). In PrOv, TNF-alpha mRNA levels in the LV were increased, in the absence of ventricular overload. IL-6 and TNF-alpha mRNA levels did not correlate in the LV, while in the RV a positive correlation was found (r = 0.574; p < 0.001).CONCLUSIONS:Acute cardiac overload induces overexpression of pro-inflammatory cytokines. This gene activation is not uniform, being higher in volume overload and involving both load-dependent and load-independent mechanisms

Diastolic tolerance to systolic pressures closely reflects systolic performance in patients with coronary heart disease

In animal experiments, elevating systolic pressures induces diastolic dysfunction and may contribute to congestion, a finding not yet translated to humans. Coronary surgery patients (63 ± 8 years) were studied with left ventricular (LV) pressure (n = 17) or pressure-volume (n = 3) catheters, immediately before cardiopulmonary bypass. Single-beat graded pressure elevations were induced by clamping the ascending aorta. Protocol was repeated after volume loading (n = 7). Consecutive patients with a wide range of systolic function were included. Peak isovolumetric LV pressure (LVP(iso)) ranged from 113 to 261 mmHg. With preserved systolic function, LVP elevations neither delayed relaxation nor increased filling pressures. With decreasing systolic function, diastolic tolerance to afterload progressively disappeared: relaxation slowed and filling pressures increased (diastolic dysfunction). In severely depressed systolic function, filling pressures increased even with minor LVP elevations, suggesting baseline load-dependent elevation of diastolic pressures. The magnitude of filling pressure elevation induced in isovolumetric heartbeats was closely and inversely related to systolic performance, evaluated by LVP(iso) (r = -0.96), and directly related to changes in the time constant of relaxation τ (r = 0.95). The maximum tolerated systolic LVP (without diastolic dysfunction) was similarly correlated with LVP(iso) (r = 0.99). Volume loading itself accelerated relaxation, but augmented afterload-induced upward shift of filling pressures (7.9 ± 3.7 vs. 3.0 ± 1.5; P < 0.01). The normal human response to even markedly increased systolic pressures is no slowing of relaxation and preservation of normal filling pressures. When cardiac function deteriorates, the LV becomes less tolerant, responding with slowed relaxation and increased filling pressures. This increase is exacerbated by volume loading

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

We investigated the endogenous production of ghrelin as well as cardiac and pulmonary vascular effects of its administration in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). Adult Wistar rats randomly received a subcutaneous injection of MCT (60 mg/kg) or an equal volume of vehicle. One week later, animals were randomly assigned to receive a subcutaneous injection of ghrelin (100 mug/kg bid for 2 wk) or saline. Four groups were analyzed: normal rats treated with ghrelin (n = 7), normal rats injected with saline (n = 7), MCT rats treated with ghrelin (n = 9), and MCT rats injected with saline (n = 9). At 22-25 days, right ( RV) and left ventricular (LV) pressures were measured, heart and lungs were weighted, and samples were collected for histological and molecular analysis. Endogenous production of ghrelin was almost abolished in normal rats treated with ghrelin. In MCT-treated animals, pulmonary expression of ghrelin was preserved, and RV myocardial expression was increased more than 20 times. In these animals, exogenous administration of ghrelin attenuated PH, RV hypertrophy, wall thickening of peripheral pulmonary arteries, and RV diastolic disturbances and ameliorated LV dysfunction, without affecting its endogenous production. In conclusion, decreased tissular expression of ghrelin in healthy animals but not in PH animals suggests a negative feedback in the former that is lost in the latter. A selective increase of ghrelin mRNA levels in the RV of animals with PH might indicate distinct regulation of its cardiac expression. Finally, ghrelin administration attenuated MCT-induced PH, pulmonary vascular remodeling, and RV hypertrophy, indicating that it may modulate PH

The use of technology and information systems in a quality improvement project developed in a Portuguese Internal Medicine Department: innovative ideas from RITUAL project

info:eu-repo/semantics/publishedVersio

Acute changes of biventricular gene expression in volume and right ventricular pressure overload

