Echocardiographic Insights into Group 2 Pulmonary Hypertension: Unveiling its Prevalence in Advanced Heart Failure Reduced Ejection Fraction

Abstract

Background:

Heart failure (HF) is a clinical syndrome that often leads to the complications such as pulmonary arterial hypertension (PAH), particularly Group 2 PAH secondary to left heart disease (PH-LHD). Echocardiography, a noninvasive tool, is used to assess the hemodynamic changes such as left ventricular ejection fraction (EF) and filling pressures. While most existing studies focused on PAH in HF with preserved EF, this study examines the incidence and hemodynamic impact of PAH in heart failure with reduced ejection fraction (HFrEF), addressing a critical gap in understanding.

Methodology:

A retrospective, analytical cohort study was conducted using the patient details retrieved from the electronic medical records of the HF clinic. Data were collected for the period between January 2018 and December 2021. The convenience sampling was used to identify the patients diagnosed with heart failure with reduced ejection fraction (HFrEF) and secondary PAH based on echocardiographic assessments.

Results:

Among the cohort, 54% of patients exhibited secondary PAH with HFrEF. The significant correlations were found between PAH and left ventricular (LV) hemodynamic changes, including reduced EF, elevated filling pressures, and valve regurgitations such as mitral, tricuspid, and pulmonic regurgitation.

Conclusion:

Despite limitations described, this research demonstrates a robust association between PAH and LV dysfunction in HFrEF patients. The study’s strengths include its adequate sample size and the application of validated echocardiographic methods to assess the hemodynamic changes.

INTRODUCTION

Heart failure (HF), a clinical syndrome that is characterized by the heart’s inability to pump blood effectively, leads to insufficient blood flow to meet the body’s metabolic demands. This condition often results in the complications such as valvular cardiomyopathy and pulmonary arterial hypertension (PAH), particularly Group 2 Pulmonary Hypertension secondary to Left Heart Disease (PH-LHD) represents the most common subtype of pulmonary hypertension (PHT).[1,2,3]

PHT is defined as a mean pulmonary arterial pressure (mPAP) exceeding 25 mmHg at rest, as measured by right heart catheterization (RHC) or echocardiography (ECHO).[4] However, no significant difference between the echo-measured and the catheter-measured pulmonary arterial pressure (0.21 ± 0.17 mL/mmHg, P = 0.23) was noted.[5] ECHO is a noninvasive technique that provides valuable insights into hemodynamic variables such as left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVI), and left ventricular (LV) filling pressure.[6]

HF is commonly classified based on ejection fraction (EF) levels, with a universal classification into Heart failure with reduced ejection fraction (HFrEF) (LVEF ≤40%), HF with mildly reduced EF (LVEF: 41%–49%), HF with preserved EF (HFpEF) (LVEF: ≥50%), and HF with improved EF.[7] Notably, prior studies reported that 83% of HFpEF patients exhibited severe PHT.[8] The impact of hemodynamic characteristics on the clinical outcomes in LV dysfunction (HFrEF) warrants further investigation.

In this study, we focused on HF with reduced EF and PHT, utilizing noninvasive parameters to assess LV function, valvular dysfunctions, and pulmonary arterial pressures.

The aim of this study is to define the incidence of PAH and enhance the understanding of echocardiographic hemodynamic changes that influence prognosis, provide a foundation for improved prediction and management strategies.

METHODOLOGY

This retrospective, analytical and cohort study was conducted at King Abdulaziz Medical City in Jeddah, King Faisal Cardiac Center, Ministry of National Guard Health Affairs-Western Region. Data were obtained from the Cardiac Noninvasive Laboratory and the HF clinics there, covering the period from January 2018 to December 2021.

The study population included all patients who were diagnosed with heart failure with reduced ejection fraction (HFrEF). The inclusion criteria were as follows: adult patients aged ≥18 years, diagnosed with HFrEF (LVEF <40%), diagnosed with arterial PHT (PAH) according to its standard definition within the past 3 years, and has undergone at least a baseline ECHO and a follow-up ECHO within 6 months. The exclusion criteria included patients lost to follow-up, patients without echocardiographic data, and those with multiple comorbidities or any active medical illnesses unrelated to HF.

