Pulmonary Hypertension Research Articles

Prognostic evaluation with cardiac magnetic resonance in patients with systemic sclerosis

Abstract Systemic sclerosis (SSc) is an autoimmune disease with multiorgan involvement. Cardiac involvement is common and impact in prognosis. Cardiac magnetic resonance (CMR) allows an evaluation in ventricular and atrial function and hemodynamics forces. Our study aimed to assess RVD prevalence in SSc patients and analyze its impact on cardiovascular events. Methods In this retrospective study, we included patients diagnosed with SSc and followed-up in a specialized unit. We collected clinical, hemodynamic, and imaging data, including baseline CMR studies. Pulmonary function tests were also performed. RVD was defined as a right ventricular ejection fraction ≤52% in men and ≤51% in women. Patients were monitored for a composite endpoint consisting of cardiovascular death and/or admissions due to heart failure (HF). We assessed the predictors of this endpoint using Cox regression analysis. Results The study included 74 patients with SSc, most were female (81 %) with a mean age of 60±12 years. RVD prevalence was 32 %. Patients with RVD had greater ventricular volumes (160±44.9 vs 130±36.2; p=0.003), lower right ventricular global strain (-18 % vs. -26 %; p <0.001) and lower right atria strain (19% vs 29%; p=<0.001). We don’t found differences in presence of LGE of both ventricles. In the multivariate analysis RVEF (HR 2.9.; p = 0.022), pulmonary trunk dilatation (HR 1.15; p= 0.004, pulmonary hypertension at baseline (HR 2.98; 0.09); RV GLS (HR 1.08; p = 0.03) and RA GLS (HR 0.96; p = 0.024) were predictors of composite outcome of cardiovascular death and/or heart failure hospitalization. During a mean follow-up of 46 months, patients with RVD had higher rates of heart failure admissions (38% vs. 12%; p = 0.01) and cardiovascular mortality (29% vs. 6%; p 0.01). No ventricular arrhythmias occurred. Conclusion RVD is common among SSc patients. RVEF and pulmonary hypertension are the strongest variables linked to increased adverse cardiovascular clinical events and decreased survival in these patients.

Prognosis in patients with residual pulmonary hypertension after transcatheter edge-to-edge repair for secondary mitral regurgitation

Abstract Background Pulmonary hypertension (PH) is an independent prognostic predictor in patients with heart failure (HF). Recently, transcatheter edge-to-edge repair (TEER) for secondary mitral regurgitation (MR) has been reported to reduce HF hospitalizations and mortality. Elevated pulmonary artery pressure (PAP) before TEER is associated with a poor prognosis; however, the impact of residual PH after TEER on clinical events has not been investigated. Purpose The purpose of this study is to clarify whether residual PH influences outcomes in patients with HF treated by TEER for secondary MR. Methods We included 63 patients who underwent TEER for severe secondary MR and post-procedural right heart catheterization in our institute from January 2016 to August 2023. Mean PAP after TEER was categorized as increased (>20mmHg) versus not increased (≤20mmHg), and we investigated the clinical outcomes between the two groups. The primary endpoint is a composite outcome of all-cause mortality and HF hospitalization. Results Among 63 patients, the average age was 78 years, and 60.3% were male. All patients had Secondary MR, and 52 patients (82.6%) had ventricular Secondary MR—right heart catheterization after TEER revealed a mean PAP of 21.6±7.7 mmHg, pulmonary vascular resistance (PVR) of 2.7±1.4 wood unit (WU), and pulmonary artery wedge pressure (PAWP) of 12.2±5.9 mmHg. Patients with residual PH had higher composite outcome rates of death from any cause or HF hospitalization compared to those without PH (56.1% vs. 19.5%; hazard ratio: 2.62; 95% confidence interval: 1.1 to 6.9; p=0.03). Multivariate Cox regression analysis showed that residual PH and higher PAWP after TEER were associated with higher mortality (hazard ratio: 1.14; 95% confidence interval: 1.03 to 1.28; p=0.01). Conclusion Our results suggest that patients with residual PH after TEER have a poor prognosis. Residual PH and high PAWP after TEER are associated with mortality.

