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Pulmonary hypertension (PH) is a life-threatening complication in dogs with cardiopulmonary disease. Epoprostenol is an intravenous pulmonary vasodilator used to treat PH in humans; however, its efficacy in dogs remains unknown. We investigated the cardiovascular effects of epoprostenol and several cardiac agents for acute heart failure in canine models of chronic PH. Six dogs with chronic PH were anesthetized and underwent right heart catheterization and echocardiography before and after infusion of epoprostenol, dobutamine, dopamine and pimobendane. (The drug administration order was the same for all dogs). High-dose epoprostenol (15–20 ng/kg/min) tended to decrease pulmonary arterial pressure (PAP) while significantly decreasing pulmonary and systemic vascular resistance and increasing left and right ventricular (LV and RV, respectively) function. Pimobendan significantly increased LV and RV functions without increasing PAP. Conversely, dobutamine and dopamine significantly increased LV and RV function as well as PAP. This study revealed the efficacy of epoprostenol in treating canine PH through its pulmonary and systemic vasodilating effects. Although catecholamines improve LV and RV function, they might worsen PH pathophysiology, and careful monitoring may be necessary when using these drugs. Pimobendan improved LV and RV function without increasing PAP; however, a stronger vasodilating effect was observed with epoprostenol.

Abstract Rationale Normal mean pulmonary arterial pressure (mPAP) is 14.0 ± 3.3 mm Hg (mean ± SD). The prognostic relevance of mildly elevated mPAP not fulfilling the definition of pulmonary hypertension (PH; mPAP ≥ 25 mm Hg) has not been prospectively evaluated in a real-world setting. Objectives To assess the association of resting mPAP with all-cause mortality in a retrospective and a prospective cohort of patients with unexplained dyspnea and/or at risk of PH. Methods Prognostic cutoffs were calculated by means of 1) classification and regression tree (CART) analysis without any preset thresholds, and 2) preset thresholds on the basis of literature data defining mPAP as lower-normal (≤mean + 1 SD), upper-normal (between mean + 1 SD and mean + 2 SD), borderline (between mean + 2 SD and 25 mm Hg), and manifest PH (≥25 mm Hg). We performed univariate and multivariate survival analysis adjusted for age and comorbidities. Measurements and Main Results We enrolled 547 patients, of whom 137, 56, 64, and 290 presented with lower-normal, upper-normal, or borderline mPAP, and manifest PH, respectively. The CART analysis on mPAP discriminated three prognostic groups: mPAP less than 17 mm Hg, 17 to 26 mm Hg, and greater than 26 mm Hg, with significantly decreasing survival. The univariate analysis on the basis of preset thresholds showed that upper-normal mPAP, borderline mPAP, and manifest PH were significantly associated with poor survival compared with lower-normal mPAP. In the multivariate model, considering age and comorbidities, only borderline mPAP (hazard ratio, 2.37; 95% confidence interval, 1.14–4.97; P = 0.022) and manifest PH (hazard ratio, 5.05; 95% confidence interval, 2.79–9.12; P < 0.001) were significantly associated with poor survival. Conclusions In patients at risk for PH and/or with unexplained dyspnea, CART analysis detects prognostic thresholds at a resting mPAP of 17 mm Hg and 26 mm Hg, and values between 20 mm Hg and 25 mm Hg represent an independent predictor of poor survival. Clinical trial registered with www.clinicaltrials.gov (NCT 01607502).

The ratio of tricuspid annular plane systolic excursion (TAPSE) to echocardiographically measured systolic pulmonary artery pressure (PASP) has been proposed as a surrogate of RV-arterial coupling. In this analysis, we assess the prognostic role of TAPSE/PASP for early clinical deterioration and short-term mortality in an often clinically challenging population of intermediate-high–risk patients with pulmonary embolism (PE). A post hoc analysis of intermediate-high–risk patients with PE enrolled in the Italian Pulmonary Embolism Registry (ClinicalTrials.gov: NCT01604538) was performed. All patients underwent transthoracic echocardiography at admission. The primary and secondary outcomes were clinical deterioration within 48 hours from admission and 30-day all-cause mortality, respectively. In 422 intermediate-high–risk patients with PE (mean age 71.2 ± 5.3 years, 238 men), 37 (8.7%) experienced clinical deterioration within 48 hours of admission. The 30-day mortality rate was 6.6% (n = 28). The receiver operating characteristic analysis established 0.33 as the optimal cut-off value for the TAPSE/PASP in predicting 48-hour clinical deterioration (area under the curve 0.79 ± 0.1). The sensitivity, specificity, positive predictive value, and negative predictive value were 81%, 88.5%, 40.5%, and 97.9%, respectively. The multivariate Cox regression analysis showed that a TAPSE/PASP ≤0.33 was an independent predictor of 48-hour clinical deterioration (hazard ratio 2.06, 95% confidence interval 1.98 to 2.11, p <0.0001) and 30-day mortality (hazard ratio 2.28, 95% confidence interval 2.25 to 2.33, p <0.001). TAPSE/PASP shows promise as a noninvasive prognostic predictor to identify intermediate-high–risk patients with PE at a higher risk of early clinical deterioration and short-term mortality.