From a population of approximately 2000 patients, a sample size of 377 was determined using the Raosoft program with a 5% margin of error and a 95% confidence level.[9] A convenience-based consecutive sampling technique (a nonprobability sampling method) was used to identify the eligible patients within the study timeframe.

Data were retrieved from the electronic medical records database and tabulated for analysis. The collected variables were demographic details (e.g., age and gender) and echocardiographic measurements from the cardiac imaging management system. Echocardiographic data encompassed geometric measurements, mPAP, LVEF, LV size, LV filling pressure, and the presence of valvular abnormalities such as mitral regurgitation (MR), pulmonary regurgitation (PR), and tricuspid regurgitation (TR).

The mPAP was estimated from pulmonary artery systolic pressure (PASP) using the TR peak velocity derived from Doppler ECHO using the Bernoulli equation (4 × TR velocity² + right atrial pressure [RAP] estimation). Where RAP was estimated based on the inferior vena cava diameter and its collapsibility. The mPAP was then approximated using the following validated formula: mPAP = 0.61 × PASP + 2 (mmHg).[10] This method provides a reliable noninvasive estimation of pulmonary pressures, correlating well with invasive RHC measurements.

LV filling pressure was assessed using was assessed using pulsed-wave Doppler-derived ratio of mitral inflow velocities (E-wave peak velocity), to tissue Doppler imaging early diastolic mitral annulus velocity (e’), known as the (E/e’ ratio). An E/e’ ratio > 15 was considered indicative of elevated LV filling pressures, while values between 8 and 15 were interpreted alongside other echocardiographic parameters, including left atrial volume index and pulmonary vein Doppler flow pattern.[11]

The severity of valvular regurgitation was assessed following the American Society of ECHO guidelines, classifying severity into trace, mild, moderate, and severe. Evaluations were based on a comprehensive color and spectral Doppler techniques, utilizing semi-quantitative and quantitative parameters such as; Color Doppler Jet Area, Vena Contracta Width, Effective Regurgitant Orifice Area, Regurgitant Volume: and Pulmonary Vein Flow Pattern for MR assessment.[12]

To ensure confidentiality, researchers assigned a unique study code to each patient, replacing medical record numbers. Data analysis was conducted using JMP software. The continuous variables were presented as medians with interquartile ranges, as most data were not normally distributed, whereas categorical variables were expressed as frequencies and percentages. Statistical tests were chosen based on variable distribution and type. P < 0.05 was considered statistically significant.

RESULTS

A total of 381 patients were diagnosed with HF reduced EF (LVEF <40%). The mean age of the patients was 63.7 years (standard deviation [SD] 14.1), with the majority of participants (61%) falling within the 61–70 age range, showcasing that HF and associated complications predominantly affect the elderly population [Figure 1]. A significant gender disparity was observed, with 270 (71%) male participants compared to 111 (29%) female participants, as displayed in Table 1.

Figure 1.

Statistical assessment of clinical characteristics in all patients with heart failure reduced ejection fraction (n = 381)

Table 1.

Comparison of demographic characteristics between heart failure reduced ejection fraction patients with pulmonary arterial hypertension and without pulmonary arterial hypertension (n=381)

Heart failure with PHT, n (%)	Heart failure without PHT, n (%)	Total, n (%)	Patients’ characteristics
			Age
3 (0.8) 7 (1.8) 19 (4.9) 47 (12.3) 57 (14.9) 43 (11.3) 27 (7.1)	6 (1.6) 6 (1.6) 17 (4.5) 40 (10.5) 59 (15.5) 32 (8.4) 18 (4.72)	9 (2.4) 13 (3.4) 36 (9.5) 87 (22.8) 116 (30.4) 75 (19.7) 45 (11.8)	18-30 31-40 41-50 51-60 61-70 71-80 >=81
203 (53.2)	178 (46.8)	381 (100)	Total
			Gender
51 (13.4) 152 (39.8)	60 (15.7) 118 (31.5)	111 (29.1) 270 (70.9)	Female Male
203 (53.2)	178 (46.8)	381 (100)	Total

The mPAP for the overall cohort was 26.5 mmHg (SD 10.5), significantly higher in male patients than in female patients. The mean LVEF was 29.6% (SD 6.5), reflecting the impaired systolic function characteristic of heart failure with reduced ejection fraction (HFrEF). In addition to that, the mean LV filling pressure was 18.1 mmHg (SD 10.1), and the mean LVEDVI was 77.7 mL/m² (SD 30). These hemodynamic parameters, measured through ECHO, provide critical insights into this population’s severity of cardiac dysfunction. Further descriptive statistics, including the confidence intervals for these measures, are shown in Figure 2 and Table 2.

