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Nazzareno Galié, Alessandra Manes, Massimiliano Palazzini, Luca Negro, Serena Romanazzi, Angelo Branzi, Pharmacological impact on right ventricular remodelling in pulmonary arterial hypertension, European Heart Journal Supplements, Volume 9, Issue suppl_H, December 2007, Pages H68–H74, https://doi.org/10.1093/eurheartj/sum055
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Abstract
The pathophysiologic mechanisms of pulmonary arterial hypertension (PAH) are initiated by the progressive obstructive changes of the pulmonary resistance vessels which lead to the increase of the afterload of the right ventricle (RV) that responds with functional and structural adaptations. The RV remodelling compensates for a variable period of time but ultimately may fail leading to heart failure and death. The depression of myocardial contractility seems to be one of the primary events in the progression of heart failure in a chronically overloaded RV. However, afterload mismatch remains the leading determinant of heart failure in patients with both PAH and chronic thrombo-embolic pulmonary hypertension. Different therapies induce a variable degree of reverse remodelling on the heart changes typical of PAH. The extent of this effect is strictly related to the reduction of RV afterload. The best results are observed in patients who underwent lung transplantation, pulmonary endoarterectomy and in vasoreactive subjects responders to chronic treatment with calcium channel blocking agents. The RV reverse remodelling effects of the new targeted therapies in non-vasoreactive PAH patients appear to be only mild to moderate.
Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular (RV) failure and premature death.1,2 According to the clinical classification of pulmonary hypertension of Venice 2003,3 PAH includes Idiopathic PAH, Familial PAH, and PAH related to risk factors or associated conditions such as connective tissue, congenital systemic-to-pulmonary shunts, portal hypertension, drugs and toxins, and HIV infection.
The pathophysiologic mechanisms of PAH are initiated by the progressive obstructive changes of the pulmonary resistance vessels (small pulmonary arteries and arteriolae) which lead to the increase of the afterload of the RV that respond with functional and structural adaptations. The RV remodelling compensates for a variable period of time but ultimately may fail leading to heart failure and death.
The pathobiologic mechanisms responsible for the initiation and progression of pulmonary vascular obstructive changes in PAH are poorly understood, and many hypotheses have been generated in the past years.4
In addition, the variable adaptive responses of the heart to the increased RV afterload may be linked to specific constitutional factors influencing the structural and biological characteristics of myocardial hypertrophy.
Mechanisms for the increases of right ventricular afterload
Pulmonary vasoconstriction was considered the leading pathobiologic mechanisms for idiopathic PAH in the first modern descriptions of this disease proposed by Dresdale et al.5 and Wood6 in the 1950s. More recently, the clinical use of standardized pulmonary vasoreactivity tests has allowed investigators to identify a minority of idiopathic PAH patients which achieve a consistent acute reduction of pulmonary arterial pressure (∼10% of the cases) and respond favourably to the chronic treatment with calcium channel blockers drugs as monotherapy (∼6% of the cases).7 If these ‘responder’ patients represent a different type of idiopathic PAH with exaggerated pulmonary vasoconstriction or an early phase of the same condition that if untreated would lead to more ‘fixed’ vascular lesions it is unknown. Although a relevant acute vasodilator effect is observed only in a minority of subjects, a continuum of responses is detected among the entire patients spectrum. Therefore, even if vasocontrictive mechanisms seem to be relevant only in a small group of subjects, these processes may be involved by a lesser extent in a broader population.
