Meta-Analysis: Pulmonary Hypertension as a Multidimensional Risk Factor Across Cardiac and Cerebrovascular Diseases

Meta-Analysis: Pulmonary Hypertension as a Multidimensional Risk Factor Across Cardiac and Cerebrovascular Diseases

Ibrahim Krenawi ¹, Mohamed Abdelrahman ², Mimoun Azizi *³

1. Consultant Neurologist, Ain Alkhaleej Hospital, Al Ain, UAE.
2. Consultant Pneumologist, Kreiskrankenhaus Frankenberg, Frankenberg, Germany.
3. Chief Physician, Senior Consultant Neurologist and Neurogeriatrician, Klinikverbund Südwest, Sindelfingen, Germany.

*Correspondence to: Mimoun Azizi, Chief Physician, Senior Consultant Neurologist and Neurogeriatrician, Klinikverbund Südwest, Sindelfingen, Germany.

Copyright

© 2026 Mimoun Azizi, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 13 July 2026

Published: 01 August 2026

DOI: https://doi.org/10.5281/zenodo.21713760

Abstract

Pulmonary hypertension (PH) is quickly emerging as a systemic vascular disease that is not restricted to the pulmonary circulation but has implications on cardiac and neurologic outcomes. This meta-analysis is a compilation of recent clinical studies designed to determine the value of PH as a multidimensional risk factor in the cardiovascular and cerebral tropes. Existing evidence shows that PH is a major risk factor that greatly increases the risk of stroke, neurologic outcome, and short and long-term survival. The mechanistic pathways are right-ventricular dysfunction, paradoxical embolism, endothelial inflammation, and systemic hypoperfusion. NT-proBNP, troponin, and IL-6 are examples of biomarkers that have prognostic value and can be used to inform individualized management. The development of molecular therapy, regenerative medicine, and AI-based diagnostics has the potential to turn around PH practices to become one based on precision prevention instead of symptomatic control. It is encouraged that clinicians consider PH as a significant predictor of systemic vascular risk and that it needs unified management that safeguards the cardiac and cerebral health.

Keywords: Pulmonary Hypertension, Stroke Risk, Heart Failure, Right Ventricular Dysfunction, Cardiovascular Disease, Cerebrovascular Events, Precision Medicine, Future Therapies, and Precision Medicine in Pulmonary Hypertension.

Abbreviations

Introduction

Pulmonary hypertension (PH) is increasingly recognized as a multidimensional cardiovascular disorder that extends well beyond the pulmonary vasculature [1]. Previously viewed as a niche pulmonary disorder, PH is now recognized as a systemic vascular syndrome, which affects the performance of the heart and the brain circulation [2]. Increased pulmonary pressures exert a chronic load on the right ventricle, disable left-sided filling, and produce endothelial dysfunction and inflammatory stimulus spread to the vascular system [3].

This understanding has been enhanced by recent analyses. Meta-analytic data published in the International Journal of Cardiology (2019, 2020) demonstrated that the population of PH subjects has approximately 46% higher odds of stroke than non-PH populations (pooled OR 1.46, 95% CI 1.07-1.99) [3]. Registry studies also indicate that PH is extremely prevalent, 30 to 60% of patients with left-sided heart failure and 20% to 50% of patients with severe aortic stenosis indicating that it is a comorbidity that is both extremely prevalent and clinically decisive [1].

PH clinically predicts increased procedural risk, increased rehospitalization, and worse neurologic recovery after cerebrovascular or cardiac events [2]. Mechanistic considerations imply that the PH is associated with cerebral ischemia and stroke through paradoxical embolism, right-ventricular dysfunction with systemic hypoperfusion, and a pro-inflammatory, pro-thrombotic vascular environment [3].

According to the European Heart Journal (2023), pulmonary hypertension is to be discussed as a systemic vascular disease, a common platform in which cardiology, pulmonology, and neurology overlap. Early diagnosis and proactive control of PH can have a significant impact on outcomes in patients in cardiovascular and cerebrovascular sectors [4].

Understanding Pulmonary Hypertension

PH is a complicated hemodynamic condition characterized by a mean pulmonary arterial pressure of ≥ 20 mm Hg, and above, which is proven by right-heart catheterization [5]. According to the World Health Organization, it belongs to 5 categories:

• Pulmonary arterial hypertension (Group 1)
• PH due to left-heart disease (Group 2)
• PH associated with lung disease or hypoxia (Group 3)
• Chronic thromboembolic PH (Group 4)
• PH with multifactorial or unclear mechanisms (Group 5).