Figure 2.

Statistical assessment of clinical characteristics in male and female patients with heart failure reduced ejection fraction (n = 381)

Table 2.

Descriptive analysis of the hemodynamic changes in patients with heart failure reduced ejection fraction (n=381)

Hemodynamics	Interquartile-range (IQR)	Median
mPAP	15.53	25.75
LVEF	10	30
LV filling pressure	10	16.3
LVEDVI	34	73.5

mPAP: Mean Pulmonary Arterial Pressure, LVEF: Left Ventricular Ejection Fraction, LVEDVI: Left Ventricular End Diastolic Volume Index

RHC was performed in 82 patients (21.5%) for confirmation of PHT and validate hemodynamic estimates derived from ECHO.

Among the study cohort, secondary PAH was diagnosed in 207 patients (54%), displaying that more than half of HFrEF patients had elevated pulmonary pressures, as shown in Figure 3. This finding highlights the high prevalence of pulmonary vascular involvement in left heart disease.

Figure 3.

The incidence of pulmonary arterial hypertension (PAH) in patients with heart failure reduced ejection fraction (HFrEF) 54.3%, (n = 381). PHT: Pulmonary hypertension, HFrEF: Heart failure with reduced ejection fraction

Valvular abnormalities were analyzed in all patients to determine their prevalence and relationship with PAH. Among the cohort, 67% of patients exhibited normal-to-trace PR, 27% had mild-to-moderate PR, and only 6% had moderate-to-severe PR. MR was classified as mild-to-moderate in 39% of cases, while 28% had trace-to-mild MR. TR was predominantly observed as trace-to-mild in 38% of patients, with 27% exhibiting normal-to-trace TR. These findings highlight the frequent coexistence of valvular dysfunction in HF patients, particularly in those with secondary PAH.

Detailed statistical analyses were performed to assess the associations between secondary PAH and other hemodynamic parameters. A nonparametric Wilcoxon signed–rank test evaluated LV characteristics in patients with LVEF ≤40%. The Chi-square tests were applied to examine the relationships between PAH and valvular regurgitations. Significant correlations were detected between mPAP and key parameters, including LVEF (P = 0.001) and LV filling pressure (P < 0.05). These results suggest that reduced EF and increased filling pressures are the vital contributors to the development of PAH in HFrEF patients. These findings are displayed in Table 3.

Table 3.

Statistical analysis of clinical characteristics in patients with heart failure reduced ejection fraction. Nonparametric Wilcoxon signed rank test used for the left ventricular assessments and Chi-square test for the valves regurgitation (n=381)

Hemodynamics	Test statistics	P	Correlation with Pulmonary Arterial Hypertension (yes/no)
Left Ventricular Ejection Fraction	5.52	0.0001	Yes
Left Ventricular End Diastolic Volume	-2.20	0.0275	Yes
Left Ventricular Filling Pressure	-6.6	0.0001	Yes
Mitral Regurgitation	63.65	0.0001	Yes
Pulmonary Regurgitation	24.39	0.0001	Yes
Tricuspid Regurgitation	148.8	0.0001	Yes

P>0.001 means there is no significant association, but if the P<0.001 means there is a significant association

Among the valvular abnormalities, severe MR was remarkably prevalent in patients with PAH compared to those without it. Specifically, 79 (20.7%) patients with PAH had severe MR, compared to 77 (20.2%) patients with mild MR but no PAH. In contrast, pulmonary valves were predominantly normal across the cohort, regardless of PAH status.

