The Significance of Right Ventricular Dysfunction in Patients With Heart Failure With Preserved Ejection Fraction

Having healthy pulmonary blood vessels, the left ventricle (LV) is able to maintain adequate circulation even in the absence of the right ventricle (RV). However, if LV systolic or diastolic dysfunction develops or pulmonary vascular disease occurs, RV function becomes crucial for maintaining normal cardiac output and preventing systemic venous congestion.

In patients with heart failure with reduced ejection fraction (HFrEF), the adverse impact of RV dysfunction (RVD) on clinical status and prognosis is well established. However, approximately half of patients with heart failure have preserved ejection fraction, while the influence, mechanisms, and prognostic significance of RVD in patients with heart failure with preserved ejection fraction (HFpEF) remain unclear. A better understanding of RV and pulmonary artery (PA) assessment in patients with HFpEF is particularly important given the current lack of effective treatment for HFpEF and the urgent need for therapies targeting the pulmonary vasculature and the right heart.

A study analyzing the hemodynamics, clinical characteristics, and prognosis of HFpEF according to the presence of RVD comprehensively evaluated and compared the impact of RVD in patients with HFpEF and controls. The investigators analyzed the clinical and hemodynamic factors associated with RVD and examined the effect of RVD on outcomes in HFpEF.

Research Methods

Two groups were studied: 96 patients with HFpEF and 46 patients in the control group. These patients were treated at the Mayo Clinic between April 2005 and August 2012 and underwent right heart catheterization and echocardiography within 48 hours. HFpEF was diagnosed by cardiologists according to the Framingham criteria.

Patients had an EF ≥50% for more than 6 months and increased PA systolic pressure ≥15 mm Hg at rest or ≥25 mm Hg during exercise. Patients with congenital heart disease, endocarditis, carcinoid syndrome, amyloidosis, constrictive pericarditis, hypertrophic cardiomyopathy, severe valvular disease, acute coronary syndrome, unstable hemodynamics, or a prosthetic mitral valve were excluded.

Patients who experienced exertional dyspnea but had no evident cardiovascular disease after right heart catheterization were included in the control group. The study was approved by the Mayo Clinic Institutional Review Board. Right heart catheterization was performed with patients in the supine position via the jugular or femoral veins using a balloon-tipped catheter. Right atrial, RV, and pulmonary artery pressures were measured at end-expiration.

The transpulmonary gradient (TPG) was calculated by subtracting pulmonary capillary wedge pressure from PA pressure, and pulmonary vascular resistance was calculated by dividing TPG by cardiac output. Pulmonary artery compliance was determined using stroke volume and PA pulse pressure. Two-dimensional and Doppler echocardiography were performed by experienced echocardiographers and cardiologists. LV ejection fraction (LVEF) was determined using the modified Quinones formula. RV and atrial dimensions were measured from the apical four-chamber view.

RV length and diastolic diameters at the base and midventricular level were measured. RV function was assessed by tricuspid annular plane systolic excursion and RV fractional area change, determined by tracing the endocardium in the apical four-chamber view during systole and diastole. RVD was diagnosed when RV fractional area change (RVFAC) was <35%, as recommended in the guidelines. Right atrial volume was assessed immediately before tricuspid valve opening to obtain the maximum right atrial volume. Tricuspid and pulmonary valve regurgitation were assessed using a standardized grading scheme.

Results

Patients with HFpEF and controls were equally distributed by sex, but patients with HFpEF were older and had higher body weight. Nearly half of the patients with HFpEF (45%) were hospitalized for decompensated HF, and 71% had class III or IV functional symptoms. HFpEF was more frequently associated with comorbidities than in the control group, including diabetes, primary hypertension, ischemic heart disease, renal insufficiency, and anemia.

Heart rate was similar in both groups. Left- and right-sided cardiac filling pressures were increased in the HFpEF group, along with increased PA pressure, pulmonary vascular resistance, and TPG, while PA compliance was lower in the HFpEF group than in the control group. Pulmonary hypertension was detected in 81% of patients with HFpEF.

LV diastolic dysfunction, LV mass, and left atrial volume were greater in the HFpEF group. LV size and LVEF were similar in both groups. Right atrial volume and RV size were greater in the HFpEF group. RV diastolic volume correlated with PA wedge pressure in the HFpEF group but not in the control group. Tricuspid and pulmonary valve regurgitation were more common in patients with HFpEF than in controls. RV systolic function was more impaired in the HFpEF group.