Since the endothelium is directly involved in the modulation of pulmonary flow and vascular resistance, endothelial dysfunction would play a key role in the pathobiological mechanisms of PAH. Physiologic vascular tone and function are regulated by the interaction between endothelial cells and smooth muscle cells of the vessel wall and between endothelial cells and circulating blood elements. The endothelial cells modulate smooth muscle cells activity by producing vasodilators/antimitotics, such as prostacyclin and nitric oxide (NO), and vasoconstrictors/mitogens, such as thromboxane A2 and endothelin-1 (ET-1). Endothelial dysfunction leads to a chronically impaired production of vasodilators (such as NO and prostacyclin) along with overexpression of vasoconstrictors (such as thromboxane A2 and ET-1), significantly affecting the physiological vascular balance.8
Although vasoconstriction has been considered as a factor that contributes to the increase of pulmonary vascular resistance, there is an agreement that in many patients additional mechanisms are required to explain the haemodynamic changes. Indeed, many vascular effectors implicated in the modulation of vascular tone are also involved in other processes such as cell proliferation.9
Pulmonary vascular proliferative remodelling in PAH involves all layers of the vessel wall and several cell types including endothelial cells, smooth muscle cells, and fibroblasts. The main pathological finding is an abnormal and disorganized cell proliferation that cause a marked thickening of all components of the vessel wall. Medial and intimal proliferative changes and the development of complex vascular lesions, such as plexiform and colander lesions, result in the obstruction of small pulmonary arteries and in the increase of pulmonary vascular resistance (Figure 1).10
Haemodynamic and structural changes of the heart
Both fixed and functional obstructive changes of the pulmonary resistance vessels lead to an increase of pulmonary vascular resistance with consequent RV pressure overload (Figure 1). Right heart failure caused by afterload mismatch and/or decompensated hypertrophic response is the leading cause of death in patient with severe PAH and a robust prognostic indicator. In fact, although the pulmonary vascular bed is the primary cause of the disease, symptoms and prognosis are strongly related to the pump function determinants of the RV (Figure 1).11
Chronic RV afterload increase leads to extensive change of cardiac morphology and function involving both the RV and the left ventricle (LV) (Figure 2A).12–14 The structural changes of the right cardiac chambers include RV hypertrophy and dilatation, right atrial enlargement, and functional tricuspid regurgitation, caused by annular valve dilatation and chordal traction due to ventricular volume increase. Tricuspid valve regurgitation in turn results in RV volume overload and presumably initiates a cycle of further progressive annular dilation and extensive RV remodelling.
The progressive increase in RV pressures adversely affect also RV structure and function due to the anatomical juxtaposition of the two ventricles and ventricular interdependence. In fact, the left side of the heart is characterized by reduced dimensions and distortion of the LV (Figure 2A). The most important pathophysiologic mechanisms responsible for LV structural changes are underfilling, caused by reduced RV cardiac output, and leftward displacement of the interventricular septum due to systolic and diastolic transeptal pressure gradient changes.14 The consequent LV diastolic dysfunction, characterized by decreased LV diastolic filling and end-diastolic volume, may play an important role in the haemodynamic altered response of PAH patients, especially during exercise. In fact, LV dysfunction results in reduced forward cardiac output and lower systemic blood pressure at rest which increase is damped during exercise. Reduced systemic blood pressure, combined with increased RV diastolic and myocardial intramural pressures, may impair the physiological pattern of RV walls coronary perfusion that no longer can be maintained throughout the heart cycle. In fact, the reduction of RV coronary artery driving pressure (mean blood pressure minus end-diastolic RV pressure) may result in RV ischaemia that facilitates the progression of RV dysfunction.15
The importance of the progression of RV failure on the outcome of PAH patients is testified by the prognostic impact of right atrial pressure, cardiac index, and pulmonary artery pressure,11 the three main determinants of RV pump function. Moreover, also non-invasive parameters, such as echocardiographic and Doppler measures, and biochemical markers related to heart chambers structure and function, underline the prognostic relevance of heart remodelling in PAH. Among echocardiographic and Doppler parameters, the presence of pericardial effusion, right atrial area dimension, LV eccentricity index, and Doppler RV Tei index are sensitive indicators of the severity of heart dysfunction and were found to be correlated to the prognosis of patients with IPAH.13,16 Recently, the Doppler-assessed area of tricuspid regurgitation, which may be considered as an indicator of RV remodelling, has been found to be a strong predictor of survival in a large series of IPAH patients.17
Metabolic and neurohormonal changes
Chronic RV pressure overload in PAH patients has been shown to alter the myocardial preference for energy substrates (myocardial glucose uptake is increased, whereas free fatty acid analogue uptake is decreased).18
RV failure may lead to increased plasma levels of various biochemical markers of myocyte endocrine function or injury such as uric acid, B-type natriuretic peptide (BNP) and troponin. Evidence has become available that these biochemical markers may be utilzed for assessing the severity and for monitoring the progression of RV dysfunction. Hyperuricaemia is common in patients with severe PH and correlates with haemodynamic abnormalities, e.g. elevated RAP, and increased mortality in IPAH.19 Elevated plasma levels of BNP, a biochemical marker of ventricular overload, was reported as an independent prognostic factor in IPAH patients;20 in addition, changes in BNP during follow-up were even more predictive of outcome, with a good prognosis in patients in whom plasma BNP levels were reduced during treatment.20
Also troponin plasma levels,21 both at baseline and after targeted treatments, have been found to have prognostic relevance in severe PAH patients supporting the role of progressive myocyte injury in the vicious circle of RV failure.