The development of pulmonary arterial hypertension (PAH) can complicate many interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). We sought to characterize the prevalence of PAH and its impact on survival in patients with advanced IPF. Retrospective analysis of consecutive IPF patients undergoing pretransplantation right heart catheterization. Lung transplant and IPF referral center. PAH was defined as a mean pulmonary artery pressure (mPAP) of > 25 mm Hg. We compared demographic, spirometric, 6-min walk test (6MWT) results, and survival outcomes between those with PAH and those without PAH. Seventy-nine patients were included in the study. PAH was present in 31.6% of patients (mean [± SD] mPAP, 29.5 ± 3.3 vs 19.1 ± 3.7 mm Hg, respectively). Those patients with PAH had a lower mean diffusing capacity of the lung for carbon monoxide (Dlco) (37.6 ± 11.3% vs 31.1 ± 10.1%, respectively; p = 0.04) and were more likely to require supplemental oxygen (66.7% vs 17.6%, respectively; p < 0.0001). Mean distance walked (143.5 ± 65.5 vs 365.9 ± 81.8 m, respectively; p < 0.001) and mean pulse oximetric saturation nadir (80.1 ± 3.7% vs 88.0 ± 3.5%, respectively; p < 0.001) during the 6MWT were also lower among those with PAH. PAH was associated with a greater risk of death during the study period (mortality rate, 60.0% vs 29.9%, respectively; odds ratio, 2.6; 95% confidence interval [CI], 2.3 to 3.1; p = 0.001). One-year mortality rates were higher in those with PAH (28.0% vs 5.5%, respectively; p = 0.002). As a predictor of mortality, PAH had a sensitivity, specificity, and accuracy of 57.1%, 79.3%, and 73.4%, respectively. There was a linear correlation between mPAP and outcomes with higher pressures associated with a greater risk of mortality (hazard ratio, 1.09; 95% CI, 1.02 to 1.16). FVC and Dlco did not predict outcomes. PAH is common in advanced cases of IPF and significantly impacts survival. A reduced Dlco, supplemental oxygen requirement, or poor 6-min walk performance should raise suspicion of the presence of underlying PAH. Identifying PAH might be an important adjunct in monitoring disease progression, triaging for transplantation, and guiding therapy.

Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase, and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting.

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.

Abstract Background Tricuspid regurgitation peak velocity (pTRV) is commonly used to estimate pulmonary arterial systolic pressure in dogs but is not always obtainable. Echocardiographic changes may suggest pulmonary hypertension (PH) probability, but not all of them equally reflect severity. Hypothesis/Objectives Develop a composite echocardiographic score predicting pTRV in dogs. Animals Client-owned dogs (n = 118) undergoing echocardiography for various cardiorespiratory reasons. Methods Multicenter retrospective study of dogs with identifiable tricuspid regurgitation. Echocardiographic findings were categorized into 6 a priori variables consisting of structural and flow-related abnormalities. Variable weighting was explored using regression analysis and cut-off scores were established for predicting pTRV ≥ 3.4 and ≥ 4.3 m/s using receiver operating characteristic (ROC) curves, and the predictive performance of the PH score also was assessed. Correlations between PH score and pTRV were analyzed, and intra- and interrater measurement reliability was evaluated. Results A final weighted PH score (25-point) incorporated semiquantification of right ventricular (RV) wall thickening (0/1/2 points), RV dilatation (0/2/4/6), right atrial (RA) enlargement (0/2/4/6), pulmonary artery enlargement (0/2/4/6), interventricular septal flattening (0/2/4), and midsystolic notching of RV outflow (0/1). In dogs without severe left atrial enlargement (LAE), 89% of cases were correctly stratified (area under the curve [AUC], 0.95), whereas performance was limited in dogs with postcapillary PH and marked LAE. Five-fold cross-validation identified final recommended thresholds of 3 (predicting pTRV ≥ 3.4 m/s) and 9 (pTRV ≥ 4.3 m/s). The PH score correlated with pTRV (rs = 0.88, P < .001) and showed excellent intra- and inter-rater agreement (intraclass correlation coefficient [ICC] > 0.95). Conclusions and clinical importance The PH score may serve as a complementary tool for evaluating PH in dogs, particularly in those without severe LAE.