RVFAC and tricuspid annular plane systolic excursion were 20–25% lower in the HFpEF group. Even after adjustment for increased PA pressure and transpulmonary resistance, RVFAC remained significantly lower in the HFpEF group than in the control group, indicating reduced primary RV contractility rather than simply increased RV afterload. The RVFAC-to-PA pressure ratio was also lower in the HFpEF group. RVFAC correlated with LVEF and systolic LV function in the HFpEF group and was closely associated with longitudinal RV contraction.

Correlation Between RVD and HFpEF

One-third (33%) of patients with HFpEF were diagnosed with right ventricular dysfunction (RVD). Compared with patients with HFpEF without RVD, RVD was more common in men and in patients with ischemic heart disease, renal insufficiency, and elevated BNP levels. Patients with RVD had higher LV filling pressures, more severe pulmonary vascular disease, and lower LVEF. Although systemic blood pressure, cardiac index, and pulmonary artery pressure were similar in groups with and without RVD, the ratio between RV filling pressure and PA wedge pressure was higher in the RVD group. In patients with HFpEF and RVD, RV volume was greater, RV ejection fraction was lower, RV dilation was more pronounced, and RV longitudinal contraction was more impaired than in patients without RVD. Tricuspid and pulmonary valve regurgitation and LV diastolic dysfunction were similar in groups with and without RVD.

Logistic regression analysis revealed that the strongest predictors of RVD were atrial fibrillation (AF), reduced LVEF, left atrial size (LAS), and lower cardiac index (Table 2). LAS did not fully explain RV dysfunction in patients with HFpEF, but in the presence of LAS and HFpEF, RV function was worse than in the control group. Age, tricuspid valve regurgitation, and PA wedge pressure were not predictors of RVD. RVD was more pronounced in men with HFpEF than in women, despite a similar severity of pulmonary hypertension. Patients with HFpEF who had sinus rhythm and AF were also compared.

In patients with AF, greater dilation of the right heart chambers, worse RV and right-sided function, and higher PA pressure were identified. Tissue Doppler imaging revealed lower septal tricuspid annular velocity in patients with AF than in those with sinus rhythm, while lateral tricuspid annular velocities were similar in both groups. In patients with HFpEF and AF, RV contraction was not related to PA pressure or transpulmonary resistance, unlike in patients with sinus rhythm. This suggests that RV contraction in patients with AF may be associated with factors independent of loading conditions.

Right Ventricular Dysfunction and Prognosis

The study participants were followed for an average of 529 days, during which 31% of patients with HFpEF died. Patients with HFpEF and RVD had a higher mortality rate than those without RVD. RVD was the strongest predictor of mortality and was more significant than RV dilation, the severity of pulmonary hypertension, or left heart dimensions and function (3).

Discussion

This was the first study to comprehensively evaluate the structure and function of the right heart chambers in well-characterized patients with HFpEF using echocardiography and invasive right heart catheterization. Compared with the control group, patients with HFpEF had enlargement of the right heart chambers, RV diastolic dysfunction, impaired RV contractility, and increased RV afterload.

RV function in HFpEF was related to hemodynamic factors, including the severity of pulmonary hypertension and ventricular function, as well as non-hemodynamic factors such as male sex, LVEF, AF, and other pathophysiological factors. RVD was associated with increased mortality in HFpEF, particularly in the presence of elevated PA pressure. These results highlight the importance of RVD in the pathophysiology of HFpEF and suggest that reducing PA pressure, maintaining interventricular septal function, and restoring and maintaining sinus rhythm may be beneficial for improving RV function and achieving more successful treatment of HFpEF.

Afterload and RVD in HFpEF

Impaired RV systolic function in HFpEF is associated with impaired myocardial contractility and increased RV afterload. In patients with HFpEF, RV shortening decreases more rapidly as PA pressure increases than in the control group. This indicates that the RV in HFpEF is particularly sensitive to increases in afterload, similar to LV sensitivity in heart failure with reduced ejection fraction. Patients with HFpEF have an increased transpulmonary gradient and PA resistance.