PH represents much more than high pulmonary pressure, clinically, and it is an indicator of dysfunction of the systemic vascularity [2]. In case the pulmonary circulation is hypertensive, the right ventricle is subjected to chronic pressure overload, and dilation, impaired forward flow, and secondary effects on the left-sided filling pressures are observed [3]. These downstream effects lower the heart output and impair cerebral perfusion, forming the physiological linkage between cardiopulmonary and neurologic pathology [1].

The epidemiology of PH underscores its broad impact. According to the Journal of the American College of Cardiology (2020), up to half of all heart-failure patients exhibit quantifiable pulmonary hypertension, with the European Heart Journal (2023) describing PH in almost one-third of all severe aortic-stenosis groups [4], [2]. This kind of prevalence proves PH to be a frequent comforter of cardiovascular disease and not a rare pulmonary condition [1].

The contemporary understanding of PH considers it to be a cardiopulmonary cerebrovascular continuum. In such a paradigm, the lungs are not a passive pipe but the active controller of the systemic vascular tone and inflammatory signals [3]. Chronic pulmonary vascular remodeling, which is typified by endothelial malfunction, loss of nitric oxide, and cytokine elevation, culminates in systemic hypertension, arrhythmogenesis, and a pro-thrombotic environment, which eventually increases the risk of stroke [4].

As the Mayo Clinic noted in 2023, pulmonary hypertension is increasingly understood as a systemic condition that links heart, lung, and brain health through shared vascular pathways [6].

Recognizing this interconnected physiology equips physicians to interpret PH not simply as an isolated diagnosis but as a warning sign of widespread vascular stress requiring comprehensive management across specialties [2].

Prevalence Across Major Cardiovascular and Systemic Conditions

Pulmonary hypertension (PH) is neither a unique nor unusual finding- it is a widespread vascular outcome of various cardiac and systemic conditions [1]. Modern registry studies and meta-reviews can attest that PH is often comorbid with left-sided heart disease, valvular pathology, and congenital lesions, as well as certain systemic pathologies: sleep-disordered breathing and sickle cell disease [7]. It is important to appreciate that the prevalence of C. perfringens is common in these environments to detect and risk-stratify them as early as possible [2].

PH in Left-Heart Disease (HFpEF and HFrEF)

Among patients with heart failure, PH represents one of the strongest markers of disease progression and adverse prognosis [4]. According to studies summarized in the Journal of the American College of Cardiology (2020) and Heart Failure Reviews (2016), 30-60 percent of persons with preserved and reduced ejection fractions have high pulmonary pressures, measured either by echocardiography or by right-heart catheterization [7]. Even slight increases in pulmonary artery systolic pressure are associated with a decrease in exercise abilities, rise in admissions, and mortality [2].

PH in Valvular Heart Disease (Aortic Stenosis)

PH in severe aortic stenosis is an indication of chronic pressure overload that is directed retrograde to the left atrium and pulmonary veins [1]. According to the analysis of transcatheter and surgical large-scale cohort data, provided in the European Heart Journal (2023), PH is found in about 20-50 percent of patients before valve intervention [2].

PH alone is a predictor of poorer peri-procedural hemodynamic and decreased long-term survival, which highlights the significance of early detection and intervention [4].

PH in Congenital Heart Disease and Pediatric Populations

Pulmonary hypertension of congenital lesions depends on the type of shunt and the size and chronicity of the defects [8]. The European Journal of Preventive Cardiology (2019) demonstrates that the pathophysiologic profiles of adults having repaired congenital defects and idiopathic or left-heart-related PH differ [9]. Invasive research like the one by Di Maria et al. (2014) in children revealed that stroke work of the right ventricles and pulmonary vascular resistance serve as powerful predictors of outcome because pediatric PH has its own prognostic and hemodynamic signature [8].

PH in Special Systemic Conditions

Beyond typical cardiac etiologies, PH manifests as systemic diseases that have chronic hypoxia or hemolytic stress. According to Pediatric Pulmonology (2023), in children with sickle-cell disease, sleep-disordered breathing, PH, and high stroke risks were associated with sleep-disordered breathing and PH [3]. Similarly, obstructive sleep apnea in adults mediates intermittent hypoxic vasoconstriction and endothelial damage, which is a promotion of PH in the absence of underlying heart disease [4].