Pulmonary valve acceleration fraction as a novel echo parameter to evaluate systolic pulmonary artery pressure during exercise echocardiography

Abstract Background/Introduction Long-COVID is a disabling chronic condition. Some patients have features of exercise-induced pulmonary hypertension (PHT) but non-invasive assessment during exercise stress echo (SE) is often limited by absence of reliable jet of tricuspid regurgitation (TR). We aimed to investigate novel Doppler echo parameters elicited from right ventricular (RV) outflow tract to aid diagnosis of exercise induced PHT among patients referred to our centre with Long-COVID symptoms. Purpose We investigated the ratio of the pulmonary valve acceleration time (PV AccT) to RV ejection time (RV ET) to calculate the pulmonary acceleration fraction (PV AccT/RV ET), thereby adjusting to heart rate. To identify its utility to estimate pulmonary artery pressure (PASP) during SE we correlated the PV AccT/RV ET and the TR-estimated RV systolic pressure (RVSP) in patients referred for evaluation of exercise-induced PHT in Long-Covid patients. Methods We developed a dedicated Covid-19 SE protocol to assess RV and pulmonary hemodynamics. From November 2022 to February 2023 all consecutive patients with Long-COVID symptoms underwent supine bike exercise with 3-min increments of workload of 25W. We did not evaluate the inferior vena cava during exercise, therefore estimated pressures from maximal TR jet velocities only. Results We enrolled 93 consecutive patients. The mean age was 50.1 years, 42.9% were female. No patients had RV impairment or RVSP >40mmHg at baseline. The average exercise time was 12.4 minutes, only 33% achieved the sub-maximum target heart rate (THR), in 50/93 (53.7%) reasons for termination were recorded as shortness of breath. The pulmonary acceleration fraction could be recorded in every patient at rest and at stress, while 20/92 (21.7%) patients had insufficient spectral Doppler profile of TR to estimate RVSP. The PV acceleration fraction was correlated with the available RVSPs during exercise (Spearman’s ϱ -0.446 (95% CI -0.606- -0.251[p<0.0001]). ROC analysis indicated a pulmonary acceleration fraction ≤0.44 was associated with the maximum Youden index to discriminate an increase in RVSP >20mmHg during exercise (AUC =0.731 [p<0.001]) with a sensitivity and specificity of 70.0% and 80.0%. In logistic regression analysis, a PV acceleration fraction ≤0.44 was independently associated with an increase in RVSP>20mmHg during exercise independently of age, gender and baseline LVEF, LVEDV, TAPSE and baseline RVSP (p<0.001). Conclusions Significant proportion of Long-COVID patients are limited by symptoms and not able to achieve THR during exercise. PV Acc T/ PV ET correlates well to RVSP and can be used to estimate PA pressure. A threshold of 0.44 appears independently associated with a benchmark of PA systolic pressure increase of >20mmHg. Further studies needed to evaluate this new marker of pulmonary hypertension in other group of patients.

Mechanisms of Bone Morphogenetic Protein 2 in Respiratory Diseases.

Bone morphogenetic protein 2 (BMP2) belongs to the transforming growth factor-β (TGF-β) superfamily and plays an important role in regulating embryonic development, angiogenesis, osteogenic differentiation, tissue homeostasis, and cancer invasion. Increasing studies suggest BMP2 is involved in several respiratory diseases. This study aimed to review the role and mechanisms of BMP2 in respiratory diseases. BMP2 signaling pathway includes the canonical and non-canonical signaling pathway. The canonical signaling pathway is the BMP2-SMAD pathway, and the non-canonical signaling pathway includes mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. The BMP2 is related to pulmonary hypertension (PH), lung cancer, pulmonary fibrosis (PF), asthma, and chronic obstructive pulmonary disease (COPD). BMP2 inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), promotes the apoptosis of PASMCs to reduce pulmonary vascular remodeling in PH, which is closely related to the canonical and non-canonical pathway. In addition, BMP2 stimulates the proliferation and migration of cells to promote the occurrence, colonization, and metastasis of lung cancer through the canonical and the non-canonical pathway. Meanwhile, BMP2 exert anti-fibrotic function in PF through canonical signaling pathway. Moreover, BMP2 inhibits airway inflammation to maintain airway homeostasis in asthma. However, the signaling pathways involved in asthma are poorly understood. BMP2 inhibits the expression of ciliary protein and promotes squamous metaplasia of airway epithelial cells to accelerate the development of COPD. In conclusion, BMP2 may be a therapeutic target for several respiratory diseases.

