Differences in right ventricular remodeling secondary to pressure overload in patients with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) includes a group of chronic lung vascular diseases frequently complicated by right ventricle (RV) dysfunction and failure (1, 2). Under physiological conditions, the RV interacts with a low-pressure, low-resistance pulmonary circulation (3). However, under pathological conditions such as PAH, the RV is—at least initially—capable of adapting to the increase in pressure overload with remarkable hypertrophy in both humans and animals (4, 5). Although the mechanisms by which pressure overload induces RV hypertrophy are partially understood, the mechanisms whereby adaptive hypertrophy becomes maladaptive are still incomplete (4, 6). Puzzling examples are the patients with Eisenmenger’s syndrome (EMS). The “resilient” RV of patients with EMS appears to be better adapted to increased pressure overload compared with the RV of patients with idiopathic PAH (IPAH) or other forms of PAH (7). Moreover, whereas most patients with IPAH frequently present with decreased cardiac output at the time of diagnosis (2), patients with EMS maintain a normal cardiac output and right atrial pressure in spite of a similar degree of pressure overload (8), at least until later stages of the disease (8). Interestingly, whereas the hemodynamic differences between patients with IPAH and those with EMS have long been recognized (8), and some structural differences of the RV have been described by cardiac tomography (7), an anatomopathological comparison between the hearts of patients with EMS and IPAH has so far not been reported. In the present study, we performed a postmortem morphometric analysis of the left ventricles (LVs) and RVs of patients with IPAH (n = 6) or EMS (n = 6) who died from RV failure. All patients with EMS had a patent ductus arteriosus as the systemic-to-pulmonary shunt. Age-matched patients who died from noncardiac, nonpulmonary disease were used as control subjects (n = 6). The majority of patients died before any PAHspecific therapies were available. However, we excluded any patient that had been treated with a PAH-specific drug later in time. Informed consent was obtained from the family of each patient. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Instituto Nacional de Cardioloǵıa “Ignacio Chávez” Institutional Review Board. We measured the anterior-to-posterior and septum-to-free-wall diameters, as well as RV and LVwall thickness at the base, middle, and apex levels (Figures 1A and 1B). Annular dimensions of tricuspid and mitral valves were also measured. Using the RV diameters, we estimated the RV-chamber area using the formula A = (p 3 dAP 3 dSW)/4, where A represents the RV-chamber area, dAP represents the anterior-to-posterior diameter, and dSW represents the septumto-free-wall diameter. This formula was derived from the formula to calculate the area of a circle. All results are reported as mean 6 standard deviation. Differences between groups were assessed by oneway or two-way analysis of variance, and Bonferroni’s post hoc test was used to assess significant differences between groups. A P value less than 0.05 was accepted as significant. Correlation analysis was done using a Spearman’s test. The mean age for all groups was 28 6 10 years. Both patients with EMS and those with IPAH had severe pulmonary hypertension (56 6 14 mm Hg in IPAH vs. 78 6 14 mm Hg in EMS, P = 0.023). Figures 1C–1E illustrate that the RV in both groups of patients responded to pressure overload with significant hypertrophy as evidenced by increased RV wall thickness. Interestingly, patients with EMS also exhibited increased LV wall thickness at the base and middle levels but not at the apex level (Figures 1F–1H). In contrast to what has been reported by cardiac magnetic resonance in patients with increased RV afterload secondary to chronic thromboembolic pulmonary hypertension (9), we did not find a reduction in LV wall thickness in the group of patients with IPAH. Table 1 summarizes the diameter measurements for RV and LV for all groups. Figures 2A–2C illustrate the correlation between the wall thickness at the base, middle, and apex levels with their respective RV-chamber area. Patients with IPAH developed significant RV hypertrophy compared with control RVs but significantly less hypertrophy compared with patients with EMS. Most importantly, compared with the EMS group, the RV of patients with IPAH had significantly less hypertrophy (RV thickness) in relationship to the RV-chamber area (Figures 2A–2C), and this relationship between area and wall thickness seemed to be more disproportionate at the apex level. It should be noted, however, that patients with EMS had a significantly higher mean pulmonary arterial pressure, and this finding could in fact explain the differences in RV hypertrophy. However, as can be appreciated in Table 1 and Figures 1F–1H, the LV of these patients is also larger and thicker, which could suggest the presence of stimuli, not directly associated with increased RV pressure overload, that led to generalized growth of the heart. However, to what extent the remodeling of the RV in patients with EMS is independent of pressure overload remains to be investigated. Interestingly, despite the fact that the RV of patients with EMS was exposed initially to volume and later to pressure overload, the RV underwent concentric (Figure 2G) rather than eccentric hypertrophy (Figure 2D). This is a particularly interesting finding given the fact that volume overload of the LV frequently leads to dilated cardiomyopathy. It is also important to underline that all patients in the EMS group had a post-tricuspid defect (patent ductus arteriosus), and our findings may not be true for all congenital heart defects leading to EMS physiology. For instance, it has been shown that pretricuspid defects (such as atrial septal defects) exhibit different cardiac remodeling than post-tricuspid defects (7). Although the present study does not provide a mechanistic explanation to account for the differences in RV remodeling, we believe these results should be considered for hypothesis generation. Indeed, whereas it has been proposed that the RV of patients with EMS has been “primed” since birth (10), the mechanism(s) by which the RV in patients with EMS achieves adequate, long-standing functional RV hypertrophy remains a mystery. Understanding the role of RV “priming” is critical, particularly because patients with EMS that remain with pulmonary hypertension after surgical Partly funded by the Victoria Johnson Center for Pulmonary Disease Research and the Medical College of Virginia Foundation.