Moderate TR was observed in 96 (25.2%) patients with PAH, compared to 65 (17%) without PAH. Notably, no patients with PAH exhibited severe PR, suggesting that it may not play a significant role in this subgroup. These detailed findings are presented in Figure 4 and Table 4.

Figure 4.

Explaining the severity of the valve regurgitation in a patient with pulmonary hypertension (PHT) and without PHT (n = 381). Upper panels: Pulmonary regurgitation (PR), Middle panels: Tricuspid regurgitation (TR), Lower panels: Mitral regurgitation (MR). Left panels show relative frequency (%) by regurgitation severity for mPAP ≤25 mmHg and >25 mmHg and Right panels show the proportion per regurgitation grade stratified by mPAP

Table 4.

Explaining the severity of the valve regurgitation in patient with pulmonary arterial hypertension and without pulmonary arterial hypertension (n=381)

Valve Regurgitation (n=381)	Normal		Mild		Moderate		Severe
	With PHT	Without PHT	With PHT	Without PHT	With PHT	Without PHT	With PHT	Without PHT
TR, n (%)	9 (2.39)	42 (11.02)	68 (17.85)	77 (20.21)	79 (20.73)	8 (2.10)	42 (11.02)	4 (1.05)
PR, n (%)	78 (20.47)	93 (24.41)	66 (17.32)	38 (9.97)	21 (5.51)	2 (0.52)	0 (0)	0 (0)
MR, n (%)	7 (1.84)	24 (6.30)	42 (11.02)	65 (17.06)	96 (25.20)	51 (13.9)	58 (15.22)	15 (3.94)

TR: Tricuspid Regurgitation, PR: Pulmonary Regurgitation, MR: Mitral Regurgitation, PHT: Pulmonary Hypertension

These results give a detailed overview of the hemodynamic and valvular characteristics of HFrEF patients with and without secondary PAH. The significant associations demonstrated in this analysis highlight the complex interplay between left heart dysfunction, pulmonary vascular changes, and valvular abnormalities, contributing to a deeper understanding of the pathophysiology of secondary PAH.

DISCUSSION

Our study reveals that PAH is highly prevalent, affecting 54% of heart failure patients with reduced ejection fraction (HFrEF) in our cohort of 381 participants. This significant prevalence aligns with prior studies that have highlighted the frequent occurrence of PAH in HF patients, particularly in those with advanced cardiac dysfunction.[13,14,15] The strong correlations noted between PAH and hemodynamic parameters, such as reduced LVEF, elevated mPAP, and increased LV filling pressures, underscore the complex interplay between left heart dysfunction and pulmonary vascular pathology. These relationships indicate the hemodynamic burden imposed by LV failure, leading to increased left-sided filling pressures and subsequent pulmonary vascular remodeling, resulting in PAH.[16,17]

Our study adds to the existing body of knowledge by focusing on HFrEF patients, an area often underrepresented in PAH research. Although existing literature has usually concentrated on HFpEF, where PAH prevalence reaches up to 83%,[8,18] our results showcase that PAH is also a critical complication in HFrEF explored in the relationship between pulmonary arterial pressures and echocardiographic parameters, including LVEF, LVEDVI, and LV filling pressures. Markedly, our findings emphasize the role of valvular dysfunction – especially mitral and tricuspid valves regurgitation in exacerbating pulmonary pressures, a relationship that has been previously reported in similar contexts.[13,14,15]

Hemodynamic insights

The pathophysiological basis for PAH in HFrEF lies in the chronic increase in left-sided pressures transmitted to the pulmonary circulation. This leads to pulmonary venous hypertension and, over time, arterial remodeling and elevated pulmonary vascular resistance.[2,3] The important correlation between LVEF and mPAP observed in this study (P = 0.001) emphasizes the direct impact of systolic dysfunction on pulmonary pressures. Similarly, the slightly elevated median LV filling pressures in patients with PAH illustrate the hemodynamic consequences of LV failure.[5] These findings are consistent with prior reports that displayed similar trends in PAH development among HF patients.[16,17]

In addition to that, our findings highlight the contribution of valvular abnormalities to PAH in HFrEF. Mitral and tricuspid valves regurgitation was significantly associated with elevated mPAP, aligning with earlier research that underscores the role of valvular dysfunction in exacerbating pulmonary pressures.[19] The regurgitant flow leads to increasing volume overload on the pulmonary vasculature, further contributing to the progression of PAH. These results suggest that comprehensive management strategies for HFrEF should address both systolic dysfunction and associated valvular abnormalities to mitigate the development and progression of PAH.