Pulmonary hypertension (PH) is a frequent and important complication of chronic obstructive pulmonary disease (COPD). It is associated with worse clinical courses with more frequent exacerbation episodes, shorter survival, and greater need of health resources. PH is usually of moderate severity and progresses slowly, without altering right ventricular function in the majority of cases. Nevertheless, a reduced subgroup of patients may present disproportionate PH, with pulmonary artery pressure (PAP) largely exceeding the severity of respiratory impairment. These patients may represent a group with an exaggerated vascular impairment (pulmonary vascular phenotype) to factors that induce PH in COPD or be patients in whom idiopathic pulmonary arterial hypertension (PAH) coexist. The present review addresses the current definition and classification of PH in COPD, the distinction among the different phenotypes of pulmonary vascular disease that might present in COPD patients, and the therapeutic approach to PH in COPD based on the available scientific evidence.

The desat max of 2-chair test, claimed to have identified the sildenafil responsiveness in COPD-PH (pulmonary hypertension), should represent high PVR (pulmonary vascular resistance). Hemodynamically diagnosed PH in CLD (chronic lung disease)-patients were analyzed statistically and divided into two groups on high or low PVR (>2 and ≤2 Wood units) to judge the power of the desat-max of 2-chair test differentiating them. Co-relationship of desat-max was sought with different spirometric, Doppler-echocardiographic, and RHC (right heart catheterization) derived parameters as TPG (trans-pulmonary gradient), PVR, mPAP (mean pulmonary pressure) and PCWP (pulmonary capillary wedge pressure). Further, the specificity and sensitivity of variable desat-max values were calculated and high PVR and a VIP plot was drawn with all available variables to see their impact on PVR compared to desat-max. We included 57 patients of CLD-PH consisting of COPD (n=26), chronic asthma (n=9), ILD (n=7), and miscellaneous diseases (n=15). When divided on high or low PVR, the two groups (n=39 and 18) stood similar in demographic, spirometric, and Doppler-echocardiography measurements. However, they differed in desat-max (-8.76±4.90 and -3.61±1.94; <0.0001) and in RHC derived mean-PVR (4.25±2.97 vs 1.20±0.53; <0.0001), mean-TPG (12.86± 4.84 vs 5.11±2.78; <0.0001), cardiac output (3.77±1.07 and 4.29±1.15; =0.02). The calculated best cut-off desat-max (>4.5%) could identify high PVR with 72.22% sensitivity and 79.40% specificity with adjusted odds ratio of 19.55. The desat-max correlated best with RHC-measured PVR (r=0.56) but not with PCWP (r=0.09). Desat-max of 2-chair test appears indicative of high PVR in CLD-PH. The revelation merits further research.

Pulmonary arterial hypertension (PAH) significantly affects the pulmonary vasculature, requiring accurate estimation of mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance index (PVRi). Although cardiac catheterization is the gold standard for these measurements, it poses risks, especially in children. This pilot study explored how machine learning (ML) can predict pulmonary hemodynamics from non-invasive cardiac magnetic resonance (CMR) cine images in pediatric PAH patients. A retrospective analysis of 40 CMR studies from children with PAH using a four-fold stratified group cross-validation was conducted. The endpoints were severity profiles of mPAP and PVRi, categorised as 'low', 'high', and 'extreme'. Deep learning (DL) and traditional ML models were optimized through hyperparameter tuning. Receiver operating characteristic curves and area under the curve (AUC) were used as the primary evaluation metrics. DL models utilizing CMR cine imaging showed the best potential for predicting mPAP and PVRi severity profiles on test folds (AUC =0.82 and AUC =0.73). True positive rates (TPR) for predicting low, high, and extreme mPAP were 5/10, 11/16, and 11/14, respectively. TPR for predicting low, high, and extreme PVRi were 5/13, 14/15, and 7/12, respectively. Optimal DL models only used spatial patterns from consecutive CMR cine frames to maximize prediction performance. This exploratory pilot study demonstrates the potential of DL leveraging CMR imaging for non-invasive prediction of mPAP and PVRi in pediatric PAH. While preliminary, these findings may lay the groundwork for future advancements in CMR imaging in pediatric PAH, offering a pathway to safer disease monitoring and reduced reliance on invasive cardiac catheterization.