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

Pattern of right ventricular pressure fall and its modulation by afterload

Pattern of right ventricular pressure (RVP) fall and its afterload dependence were examined by analyzing ventricular pressure curves and corresponding pressure-dP/dt phase planes obtained in both ventricles in the rat heart in situ. Time and value of dP/dt(min), and the time constant tau were measured at baseline and during variable RV afterload elevations, induced by beat-to-beat pulmonary trunk constrictions. RVP and left ventricular pressure (LVP) decays were divided into initial accelerative and subsequent decelerative phases separated by corresponding dP/dt(min). At baseline, LVP fall was decelerative during 4/5 of its course, whereas only 1/3 of RVP decay occurred in a decelerative fashion. During RV afterload elevations, the absolute value of RV-dP/dt(min) and RV-tau increased, whilst time to RV-dP/dt(min) decreased. Concomitantly, the proportion of RVP decay following a decelerative course increased, so that in highly RV afterloaded heartbeats RVP fall became more similar to LVP fall. In conclusion, RVP and LVP decline have distinct patterns, their major portion being decelerative in the LV and accelerative in the RV. In the RV, dP/dt(min), tau and the proportional contribution of accelerative and decelerative phases for ventricular pressure fall are afterload-dependent. Consequently, tau evaluates a relatively much shorter segment of RVP than LVP fall

Differential right and left ventricular diastolic tolerance to acute afterload and NCX gene expression in Wistar rats

This study evaluated right ventricular (RV) and left ventricular (LV) diastolic tolerance to afterload and SERCA2a, phospholamban and sodium-calcium exchanger (NCX) gene expression in Wistar rats. Time constant tau and end-diastolic pressure-dimension relation (EDPDR) were analyzed in response to progressive RV or LV afterload elevations, induced by beat-to-beat pulmonary trunk or aortic root constrictions, respectively. Afterload elevations decreased LV-tau, but increased RV-tau. Whereas LV-tau analyzed the major course of pressure fall, RV-tau only assessed the last fourth. Furthermore, RV afterload elevations progressively upward shifted RV-EDPDR, whilst LV afterload elevations did not change LV-EDPDR. SERCA2a and phospholamban mRNA were similar in both ventricles. NCX-mRNA was almost 50% lower in RV than in LV. Left ventricular afterload elevations, therefore, accelerated the pressure fall and did not induce diastolic dysfunction, indicating high LV diastolic tolerance to afterload. On the contrary, RV afterload elevations decelerated the late RV pressure fall and induced diastolic dysfunction, indicating small RV diastolic tolerance to afterload. These results support previous findings relating NCX with late Ca2+ reuptake, late relaxation and diastolic dysfunction

Differential right and left ventricular diastolic tolerance to acute afterload and NCX gene expression in Wistar rats

This study evaluated right ventricular (RV) and left ventricular (LV) diastolic tolerance to afterload and SERCA2a, phospholamban and sodium-calcium exchanger (NCX) gene expression in Wistar rats. Time constant tau and end-diastolic pressure-dimension relation (EDPDR) were analyzed in response to progressive RV or LV afterload elevations, induced by beat-to-beat pulmonary trunk or aortic root constrictions, respectively. Afterload elevations decreased LV-tau, but increased RV-tau. Whereas LV-tau analyzed the major course of pressure fall, RV-tau only assessed the last fourth. Furthermore, RV afterload elevations progressively upward shifted RV-EDPDR, whilst LV afterload elevations did not change LV-EDPDR. SERCA2a and phospholamban mRNA were similar in both ventricles. NCX-mRNA was almost 50% lower in RV than in LV. Left ventricular afterload elevations, therefore, accelerated the pressure fall and did not induce diastolic dysfunction, indicating high LV diastolic tolerance to afterload. On the contrary, RV afterload elevations decelerated the late RV pressure fall and induced diastolic dysfunction, indicating small RV diastolic tolerance to afterload. These results support previous findings relating NCX with late Ca2+ reuptake, late relaxation and diastolic dysfunction