Comparison with previous studies

A retrospective study conducted in 2019 with 351 participants similarly examined the relationship between PAH and outcomes in HFrEF.[16] That study reported elevated PASP within 6 months of discharge (P = 0.002) as a marker of PAH progression. Relatively, our study demonstrated significant elevations in mPAP (P < 0.001) over 4 years, further emphasizing the persistent hemodynamic burden in these patients. These findings complement previous work by providing a longer-term perspective on the progression of PAH in HFrEF, reinforcing the need for ongoing monitoring and intervention.[16]

While existing research has drawn parallels between the hemodynamic patterns of HFpEF and HFrEF, our study focuses on the unique challenges PAH poses in the latter group. Although HFpEF patients tend to display a higher prevalence of PAH, HFrEF patients face distinct hemodynamic stressors, including reduced cardiac output and heightened pulmonary vascular resistance that contribute to disease progression.[15,16,17]

Therapeutic strategies for HFrEF patients with pulmonary arterial hypertension

Management strategies for HFrEF and PAH are based on current Guideline-Directed Medical Therapy (GDMT). Optimization of HFrEF therapies, including beta-blockers, renin angiotensin system-inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors, was prioritized to improve LV function and reduce pulmonary pressures.[20] The role of pulmonary vasodilators (e.g., phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators) remains controversial in PAH secondary to left heart disease (Group 2 PH). The current evidence suggests that vasodilators should be used selectively in patients with precapillary or combined post/precapillary PH phenotypes.[21] Correction of MR either Surgical mitral valve repair or replacement: Considered in patients with severe symptomatic MR despite GDMT.[22] Transcatheter mitral valve repair (e.g., MitraClip): Beneficial in selected patients with secondary MR and HFrEF, demonstrating a reduction in pulmonary pressures and improved clinical outcomes.[23] These therapeutic considerations highlight the importance of a multidisciplinary approach in managing PAH in HFrEF, integrating hemodynamic optimization, valvular intervention, and tailored pharmacotherapy to improve outcomes.

Strengths and limitations

This study has several strengths that enhance its contribution to the field. The robust sample size provides statistical power, drawing meaningful inferences. In addition, using validated echocardiographic methods, including Doppler assessments, offers reliable and noninvasive insights into pulmonary and cardiac hemodynamics. These techniques are well-established as the standard tools for evaluating PAH and HF parameters.[6] Furthermore, the study provides a nuanced understanding of the relationship between PAH and HFrEF, strengthening the existing literature.

Nevertheless, the study also has some limitations. The retrospective design constrained the temporal scope, limiting our ability to establish the causative relationships or assess long-term outcomes. In addition to that, incomplete patient records posed challenges, although these were mitigated by employing the validated formulas to estimate missing values. The absence of longitudinal follow-up data further limits our understanding of the progression of PAH and its impact on the clinical outcomes.

Future directions

Future research should focus on evaluating the prognostic implications of PAH in HFrEF patients, particularly concerning the long-term outcomes such as hospitalizations, quality of life, and mortality. In addition, studies exploring the efficacy of targeted therapeutic interventions, including pulmonary vasodilators and optimized management of valvular dysfunction, could provide valuable insights into improving the clinical outcomes in this high-risk population.

CONCLUSION

This study exhibited a high prevalence of PAH among patients with HF and HFrEF. Significant correlations between PAH and key hemodynamic changes, including reduced LVEF, elevated LV filling pressures, and valvular regurgitations, were identified. These findings highlight the significance of early detection and management of PAH in patients with left heart dysfunction to improve the clinical outcomes. Despite our limitations, our research provides a valuable foundation for future studies aimed at better understanding the interplay between pulmonary and LV hemodynamics.

Ethical statement

Obtained from King Abdullah International Medical Research Center IRB/1814/22, study #: SP22J/110/08.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.