Stroke refers to brain, spinal cord, or retinal cell death attributable to ischemia (Sacco et al., 2013). Stroke is one of the leading causes of death and disability worldwide. In 2020, about 7.08 million deaths worldwide were attributable to cerebrovascular disease. Every year, about 795,000 strokes are reported in the United States, of which around 23% are recurrent (Tsao et al., 2023).

Ischemic strokes can be sub-grouped based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) Criteria (Adams et al., 1993). Strokes are most commonly ischemic (Tsao et al., 2023) and, based on the TOAST criteria, can be subdivided into large artery atherosclerosis, lacunar strokes, cardioembolic, embolic strokes of undetermined source, and others. Risk factors can be both modifiable and non-modifiable. The most common modifiable risk factors are Hypertension, smoking, diet, and physical inactivity (Boehme et al., 2017).

As the pathophysiologic mechanisms of different subgroups of strokes are better studied, additional contributory causes are being postulated to cause strokes. One such uncommon association of stroke is pulmonary Hypertension (PH).

Pulmonary Hypertension encompasses a broad spectrum of disorders affecting the pulmonary vascular bed, resulting in increased pulmonary arterial pressure (Anderson and Lau, 2022). Progressive remodeling of the pulmonary vascular bed leads to right ventricle dysfunction. Pulmonary Hypertension is classified based on clinical features and pathophysiology, among which pulmonary Hypertension secondary to pulmonary disease and left heart diseases are much more common.

Pulmonary Hypertension is subdivided into five groups: Pulmonary arterial hypertension (PAH) (group 1), PH with left heard disease (group 2), PH- associated with lung diseases (group 3), chronic thromboembolic pulmonary hypertension (group 4), and unclear and multifactorial mechanisms (group 5) (Anderson and Lau, 2022). The prevalence varies among the subgroups; the prevalence in group 1 is 12.4–268 ppm (patients per million)while in group 4, the prevalence is 14.5–144 ppm (Leber et al., 2021). In one population study in the Netherlands, PH diagnosed by echocardiography has a prevalence of 2.6% (Moreira et al., 2015). The age-adjusted PH mortality rate was 7.9 per 100,000 individuals, and the study also noted an increase of 1.9% per year between 1999 and 2019 (Kang et al., 2022).

Careful assessment of medical history, physical examination, echocardiograms, and hemodynamic parameters (obtained via right-sided heart catheterization) is essential to diagnose and characterize the different forms of PH effectively.

Our study included 7 million inpatient discharge encounters among which 553,085 patients had ischemic stroke. Among this, 16,830 had PH and 536,255 did not have PH. We observed that patients with stroke and PH were, on average, older (76.7 years vs. 69.7 years) and, more commonly, female (63.8% vs. 48.8%; p < 0.0001). A higher proportion of stroke patients with PH died in the hospital (5.7% vs. 3.7%; p < 0.0001) as well as had a longer average LOS [6.3 days (SD 6.2) vs. 5.0 days (SD 6.8); p < 0.0001]. PH patients experienced a higher number of comorbidities than non-PH patients, with 55.8% of PH patients and 26% of non-PH patients having an Elixhauser score of 16 or above. Our study noted that black patients with PH were the youngest [70.5 years (SD 13.8)]. Black patients had the longest (7.8 days SD 8.3) (p < 0.0001). Moreover, after full adjustment, the average patient with stroke and PH had a hospital stay that was 10.5% longer than those without PH [β = 0.1 (0.07, 0.13); p < 0.0001]. In our analysis, patients diagnosed with atrial fibrillation have almost 100% higher odds [OR 1.99 (1.8, 2.2)], and those diagnosed with congestive heart failure (CHF) have 220% higher odds of being diagnosed with PH [OR 3.2 (2.9, 3.5)].

Pulmonary hypertension (PH) is a pulmonary vascular dysfunction with elevated mean pulmonary artery pressure < 20 mm Hg (Simonneau et al., 2019). Early diagnosis and initiation of treatment are crucial as it is estimated that an about 2-year delay in diagnosis is associated with increased disease burden (Maron, 2023). Signs and symptoms are often subtle and non specific. The most common symptoms are progressive dyspnea, fatigue and exhaustion, and decreased exercise capacity. Chest pain, syncope, and symptomatic heart failure can be seen in advanced situations. On exam, loud P2 component of second heart sound, jugular venous distension, S3 gallop, and murmur related to tricuspid regurgitation are present (Hoeper et al., 2017; Frost et al., 2019). The diagnosis is often delayed because of the nonspecific nature of the symptoms.