Right ventricular dysfunction progression and effects of treatments
The depression of myocardial contractility seems to be one of the primary events in the progression of heart failure in a chronically overloaded RV. Possible mechanisms that favour the progression of contractile dysfunction in failing myocardium include RV ischaemia,15 changes in the adrenergic pathways of RV myocytes,22 alteration of gene expression of the sarcomere proteins,23 and activation of myocardial renin angiotensin system.24 However, afterload mismatch remains the leading determinant of heart failure in patients with both PAH and chronic thrombo-embolic PH.
In fact, successful lung transplantation in PAH25 and pulmonary endoarterectomy in chronic thrombo-embolic PH26,27 lead almost invariably to a progressive and sustained recovery of RV function and global heart remodelling (Figure 2). Normalization of echocardiographic RV myocardial indexes of dysfunction as well as rapid decrease of plasma BNP levels after such procedures suggest the possibility of non-invasive monitoring of the changes in RV function in PAH patients.
Consistent improvements of RV pump function may be observed also in the minority of patients defined as ‘responders’ to acute vasoreactivity test (∼10% of idiopathic PAH patients).1 In fact, in these cases the mechanism of vasoconstriction is the main determinant of the RV afterload increase and the acute reduction of pulmonary vascular resistance achieved by the use of selective pulmonary vasodilators (inhaled NO) lead to the improvement of RV pump function. This vasodilator reserve can be recruited on a long-term basis by the use of calcium channel blocker drugs that, in a proportion of the cases (long-term responders1), may almost normalize both pulmonary haemodynamics and RV pump function.7,28 The prognosis of these patients is definitely better when compared with patients non-responder to the vasoreactivity test. In Figures 3 and 4, the ECG and echochardiographic reverse remodelling changes of an acute and long-term ‘responder’ patient are shown.
In the remaining 90% of PAH patients (non-responders to acute vasoreactivity tests), changes of heart morphology and function after targeted treatments are often minor and difficult to document in the individual subjects. Clinical experience seems to indicate that echocardiographic indices related to RV systolic and LV diastolic function may be more useful in detecting the effects of treatments rather than echocardiographics estimates of systolic pulmonary arterial pressure. In one study12 involving 81 patients equally randomized to receive 12-week intravenous infusion of epoprostenol or conventional treatment alone, a beneficial effects was shown on RV size and on LV eccentricity index in the epoprostenol treated group (36). In another trial29 comparing the effect of bosentan (n = 56) for 16 weeks to placebo (n = 29), an increase of LV early diastolic filling velocity and of LV end-diastolic area, and an improvement of LV systolic eccentricity index and RV-to-LV diastolic areas ratio were assessed. RV changes in the bosentan treated group included reduction of RV end-systolic area and improvement in RV Tei index. The patients treated with bosentan had also significant improvement in the pericardial effusion score when compared with those receiving placebo.
In a study on 26 PAH patients assessed by nuclear magnetic resonance imaging, phosphodiesterase-5 inhibitor sildenafil was apparently able to reduce RV myocardial mass whereas bosentan did not.30 However, this study appears small sized and further confirmation is required.
Despite the RV, [18F]fluorodeoxyglucose accumulation was significantly increased in accordance with the severity of the RV pressure overload in PAH patients, epoprostenol treatment corrected these changes in proportion with the degree of reduction in the pulmonary vascular resistance and RV peak-systolic wall stress.18 However, it is not clear how these metobolic ‘corrections’ may influence RV dysfunction progression.