Objective: We investigated the effects of acute volume and RV pressure overload on biventricular function and gene expression of BNP, proinflammatory cytokines (IL-6 and TNF-alpha), iNOS, growth factors (IGF-1, ppET-1), ACE and Ca2+-handling proteins (SERCA2a, phospholamban and calsequestrin). Methods: Male Wistar rats (n =45) instrumented with pressure tip micromanorneters in right (RV) and left ventricular (LV) cavities were assigned to one of three protocols: i) Acute RV pressure overload induced by pulmonary trunk banding in order to double RV peak systolic pressure, during 120 or 360 min; ii) acute volume overload induced by dextran40 infusion (5 ml/h), during 120 or 360 min; iii) Sham. RV and LV samples were collected for mRNA quantification. Results: BNP upregulation was restricted to the overloaded ventricles. TNF-alpha, IL-6, ppET-1, SERCA2a and phospholamban gene activation was higher in volume than in pressure overload. IGF-1 overexpression was similar in both types of overload, but was limited to the RV. TNF-alpha and CSQ mRNA levels were increased in the non-overloaded LV after pulmonary trunk banding. No significant changes were detected in ACE or iNOS expression. RV end-diastolic pressures positively correlated with local expression of BNP, TNF-alpha, IL-6, IGF- 1, ppET-1 and SERCA2a, while RV peak systolic pressures correlated only with local expression of IL-6, IGF-1 and ppET-1. Conclusions: Acute cardiac overload alters myocardial gene expression profile, distinctly in volume and pressure overload. These changes correlate more closely with diastolic than with systolic load. Nonetheless, gene activation is also present in the non-overloaded LV of selectively RV overloaded hearts

Ghrelin reverses molecular, structural and hemodynamic alterations of the right ventricle in pulmonary hypertension

Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by stimulating release of growth hormone. There is increasing evidence that ghrelin has a potent vasodilator effect. Recently, we demonstrated that exogenous administration of ghrelin modulates its endogenous levels and attenuates the majority of alterations induced by monocrotaline (MCT). In the present study, we evaluate the effects of chronic administration of ghrelin on hemodynamic and morphometric parameters of the right ventricle, as well as on myocardial levels of SERCA2a and endothelin-1. Adult Wistar rats were injected with MCT (60 mg/kg, sc) or just the vehicle (day 0). One week later, the animals treated with MCT were randomly divided into two groups and treated with ghrelin (100 microg/kg, bid, sc) or with a similar volume of vehicle. Between days 21-25 the animals were instrumented to record right ventricular (RV) pressures and samples were collected for morphological and molecular analysis. Ghrelin treatment attenuated the effects of MCT, namely: RV myocyte fiber diameter, pulmonary vascular remodeling (evaluated by % medial wall thickness of peripheral arteries), RV peak systolic pressure, RV end-diastolic pressure, time constant tau, and SERCA2a and endothelin-1 mRNA levels. Chronic ghrelin administration attenuates MCT-induced pulmonary hypertension, vascular remodeling and RV hypertrophy. These results suggest a potential therapeutic role for the ghrelin-growth hormone axis in pulmonary hypertension

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged tau and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.Supported by Portuguese grants from FCT (POCI/SAU-FCF/60803/2004 and POCI/SAU-MMO/61547/2004) through Cardiovascular R&D Unit (FCT No. 51/94)

Assessing bird exclusion effects in a wetland crossed by a railway (Sado estuary, Portugal)

L. Borda-de-Água et al. (eds.), Railway Ecology, Chapter 11, p. 179-195Linear transportation infrastructures may displace wildlife from nearby areas that otherwise would provide adequate habitat conditions. This exclusion effect has been documented in roads, but much less is known about railways. Here we evaluated the potential exclusion effect on birds of a railway crossing a wetland of international importance (Sado Estuary, Portugal). We selected 22 sectors representative of locally available wetland habitats (salt pans, rice paddy fields, and intertidal mudflats); of each, half were located either close to (0–500 m) or far from (500–1500 m) the railway line. Water birds were counted in each sector between December 2012 and October 2015, during two months per season (spring, summer, winter, and autumn) and year, at both low and high tide. We recorded 46 species, of which the most abundant (>70% of individuals) were black-headed gull, greater flamingo, northern shoveler, black-tailed godwit, and lesser black-backed gull. Peak abundances were found in autumn and winter. There was no significant variation between sectors close to and far from the railway in species richness, total abundance, and abundance of the most common species. Some species tended to be most abundant either close to or far from the railway albeit not significantly so but this often varied across the tidal and annual cycles. Overall, our study did not find noticeable exclusion effects of this railway on wetland birds, with spatial variation in abundances probably reflecting habitat selection and daily movement patterns. Information is needed on other study systems to assess the generality of our findingsinfo:eu-repo/semantics/publishedVersio