Mariëlle C. van de Veerdonk

Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy.

OBJECTIVES The purpose of this study was to examine the relationship between changes in pulmonary vascular resistance (PVR) and right ventricular ejection fraction (RVEF) and survival in patients with pulmonary arterial hypertension (PAH) under PAH-targeted therapies. BACKGROUND Despite the fact that medical therapies reduce PVR, the prognosis of patients with PAH is still poor. The primary cause of death is right ventricular (RV) failure. One possible explanation for this apparent paradox is the fact that a reduction in PVR is not automatically followed by an improvement in RV function. METHODS A cohort of 110 patients with incident PAH underwent baseline right heart catheterization, cardiac magnetic resonance imaging, and 6-min walk testing. These measurements were repeated in 76 patients after 12 months of therapy. RESULTS Two patients underwent lung transplantation, 13 patients died during the first year, and 17 patients died in the subsequent follow-up of 47 months. Baseline RVEF (hazard ratio [HR]: 0.938; p = 0.001) and PVR (HR: 1.001; p = 0.031) were predictors of mortality. During the first 12 months, changes in PVR were moderately correlated with changes in RVEF (R = 0.330; p = 0.005). Changes in RVEF (HR: 0.929; p = 0.014) were associated with survival, but changes in PVR (HR: 1.000; p = 0.820) were not. In 68% of patients, PVR decreased after medical therapy. Twenty-five percent of those patients with decreased PVR showed a deterioration of RV function and had a poor prognosis. CONCLUSIONS After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR. Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

Right ventricular ejection fraction is better reflected by transverse rather than longitudinal wall motion in pulmonary hypertension

BackgroundLongitudinal wall motion of the right ventricle (RV), generally quantified as tricuspid annular systolic excursion (TAPSE), has been well studied in pulmonary hypertension (PH). In contrast, transverse wall motion has been examined less. Therefore, the aim of this study was to evaluate regional RV transverse wall motion in PH, and its relation to global RV pump function, quantified as RV ejection fraction (RVEF).MethodsIn 101 PH patients and 29 control subjects cardiovascular magnetic resonance was performed. From four-chamber cine imaging, RV transverse motion was quantified as the change of the septum-free-wall (SF) distance between end-diastole and end-systole at seven levels along an apex-to-base axis. For each level, regional absolute and fractional transverse distance change (SFD and fractional-SFD) were computed and related to RVEF. Longitudinal measures, including TAPSE and fractional tricuspid-annulus-apex distance change (fractional-TAAD) were evaluated for comparison.ResultsTransverse wall motion was significantly reduced at all levels compared to control subjects (p < 0.001). For all levels, fractional-SFD and SFD were related to RVEF, with the strongest relation at mid RV (R2 = 0.70, p < 0.001 and R2 = 0.62, p < 0.001). For TAPSE and fractional-TAAD, weaker relations with RVEF were found (R2 = 0.21, p < 0.001 and R2 = 0.27, p < 0.001).ConclusionsRegional transverse wall movements provide important information of RV function in PH. Compared to longitudinal motion, transverse motion at mid RV reveals a significantly stronger relationship with RVEF and thereby might be a better predictor for RV function.

Progressive Changes in Right Ventricular Geometric Shortening and Long-term Survival in Pulmonary Arterial Hypertension

BACKGROUND Until now, many investigators have focused on describing right ventricular (RV) dysfunction in groups of patients with pulmonary arterial hypertension (PAH), but very few have addressed the deterioration of RV function over time. The aim of this study was to investigate time courses of RV geometric changes during the progression of RV failure. METHODS Forty-two patients with PAH were selected who underwent right-sided heart catheterization and cardiac MRI at baseline and after 1-year follow-up. Based on the survival after this 1-year run-in period, patients were classified into two groups: survivors (26 patients; subsequent survival of > 4 years) and nonsurvivors (16 patients; subsequent survival of < 4 years). Four-chamber cine imaging was used to quantify RV longitudinal shortening (apex-base distance change), RV transverse shortening (septum-free wall distance change), and RV fractional area change (RVFAC) between end diastole and end systole. RESULTS Longitudinal shortening, transverse shortening, and RVFAC measured at the beginning of the run-in period and 1 year later were significantly higher in subsequent survivors than in nonsurvivors (P < .05). Longitudinal shortening did not change during the run-in period in either patient group. Transverse shortening and RVFAC did not change during the run-in period in subsequent survivors but did decrease in subsequent nonsurvivors (P < .05). This decrease was caused by increased leftward septal bowing. CONCLUSIONS Progressive RV failure in PAH is associated with a parallel decline in longitudinal and transverse shortening until a floor effect is reached for longitudinal shortening. A further reduction of RV function is due to progressive leftward septal displacement. Because transverse shortening incorporates both free wall and septum movements, this parameter can be used to monitor the decline in RV function in end-stage PAH.