Interaction between microcirculatory pathologic changes and right ventricular dysfunction progression
The haemodynamic profile and the prognosis of patients with PAH are related to the complex pathophysiologic interactions between the rate of progression (or regression) of the obstructive changes of pulmonary circulation and the compensatory adaptation of the overloaded RV. Initially, RV hypertrophy compensate for the increased afterload. The RV begins to fail when the afterload rate of progression overcome the compensatory mechanisms such as hypertrophy and dilatation. It has been shown that some patients develop an appropriate adaptation to increased RV afterload and experience only moderate functional limitations even with suprasystemic pulmonary pressures (typically subjects with congenital heart diseases), whereby others demonstrate RV failure with definitely lower afterload increases. The mechanisms that influence RV compensatory adaptation are largely unknown and may include constitutional factors and the rate of progression and timing of afterload increase (Figure 5).
Among constitutional factors, there is evidence that genetic determinants may influence both structural and functional RV compensatory changes.24 In fact, it has been shown that specific polymorphisms of the angiotensin converting enzyme (ACE) gene are correlated with different rate of progression of RV failure: in particular, IPAH patients with DD-ACE genotype have a better haemodynamic stability compared with subjects with the II or ID genotype. One potential explanation for this phenomenon is a more vigorous induction of the myocardial renin angiotensin system in DD genotype patients leading to a greater stimulus for parallel sarcomere assembly with consequent development of a more appropriate RV hypertrophy.
The relevance of the timing of the afterload increase and its rate of progression on RV remodelling may explain differences on haemodynamic adaptation in diverse types of PAH. In fact, in patients with congenital heart diseases with shunts, the RV is ‘trained’ to sustain an increased afterload since the intrauterine period of life and the ‘physiologic’ RV foetal hypertrophy is maintained after birth allowing an effective adaptation for decades (as observed in the Eisenmenger syndrome). In contrast, in patients with PAH acquired in the adult life (such as the idiopathic and most of the associated forms), the ‘compensatory’ RV hypertrophy appears to be less appropriate and short lasting.
Clinical phases of right ventricular dysfunction progression
The hypothetical progression of the haemodynamic changes in patients with acquired PAH is shown in Figure 6. Arbitrarily, the process is divided in asymptomatic (pre-clinical), symptomatic (clinical), and decompensated (terminal) phases. The duration of each phase may vary largely in individual patients and in different types of PAH.
In the asymptomatic phase, a progressive increase of pulmonary vascular resistance due to the pathologic obstructive changes is hypothesized with consequent RV pressure overload and pulmonary arterial pressure elevation. In this phase, RV compensatory structural changes may allow the maintenance of an appropriate pump function and cardiac output at rest or on mild to moderate physical activity. However, cardiac output increase limitation may occur for relevant exercises and symptoms (such as syncopal episodes) may appear also in this phase.
The overt symptomatic phase is characterized by a further increase of pulmonary vascular resistance due to the progression of the obstructive changes of the pulmonary resistance vessels, and by a reduction of cardiac output at rest or on mild to moderate exercises which reflects the initial failure of the RV compensatory response. Patients are usually diagnosed in this phase and they show different clinical and haemodynamic impairments (interupted lines in Figure 6) according to the precocity of the diagnosis. Pulmonary artery pressure values are usually stable in the symptomatic phase because the progressive increase of RV afterload causes the reduction of cardiac output.
In the decompensated phase, the RV is unable to maintain an appropriate cardiac output even at rest and signs and symptoms of severe congestive heart failure and poor organs perfusion appear. Pulmonary arterial pressure values may decline in this phase due to the marked reduction of cardiac output and the prognosis of the patients is definitely poor.
Conclusions
Different therapies induce a variable degree of reverse remodelling on the heart changes typical of PAH. The extent of this effect is strictly related to the reduction of RV afterload. The best results are observed in patients who underwent lung transplantation, pulmonary endoarterectomy and in vasoreactive patients responders to chronic treatment with calcium channel blocking agents. The RV reverse remodelling effects exerted by the new targeted therapies in non-vasoreactive PAH patients appear to be only mild to moderate (at best).
Conflict of interest: Prof. Nazzareno Galié has participated to steering advisory boards of the following companies: Actelion, Glaxo Smith Kline and Pfizer.