Efficacy of specific drug class therapy in pulmonary arterial hypertension associated with HIV, portal hypertension or both: a single Center experience

Abstract Background Pulmonary arterial hypertension (PAH) is a rare complication of both HIV infection (HIV-PAH) and portal hypertension (Po-PAH); it can occur in patients with both diseases (HIV/Po-PAH). The use of the PAH-specific drug classes (prostanoids, endothelin-1 receptor antagonists [ERA] and phosphodiesterase-5 inhibitors [PDE5-i]) is largely justified by retrospective and observational case reports since, to date, there are no randomized clinical trials except for the PORTICO trial which demonstrated the efficacy of macitentan in Po-PAH. Purpose the aim of the study was to evaluate the efficacy of PAH-specific drugs, both monotherapy and dual oral upfront therapy (ERA + PDE5i started within 1 month apart), in patients with Po-PAH, HIV/Po-PAH and HIV-PAH. Methods Between 1998 and 2023 we enrolled patients with Po-PAH, HIV-PAH and HIV/Po-PAH referred to our Center and undergoing monotherapy with prostanoid, ERA and PDE5-I or dual upfront oral therapy. The efficacy of the drugs was assessed by comparing clinical parameters (NYHA functional class), exercise capacity (six-minute walking test) and hemodynamic parameters at baseline and after a treatment period of 3-6 months. The data are expressed as mean and standard deviation and were compared with Student's t-test for paired data. Results 128 patients were enrolled (83 Po-PAH, 23 HIV/Po-PAH and 22 HIV-PAH). 20 were treated with ERA monotherapy, 90 with PDE5-I, 13 with prostanoids and 5 treated with dual oral upfront therapy. Conclusions Prostanoids, ERAs and PDE5-Is, both in monotherapy and as dual upfront oral therapy, are associated with a significant improvement in functional class, exercise capacity and hemodynamic parameters. The effect of such drugs is similar to patients suffering from other forms of PAH.

Prognostic value of right ventricular-pulmonary arterial coupling indices in patients with moderate to severe mitral stenosis

Abstract Background Right ventricular-pulmonary arterial (RV-PA) coupling represents the relationship of RV contractility and RV afterload. The ability of RV to adapt to changes in RV afterload (i.e. increased pulmonary arterial (PA) loading) has prognostic implications in various cardiovascular diseases such as heart failure and pulmonary arterial hypertension. RV-PA uncoupling occurs when RV contractility cannot match RV afterload, resulting in right heart dysfunction. However, RV-PA coupling has not been investigated in mitral stenosis patients. Purpose To evaluate the prognostic significance of various non-invasive RV-PA coupling parameters (TAPSE/PASP and RVFWLS/PASP) in patients with moderate to severe mitral stenosis. Methods This was a single-center retrospective study of 237 patients with moderate or severe mitral stenosis enrolled between January 2010 to December 2022. Baseline clinical and echocardiographic parameters were collected. RV free wall longitudinal strain (RVFWLS) was subsequently analyzed using TOMTEC software. Echocardiography-derived RV-PA coupling parameters were collected, including TAPSE/PASP and RVFWLS/PASP. The primary endpoint was a composite outcome of all-cause mortality, heart failure hospitalization and valve intervention (percutaneous transvenous mitral commissurotomy and surgical intervention). RV parameters were analyzed separately to avoid collinearity. Results A total of 237 patients were included in the study. The patients had a mean age was 66.56 ± 13.61 years-old and were predominantly female (67.9%). The median follow-up duration was 4.54 years (IQR 1.44 – 6.44). Mean left ventricular ejection fraction (LVEF) was 56.86 ± 10.51%, mean TAPSE 18.29 ± 5.36 mm and mean RVFWLS was -23.60 ± 7.96 %. In separate multivariable Cox regression models after adjustment for age , sex and mitral stenosis severity, TAPSE/PASP ratio < 0.36mm/mmHg (HR 2.025 , 95% CI 1.395-2.939, p < 0.001 ) and RVFWLS/PASP ratio ≥ - 0.5%/mm Hg (HR 2.031 95% CI 1.404 – 2.938 , p< 0.001) remained independently associated with mortality , heart failure hospitalization and valve intervention. Conclusion TAPSE/PASP and RVFWLS/PASP were independently associated with all-cause mortality, heart failure hospitalization and valve intervention in patients with moderate to severe mitral stenosis.