Table 1: Reported Prevalence of Pulmonary Hypertension Across Major Disease Categories

All these data indicate that PH is not only very common in the spectrum of cardiovascular diseases but also a strong predictor of the hemodynamic burden and systemic vascular stress. This prevalence places the clinicians on alert- regular screening of the echocardiogram in the high-risk groups can identify the early changes in the pulmonary vascular system before the conditions develop to severe dysfunction [2].

Quantitative Analysis and Results

Association Between Pulmonary Hypertension and Stroke

In the last few years, the relationship between pulmonary hypertension (PH) and the risk of stroke has been investigated in two independent systematic reviews and meta-analyses. The largest of these studies, which aimed to determine the stroke prevalence and the unadjusted odds ratio (OR) of patients with PH against non-PH controls, were reported by Shah TG, Sutaria JM, Vyas MV (International Journal of Cardiology, 2019; 2020) and showed that patients with PH were reported to have a pooled stroke prevalence of 8.0 percent (95 % CI 5.1 -10.9) and an unadjusted odds ratio (OR) of 1.46 (95 % CI 1.07 – 1.99) for stroke compared with non-PH controls. Despite heterogeneity across cohorts (I² ≈ 55%), the directional association remained consistent, confirming PH as an independent cerebrovascular risk amplifier [3].

This graph visually summarizes the meta-analytic evidence linking pulmonary hypertension (PH) to increased stroke risk, based on data extracted from Shah TG, Sutaria JM, Vyas MV (2019, 2020), Khattar G, El Gharib K, Chapman W, et al. (2023), and Pana TA, Dawson DK, Mohamed MO, et al. (2021) [1],[3].

Interpretation:

Each horizontal line represents a study’s estimated odds ratio (OR) for stroke in patients with PH compared to those without PH, along with its 95% confidence interval (CI).

• The boxes (navy squares) mark the point estimate (the measured OR).
• The horizontal lines show the range of uncertainty (95% CI).

The vertical dashed line at OR = 1.0 represents the “no difference” threshold.Moreover, a 2023 study by Khattar G, El Gharib K, Chapman W, et al. (Journal of Stroke and Cerebrovascular Diseases, 2023) also supported these findings, noting that PH is an under-recognized risk factor for stroke among patients with atrial fibrillation (AF). This result in that review correlated the presence of PH with AF with a much greater incidence of embolic stroke than AF alone, indicating synergistic pathophysiology attributable to right-atrial stasis, increased systemic load, and endothelial dysfunction.

This Graph illustrates the difference in stroke incidence among patients with atrial fibrillation (AF), comparing those with pulmonary hypertension (PH) to those without it. The data are derived from Khattar G, El Gharib K, Chapman W, et al. (Journal of Stroke and Cerebrovascular Diseases, 2023) [1].

Interpretation:

The bar chart shows that stroke incidence in AF patients without PH is approximately 6.5%, whereas those with AF and PH experience a markedly higher rate of around 11%. The clear separation between the two bars visually reinforces the conclusion that PH significantly augments thromboembolic risk in the AF population.

Subgroup and Modifier Analyses

Atrial Fibrillation (AF):

In AF cohorts, PH continuously increases thromboembolic risk. The mechanisms suggested by the impaired right-atrial emptying, systemic venous stasis, and an increased inflammatory signaling are known as the mechanisms of the mechanistic hypothesis. This trend is in line with the suggestion made by Khattar G, El Gharib K, Chapman W, et al. (2023), according to which PH ought to be included in AF stroke-risk models [1].

Sex Differences:

Pana TA, Dawson DK, Mohamed MO, et al. (Journal of the American Heart Association, 2021) found that data made the sex-specific differences in the results of ischemic strokes in patients with PH [10]. While pulmonary hypertension did not show a significant link to in-hospital death, it was connected to longer hospital stays and unfavorable discharge outcomes. Male patients with PH had a higher likelihood of experiencing in-hospital mortality compared to female patients. The recovery patterns of women with PH differed of men, which could be due to hormonal adjustment in vascular tone and microvascular responsiveness.

Congenital Heart Disease (CHD):

Lavie CJ, et al. (European Journal of Preventive Cardiology, 2019) note that in adults with CHD, right-to-left shunts allow paradoxical embolism, and this phenomenon complicates PH, which supports a possible causal relationship between the physiology of PH and ischemic cerebral events [11].