Ventricular BNP gene expression in acute cardiac overload

INTRODUCTION:B-type natriuretic peptide (BNP) plasma levels have important diagnostic and prognostic implications in heart failure (HF). Recently, aside from its natriuretic effect, antiproliferative and antifibrotic actions of BNP on the cardiovascular system have been described. Under physiological conditions the atria are the main source of this peptide, while its ventricular expression is still controversial. The aim of this work was to evaluate, in an animal model, the ventricular expression of BNP in normal hearts, at baseline and under acute cardiac overload.METHODS:Anesthetized open chest male Wistar rats (n=18) were instrumented with a micromanometer in the right ventricular cavity for pressure assessment. Randomization for three different protocols was then performed: (i) pressure overload for a period of 6 hours (SPr; n = 6), by pulmonary trunk banding, in order to double basal right ventricular systolic pressure; (ii) volume overload with a six-hour perfusion of Dextran 40 (SVol; n = 6), to raise end-diastolic right ventricular pressure fourfold; (iii) sham operated rats (n = 6). Transmural samples from the right ventricular free wall were then obtained for quantification of BNP mRNA by RT and quantitative real-time PCR. The results are expressed as mean+/-SEM (number molecules of mRNA BNP)/(ng total mRNA); p < 0.05.RESULTS:A basal expression of BNP was identified in the sham group (3.6x10(7) +/- 1.7x10(7)). BNP mRNA levels were elevated in both the SPr and SVol groups (+123.1 +/- 46.3% SPr and +171.6 +/- 87.7% SVol).CONCLUSIONS:Acute cardiac pressure and volume overload are associated with increased ventricular BNP gene expression. Our results suggest that BNP may be involved in early ventricular remodeling

Contractile effects of Ghrelin and expression of its receptor GHS-R1a in normal and hypertrophic myocardium

INTRODUCTION:Ghrelin, isolated in 1999, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Recent studies suggest that it may influence the function of normal and failing hearts. Nonetheless, it has been difficult to differentiate its effects on the intrinsic properties of the myocardium from the secondary effects resulting from growth hormone release and vasomotor action. This study investigated the contractile effects of ghrelin and expression of its receptor GHS-R1a in normal and hypertrophic myocardium.METHODS:Adult Wistar rats randomly received monocrotaline (MCT; n=9; 60 mg/kg, s.c.) or vehicle (n=7; 1 ml/kg). Three weeks later, after right ventricular (RV) hemodynamic evaluation, the effects of 10(-6) M of a pentapeptide active fragment of ghrelin (fG) were tested on contractile parameters of RV papillary muscles (Normal, n=7; MCT, n=9). GHS-R1a mRNA expression was estimated in RV transmural free-wall samples (Normal, n=7; MCT, n=9), using real-time RT-PCR.RESULTS:In the Normal group, fG reduced active tension (AT), maximum velocity of tension rise (dT/dt(max)) and maximum velocity of tension decline (dT/dt(min)), by 27.9 +/- 4.0%, 28.5 +/- 6.7% and 21.4 +/- 4.2% respectively. In the MCT group, fG reduced AT, dT/dt(max) and dT/dt(min) by 24.1 +/- 6.3%, 24.3 +/- 6.5% and 24.5 +/- 6.1% respectively. GHS-R1a mRNA expression was similar in the two groups (Normal: 2.3*10(5) +/- 5.4*10(4); MCT: 3.0*10(5) +/- 1.1*10(5): p > 0.05).CONCLUSION:This study shows that ghrelin has negative inotropic and lusitropic effects. These effects and expression of its receptor are preserved in RV hypertrophy, suggesting that ghrelin may be a new target in progression to heart failure

Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

Falcao-Pires I, Goncalves N, Henriques-Coelho T, Moreira-Goncalves D, Roncon-Albuquerque R Jr, Leite-Moreira AF. Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 296: H2007-H2014, 2009. First published April 3, 2009; doi: 10.1152/ajpheart.00089.2009.-We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 mu g.kg(-1).day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation

Evaluation of biventricular function in the rat: a new experimental model

The use of small animals in cardiovascular research has increased over recent years. This might be a limitation when evaluation of biventricular function is required. Although evaluation of left ventricular (LV) pressure and volume is already possible in small animals, concomitant evaluation of right ventricle function has been limited to large animals. The study describes a new model to assess pressures and dimensions of both ventricles simultaneously in the adult rat. Adult Wistar rats (n = 12), weighing 372 +/- 16 g, were anesthetized with pentobarbital (60 mg/kg, i.p.) and ventilated through a tracheostomy (60 cpm, 1 ml/100 g). Under a dissecting microscope (6x) the right jugular vein was catheterized. After sternotomy and pericardiotomy, three crystals were placed along the major cardiac transverse diameter: in the right subendocardium of the interventricular septum and on the epicardial surfaces of the RV and LV free walls. In addition, two high-fidelity catheters were introduced through the apex into the RV (2F, Millar) and LV (3F, Millar) cavities. This allowed the measurement of all parameters derived from pressure and dimension curves of the RV and LV, including pressure-dimension loops. This study describes, for the first time, a model that allows simultaneous evaluation of biventricular pressure and dimensions in an animal model as small as an adult rat. This model opens up new perspectives for the establishment of correlations between molecular biology and hemodynamic data in both ventricles, which is particularly important as more differences between the two ventricles are being found

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