The Right Ventricle Explains Sex Differences in Survival in Idiopathic Pulmonary Arterial Hypertension

BACKGROUND Male sex is an independent predictor of worse survival in pulmonary arterial hypertension (PAH). This finding might be explained by more severe pulmonary vascular disease, worse right ventricular (RV) function, or different response to therapy. The aim of this study was to investigate the underlying cause of sex differences in survival in patients treated for PAH. METHODS This was a retrospective cohort study of 101 patients with PAH (82 idiopathic, 15 heritable, four anorexigen associated) who were diagnosed at VU University Medical Centre between February 1999 and January 2011 and underwent right-sided heart catheterization and cardiac MRI to assess RV function. Change in pulmonary vascular resistance (PVR) was taken as a measure of treatment response in the pulmonary vasculature, whereas change in RV ejection fraction (RVEF) was used to assess RV response to therapy. RESULTS PVR and RVEF were comparable between men and women at baseline; however, male patients had a worse transplant-free survival compared with female patients (P = .002). Although male and female patients showed a similar reduction in PVR after 1 year, RVEF improved in female patients, whereas it deteriorated in male patients. In a mediator analysis, after correcting for confounders, 39.0% of the difference in transplant-free survival between men and women was mediated through changes in RVEF after initiating PAH medical therapies. CONCLUSIONS This study suggests that differences in RVEF response with initiation of medical therapy in idiopathic PAH explain a significant portion of the worse survival seen in men.

Clinically Significant Change in Stroke Volume in Pulmonary Hypertension

BACKGROUND Stroke volume is probably the best hemodynamic parameter because it reflects therapeutic changes and contains prognostic information in pulmonary hypertension (PH). Stroke volume directly reflects right ventricular function in response to its load, without the correction of compensatory increased heart rate as is the case for cardiac output. For this reason, stroke volume, which can be measured noninvasively, is an important hemodynamic parameter to monitor during treatment. However, the extent of change in stroke volume that constitutes a clinically significant change is unknown. The aim of this study was to determine the minimal important difference (MID) in stroke volume in PH. METHODS One hundred eleven patients were evaluated at baseline and after 1 year of follow-up with a 6-min walk test (6MWT) and cardiac MRI. Using the anchor-based method with 6MWT as the anchor, and the distribution-based method, the MID of stroke volume change could be determined. RESULTS After 1 year of treatment, there was, on average, a significant increase in stroke volume and 6MWT. The change in stroke volume was related to the change in 6MWT. Using the anchor-based method, an MID of 10 mL in stroke volume was calculated. The distribution-based method resulted in an MID of 8 to 12 mL. CONCLUSIONS Both methods showed that a 10-mL change in stroke volume during follow-up should be considered as clinically relevant. This value can be used to interpret changes in stroke volume during clinical follow-up in PH.

Accurate assessment of load-independent right ventricular systolic function in patients with pulmonary hypertension.

BACKGROUND End-systolic elastance (E(es)), a load-independent measure of ventricular function, is of clinical interest for studies of the right ventricle (RV) in patients with pulmonary arterial hypertension (PAH). The objective of this study was to determine whether, in PAH patients, E(es) can be estimated from mean pulmonary artery pressure (mPAP) and end-systolic volume (ESV) only. METHODS Right heart catheterization was used to measure mPAP. Maximal isovolumic pressure (P(iso)) was estimated from RV pressure curves with the so-called single-beat method. Cardiac magnetic resonance imaging (MRI) was used to assess RV end-diastolic and end-systolic volumes (EDV and ESV). E(es) was then calculated as: E(es) = (P(iso)-mPAP) / (EDV-ESV), and as E(es,V0 = 0) = mPAP/ESV (simplified method, with V0 = 0, is negligible volume at zero pressure). Right ventricular volume at zero pressure (V(0)) was then defined as the intercept of the end-systolic pressure-volume relation (single-beat method) with the horizontal axis. RESULTS E(es,V0 = 0) was significantly lower compared with E(es) (0.61 vs 1.34 mm Hg/ml, respectively, p<0.01). A modified Bland-Altman analysis showed a contractility-dependent difference between E(es,V0 = 0) and E(es). Moreover, V(0) ranged from-8 up to 171 ml, and a moderate and good correlation was found between V(0) and EDV, and V(0) and ESV, respectively (r = 0.65 and r = 0.87, p< 0.01). CONCLUSIONS These findings show that V(0) is dependent on RV dilation. Therefore, the assumption that V(0) is negligible in PAH is incorrect. Consequently, for an accurate assessment of load-independent RV systolic function, RV volumes and pressure curves are required.

Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension

BACKGROUND After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function. OBJECTIVES The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients. METHODS LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. RESULTS Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (~30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (~25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ~30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation. CONCLUSIONS The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.

Signs of Right Ventricular Deterioration in Clinically Stable Patients With Pulmonary Arterial Hypertension

BACKGROUND Even after years of stable response to therapy, patients with idiopathic pulmonary arterial hypertension (IPAH) may show an unexpected clinical deterioration due to progressive right ventricular (RV) failure. Therefore, the aim of this study was to assess in 5-year clinically stable patients with IPAH whether initial differences or subsequent changes in RV volumes precede late clinical progression. METHODS Included were 22 clinically stable patients with IPAH as reflected by stable or improving New York Heart Association functional class II-III and exercise capacity during 5 years of follow-up. Twelve patients subsequently remained stable during a total follow-up of 10 years, whereas 10 other patients showed late progression leading to death or lung transplantation after a follow-up of 8 years. All patients underwent right-sided heart catheterization and cardiac MRI at baseline and at 1½, 3½, 6½, and, if still alive, 10 years follow-up. RESULTS Baseline hemodynamics were comparable in both groups and remained unchanged during the entire follow-up period. Baseline RV end-systolic volume (RVESV) was higher and RV ejection fraction (RVEF) was lower in late-progressive patients. Late-progressive patients demonstrated a gradually increased RV end-diastolic volume and RVESV and a decline in RVEF, whereas long-term stable patients did not show any RV changes. CONCLUSIONS In patients with stable IPAH for 5 years, subsequent late disease progression is preceded by changes in RV volumes. The results indicate that monitoring RV volumes anticipates clinical worsening, even at a time of apparent clinical stability.

Prognostic Relevance of Changes in Exercise Test Variables in Pulmonary Arterial Hypertension

Introduction Exercise variables determined in patients with pulmonary arterial hypertension (PAH) at the time of diagnosis, predict survival. It is unknown whether upon treatment, subsequent changes in these exercise variables reflect improvements in survival. The aim of this study was to determine changes in exercise variables in PAH patients and to relate these changes to survival. Methods Baseline cardiopulmonary exercise test (CPET) variables and six-minute-walk-distance (6MWD) were available from 65 idiopathic PAH patients (50 females; mean age 45±2yrs). The same variables were determined after treatment (13months) in a sub group of 43 patients. To estimate the association between changes in exercise variables and changes in cardiac function, right-ventricle ejection fraction (RVEF) was measured by cardiac MRI at baseline and after treatment in 34 patients. Mean follow-up time after the second CPET was 53 (range: 4-111) months. Kaplan-Meier analysis was used to relate survival to baseline and treatment-associated changes in exercise variables. Results Survivors showed a significantly greater change in maximal oxygen uptake than non-survivors and this change in aerobic capacity was significantly related to changes in RVEF. From baseline until the end of the study period, two patients underwent a lung transplantation and 19 patients died. Survival analysis showed that baseline 6MWD (p<0.0001), maximal heart rate (p<0.0001) and the slope relating ventilation with carbon dioxide production (p≤0.05) were significant predictors of survival, whereas baseline oxygen uptake and oxygen pulse held no predictive value. Treatment associated changes in 6MWD (p<0.01), maximal heart rate (p<0.05), oxygen uptake (p<0.001) and oxygen pulse predicted survival (p<0.05), whereas changes in the slope relating ventilation with carbon dioxide production did not. Conclusion Exercise variables with prognostic significance when determined at baseline, retain their prognostic relevance after treatment. However, when changes in exercise variables upon treatment are considered, a different set of variables provides prognostic information.

The right ventricle and pulmonary hypertension

Abstract In patients with pulmonary hypertension (PH), the primary cause of death is right ventricular (RV) failure. Improvement in RV function is therefore one of the most important treatment goals. In order to be able to reverse RV dysfunction and also prevent RV failure, a detailed understanding of the pathobiology of RV failure and the underlying mechanisms concerning the transition from a pressure-overloaded adapted right ventricle to a dilated and failing right ventricle is required. Here, we propose that insufficient RV contractility, myocardial fibrosis, capillary rarefaction, and a disturbed metabolism are important features of a failing right ventricle. Furthermore, an overview is provided about the potential direct RV effects of PH-targeted therapies and the effects of RV-directed medical treatments.