This confirms the significant role of pulmonary vasculopathy in patients with HFpEF. RVD is related to the transpulmonary gradient but not to PA wedge pressure. Therefore, reducing PA pressure may be more important for improving RV function than simply reducing preload through an effect on PA wedge pressure. The increased RV afterload observed in this study, together with the inverse relationship between RV function and PA pressure, suggests that new therapies targeting the pulmonary vasculature may be effective in patients with HFpEF. Pulmonary vascular resistance was only slightly increased, but treatment targeting the pulmonary vasculature may nevertheless be beneficial in reducing afterload-dependent RVD.

Sex and RVD in HFpEF

Male sex is a predictor of RVD in patients with HFpEF, independent of the severity of pulmonary hypertension and LV dysfunction. There is evidence that men with pulmonary hypertension have shorter survival and more impaired RV function than women, despite similar treatment with pulmonary vasodilators.

Previous studies involving patients with HFpEF have shown lower survival rates in men than in women, and much of the evidence from this study also indicates that this sex difference may be related to differences in RV function and structure.

Atrial Fibrillation and RVD in HFpEF

The study found that the presence of AF is an independent predictor of RVD in patients with HFpEF. Patients with heart failure with reduced ejection fraction, RVD, and normal PA pressure are more likely to have AF. Cardioversion from AF to sinus rhythm may improve RV function, most likely through improved longitudinal contraction of the septum.

This finding is consistent with the observation that, in patients with HFpEF and AF, systolic tricuspid annular velocity assessed by tissue Doppler imaging is lower at the septal annulus than at the lateral annulus. Atrial fibrillation is quite common among patients with HFpEF—approximately 66% of the HFpEF group had previously experienced or currently had AF. Recent studies indicate that neurohumoral activation, functional impairment, and worse outcomes are characteristic of patients with HFpEF and concomitant AF, supporting the importance of restoring and maintaining sinus rhythm.

Interaction Between the Left and Right Ventricles in HFpEF

The left and right ventricles are connected in series, but because they contract side by side, they also influence each other through the interventricular septum and the pericardium, which provide mechanical support. These factors can significantly alter RV function during systole and diastole. Diastolic ventricular interaction is more pronounced in patients with heart failure and enlarged right heart chambers because of increased pericardial constraint. In patients with HFpEF and RVD, this study found an increased ratio between RV diastolic pressure and PA wedge pressure, as well as a positive correlation between RV diastolic volume and PA wedge pressure, indicating increased diastolic ventricular interaction.

RVD and Prognosis in HFpEF

Interestingly, measures of RV function in this study correlated more strongly with prognosis than measures of LV function. Consistent with previous studies, pulmonary hypertension was a predictor of increased mortality in patients with HFpEF. An important finding was that RVD in HFpEF was a stronger predictor of prognosis than the severity of pulmonary hypertension. It is assumed that RVD in HFpEF develops as a consequence of pulmonary hypertension; therefore, treatment directed at the right ventricle—reducing RV afterload, maintaining sinus rhythm, and improving RV contraction—may offer the potential for better outcomes.

Limitations

This retrospective study was conducted according to predefined eligibility criteria. Because good-quality echocardiographic images were required, obese patients constituted a minority of the study population. Hemodynamic and echocardiographic assessments were not performed simultaneously but within 48 hours of each other. Accurate assessment of RV function was not always possible because of the complex geometry of the RV. The sample size and number of outcomes in this study were small.

Conclusions

Remodeling and impaired function of the right heart occur in HFpEF and are associated with increased mortality and morbidity. RVD in HFpEF is associated with increased afterload, but it does not develop solely as a consequence of increased afterload.

RVD is independently associated with male sex and atrial fibrillation. RVD is a predictor of mortality in HFpEF and ultimately results from pulmonary vascular disease and venous congestion. Therefore, further studies are needed to evaluate the effectiveness of therapies aimed at improving RV function by treating cardiac rhythm disturbances, the pulmonary vasculature, and the right heart itself.

According to the article by V. Melenovsky, S. J. Hwang, G. Lin et al., “Right Heart Dysfunction in Heart Failure With Preserved Ejection Fraction,” published in the European Heart Journal (2014).

Prepared by Card. Res. M. Kundrotas

Source: “Lietuvos gydytojo žurnalas”