The predisposing factors to heart failure diagnosis and early mortality among young adults in Africa: a narrative review

Abstract Introduction Heart failure (HF) is a major health concern mainly diagnosed among elderly individuals. Primarily, researchers have focused on this age group, nevertheless, compared to individuals from other regions of the world, Africans presents with HF two decades sooner (52 versus 79 years). Even though it manifests early, young persons (18–35 years old) are also diagnosed with HF with prognoses comparable to the older group. Less is known about how much study is concentrated on this age range, although globally, young adults of African origin make up the majority of those with an early onset of heart failure. Additionally, obtaining information about how HF impacts African youth remains challenging. Purpose To determine the cause of Africans' early HF diagnosis as well as the risk factors for HF diagnosis and early mortality among young adults. Methodology Three electronic databases— MEDLINE Ovid, Scopus, and CINAHL Plus—were searched using the Boolean operators. The first retrieved hits were checked for relevancy by titles and abstracts. Then, publications were fully screened for inclusion in the review based on the pre-established criteria. Also, reference lists of the articles were snowballed for pertinent studies. The scientific integrity of the studies was evaluated using a guided, in-depth peer-reviewed article on how to critically analyse clinical research and the Critical Appraisal Skill Programme (CASP) tool cohort checklist. Pertinent information regarding the study was analysed using a narrative review methodology. Eleven (11) articles out of the 135 pulled from the databases met the requirements for inclusion in the review after a thorough screening. One article was eliminated upon critical evaluation of the research's methodology, and an eligible article was discovered from snowballing reference lists. Therefore, only 11 articles qualified for this review study. Results Findings from the review show that HF is diagnosed earlier among Africans due to the early presentation of the major causes of HF before the age of 30 years. Rheumatic heart disease, cardiomyopathy, ischemic heart disease, HTN, and pulmonary illnesses (COPD, TB, and pulmonary arterial hypertension) are known aetiologies. More so, young adults who are diabetic, obese, have hyperlipidaemia or smoke cigarettes are more likely to develop HF. Furthermore, socioeconomic status, alcohol use, smoking, renal dysfunction, higher serum levels of brain natriuretic peptide (BNP) and creatine kinase (Isomer MB), cardiogenic shock, and decreased ejection fraction were the predictors of death with significant p-values (0.05). Conclusion Although HF affects young African adults disproportionately causing them to live lower quality of life and shorter lives, no research before this has been conducted. Therefore, further study is required to understand how HF affects this target age range (18 to 35 years) and to develop a long-term plan to fight this illness before it worsens.

RV-PA uncoupling is a strong predictor of 3-year all-cause mortality in transthyretin amyloid cardiomyopathy