Initial clues to the diagnosis can be seen with a transthoracic echocardiogram showing increased tricuspid regurgitant jet velocity >2.8 m/s, suggesting elevated pulmonary artery systolic pressure (Maron, 2023). As with all the non-invasive measures, echocardiography has limitations, including suboptimal acoustic windows and the inability to estimate pulmonary artery wedge pressure.

Stroke is a complex neurovascular syndrome caused by varied causes. Effective management of ischemic stroke involves identifying risk factors and managing all the risk facts appropriately to prevent recurrence. About one in three strokes are recurrent and significantly impact patient and health care costs.

There is growing evidence of a relationship between pulmonary hypertension and ischemic stroke. A meta-analysis, including 32,523 patients, showed pooled prevention of stroke in patients with PH to be at 8% and 1.46 more significant risk of stroke in patients with PH than without PH (Shah et al., 2019). In another study using the NIS, PH was noted to independently increase the incidence of all-cause strokes in patients with Atrial fibrillation, leading to increased inpatient stay and mortality (Khattar et al., 2023). A previous study also noted higher inpatient mortality in male patients with pulmonary hypertension and ischemic stroke (Pana et al., 2021). In an observational study of patients with Atrial fibrillation, PH was more commonly associated with ischemic stroke (Karadavut and Cetin, 2022).

The exact pathophysiology is unclear, but possible mechanisms include underlying arteriopathy and hypercoagulable state. PH is a complex vasculopathy that can lead to multiple comorbidities, such as right heart failure and an increased stroke risk. Pulmonary hypertension is also associated with an increased risk of atrial fibrillation and risk of embolic events. Arteriopathy in PH resembles arteriopathy in ischemic stroke patients with sickle cell disease, suggesting shared physiology leading to proliferative vascular intimal and smooth muscle hypertrophy and thrombosis: reduced nitric oxide bioactivity and increased hemolysis (Kato et al., 2006).

In addition to the vasculopathy that underlies PH, a hypercoagulable state is also postulated to be present (Bazan and Fares, 2018). Patients are at an increased risk of developing thrombi. In pulmonary arterial hypertension, there is dysregulation of the coagulation cascade and fibrinolytic system. Postmortem studies reveal a high prevalence of vascular thrombotic lesions—the dysregulation of the fibrinolytic system characterized by increased plasma levels of fibrinogen and fibrinopeptide A- and D-dimers.

The epithelial dysfunction due to the underlying vasculopathy leads to increased plasma levels of von Willebrand factor and plasminogen activator inhibitor type 1, leading to a procoagulant state. The shear effect of the blood on the dysfunctional epithelial surface potentially generates a thrombogenic surface, resulting in increased thrombosis. Tissue factor is a glycoprotein that initiates a coagulation cascade and binds to factor VII to activate factor X. Studies have shown upregulation of tissue factor, and another study found increased tissue factor expressing endothelial microparticles in the circulation.

Our study has important strengths and limitations. The large sample size is a significant strength. In addition, a diverse representation of patients allows for population analysis. Certain limitations are to be considered. Since it is a retrospective study, particular inherent biases come with the study design. The database depends on the use of appropriate ICD-9 coding. So, inconsistencies in coding could have led to missing data. The sample represents about 20% of the admissions, and the sampled discharges within a state are variable. This could lead to underrepresentation and under-sampling. We included data from a single calendar year and could not assess the recent trend.

Pulmonary hypertension is a crucial comorbidly for inpatients, which can potentially lead to increased hospital stay and worse outcomes. In our study, we found that black patients had more extended hospital stays, were younger and Hispanic patients were likely to die in the hospital. Individualized treatment strategies to identify the associated comorbidities can potentially lead to better outcomes for patients admitted with ischemic stroke. More animal models are needed to assess the intricate relationship between stroke and pulmonary hypertension. More clinical trials are needed to assess long-term mortality and morbidity and the effects of antithrombotics on the outcome. More studies is needed to understand the racial differences in the outcomes of patients with ischemic stroke and pulmonary hypertension.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

DJ: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. SK: Formal analysis, Investigation, Methodology, Writing – original draft. GM: Writing – original draft. DR: Conceptualization, Validation, Investigation, Resources, Writing – original draft, Writing – review & editing.