Abstract Background Right ventricle to pulmonary artery coupling (RV-PAc) describes the right ventricle's ability to adjust to an increased afterload which, in case of transthyretin amyloid cardiomyopathy (ATTR-CM), can result from increased left ventricular diastolic stiffness due to fibril deposition. While RV-PAc is a validated prognostic parameter in pulmonary arterial hypertension (PAH), its prognostic relevance in ATTR-CM remains unclear. This study sought to evaluate the prognostic implications of impaired RV-PAc on survival in ATTR-CM. Methods In this two-centre study, RV-PAc was investigated by the echocardiographic surrogate of ratio of tricuspid annular plane systolic excursion to estimated pulmonary arterial systolic pressure (TAPSE/PASP) in 418 ATTR-CM patients, all treated with TTR stabilizer. The primary outcome was all-cause mortality. Receiver operation curves and Youden’s J analysis were applied to identify an optimal cut-off value of RV-PAc ratio. Results Within a median time of 631 (IQR 361-983) days after diagnosis, 14.4% of patients died. RV-PAc ratio at first presentation emerged as a robust marker for risk stratification with a determined optimal cut-off of 0.382mm/mmHg (area under the curve (AUC) 0.746, 95% CI 0.68-0.82). Patients with RV-PAc ratio ≤0.382mm/mmHg (impaired RV-PAc, n=158) exhibited significantly lower survival (HR 4.07, 95% CI 2.26-7.33, p<0.001) within 3 years of follow up than those with RV-PAc ratio > 0.382mm/mmHg. In multivariate Cox regression analysis, incorporating a range of known prognostic variables, reduced RV-PAc was a strong echocardiographic predictor of mortality (Hazard Ratio (HR) 2.99, 95% Confidence Interval (CI) 1.63-5.51, p <0.001). Conclusion Impaired adaption of the RV to increased afterload is associated with worse outcome in ATTR-CM patients. RV-PAc ratio can serve as an echocardiographic predictor for all-cause mortality within three years after diagnosis. Therefore, determination of RV-PAc could improve risk stratification for ATTR-CM patients.Figure_1_Kaplan-Meier curves

Clinical Characteristics of Anti-Synthetase Syndrome: Analysis from the CLASS project.

Anti-synthetase syndrome (ASSD) is a rare systemic autoimmune rheumatic disease (SARD) with significant heterogeneity and no shared classification criteria. We aimed to identify clinical and serological features associated with ASSD that may be suitable for inclusion in the data-driven classification criteria for ASSD. We utilized a large, international, multi-center "Classification Criteria for Anti-synthetase Syndrome" (CLASS) project database, which includes both ASSD patients and controls with mimicking conditions, namely SARDs and/or interstitial lung disease (ILD). The local diagnoses of ASSD and controls were confirmed by project team members. We employed univariable logistic regression and multivariable Ridge regression to evaluate clinical and serological features associated with an ASSD diagnosis in a randomly selected subset of the cohort. Our analysis included 948 ASSD cases and 1077 controls. Joint, muscle, lung, skin, and cardiac involvement were more prevalent in ASSD than in controls. Specific variables associated with ASSD included arthritis, diffuse myalgia, muscle weakness, muscle enzyme elevation, ILD, mechanic's hands, secondary pulmonary hypertension due to ILD, Raynaud phenomenon, and unexplained fever. In terms of serological variables, Jo-1 and non-Jo-1 anti-synthetase autoantibodies, antinuclear antibodies with cytoplasmic pattern, and anti-Ro52 autoantibodies were associated with ASSD. In contrast, isolated arthralgia, dysphagia, electromyography/MRI/muscle biopsy findings suggestive of myopathy, inflammatory rashes, myocarditis, and pulmonary arterial hypertension did not differentiate between ASSD and controls or were inversely associated with ASSD. We identified key clinical and serological variables associated with ASSD, which will help clinicians and offer insights into the development of data-driven classification criteria for ASSD.

Pregnancy complications and long-term risk of cardiovascular events in women with heart disease

Abstract Background/Introduction Women with congenital heart or acquired heart disease are at increased risk of atherosclerotic cardiovascular disease. Pregnancy complications are established risk factors for cardiovascular disease in the general population, but their prognostic value for cardiovascular outcomes in the population with congenital or acquired heart disease is unknown. Purpose To determine the frequency and prognostic value of pregnancy complications for the risk of cardiovascular outcomes in women with congenital or acquired heart disease. Methods This nationwide registry-based cohort study included women in Sweden with heart disease (pulmonary arterial hypertension, congenital heart disease or acquired valvular heart disease) with singleton births registered in the national Medical Birth Register between 1973 and 2014. Exposures of pregnancy complications (preeclampsia/gestational hypertension, preterm birth or birth of an infant small for gestational age) were collected from the Medical Birth Register, and cardiovascular outcomes (mortality and hospitalizations) from the Cause of Death Register and the National Inpatient Register. Cox regression models were performed with time-dependent covariates, to determine the possible prognostic value of the studied pregnancy complications for cardiovascular outcomes including atherosclerotic cardiovascular disease, heart failure and arrythmias after adjustment for major confounding including smoking and body mass index. Results Among the total of 2,134,239 women included from the Medical Birth Register, 2,554 women with 5,568 singleton births were affected by heart disease. Preeclampsia/gestational hypertension affected 5.8% of pregnancies, preterm birth 9.7%, and birth of an infant small for gestational age 2.8%. Preterm birth (adjusted HR 1.91 (95% CI 1.38-2.64)) was associated with an increased risk of maternal all-cause mortality. Preeclampsia/gestational hypertension (adjusted HR 1.64 (95% CI 1.18-2.29)) and preterm birth (adjusted HR 1.56 (95% CI 1.19-2.04)) were associated with an increased risk of hospitalizations for atherosclerotic cardiovascular disease. Conclusions Pregnancy complications were frequent in women with congenital or acquired heart disease. With a median follow-up time of 22 years, preterm birth was associated with a higher risk of cardiovascular mortality, and preeclampsia/gestational hypertension and preterm birth were associated with cardiovascular morbidity. In women with heart disease, pregnancy complications may provide additional information for the risk assessment of future cardiovascular outcomes.Overview of study designPrevalence and risk estimation

A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity.

Congenital anomalies of the knee are a spectrum of rare disorders with wide clinical and genetic variability, which are mainly due to the complex processes underlying knee development. Despite progresses in understanding pathomechanisms and associated genes, many patients remain undiagnosed. To uncover the genetic bases of a congenital patellar dislocation affecting multiple family members with variable severity. We performed ES in the proband and his father, both showing bilateral patellar dislocation, his sister with a milder similar condition, and his unaffected mother. Sanger sequencing was then performed in the proband's brother and paternal aunt, both affected as well. ES and Sanger sequencing identified the presence of the novel heterozygous frameshift mutation c.735delT in the TBX4 gene in all affected family members. TBX4 is associated with autosomal dominant ischio-coxo-podo-patellar syndrome with/without pulmonary arterial hypertension (ICPPS, #147891), reaching a diagnosis in the family. Intrafamilial clinical heterogeneity suggests that other factors might be involved, such as additional variants in TBX4 or in other modifier genes. Interestingly, we identified three additional variants in the TBX4 gene in the proband only, whose phenotype is more severe. Despite being classified as benign, one of these variants is predicted to disrupt a splicing protein binding site, and may therefore affect TBX4 alternative splicing, accounting for the more severe phenotype of the proband. We expand and further delineate the genotypic and phenotypic spectrum of ICPPS. Further studies are necessary to shed light on the potential effect of this variant and on the variable phenotypic expressivity of TBX4-related phenotypes.

Ambrisentan reverses the prosenescent and anti-autophagic effect of high glucose on human pulmonary artery endothelial cells exposed to hypoxia

Abstract Background Cardiovascular (CV) comorbidities (systemic hypertension, hyperlipidemia, obesity, diabetes mellitus, peripheral arterial disease, coronary artery disease) are associated with reduced treatment response to specific drugs for group 1 pulmonary arterial hypertension (PAH). Often this epidemiological evidence is the result of misdiagnosis of group 2 PH associated with left heart disease, but it can also be explained as the intrinsic loss of the ability of pulmonary endothelial cells to respond to specific antiremodeling drugs. Aims To evaluate the impact of high glucose and hyperosmolar stress on the responsiveness of human pulmonary artery endothelial cells (hPAECs) to the endothelin receptor antagonist ambrisentan in terms of senescence, autophagic activity, viability and expression of some microRNAs involved in pulmonary arterial remodeling. Methods We incubated hPAECs with high glucose (HG, 30.5 mM) or high mannitol (HM, 25 mM), with/without ambrisentan (0.02 nM) in normoxia (N) or hypoxia (H) for 24 h and tested them for cell viability (MTT assay), protein and miRNA levels, autophagy and senescence (β-Gal assay) in vitro. Results H induced cell death as compared to N (752 ± 44 vs 701 ± 45 Abs units, p = 0.03). H reduced autophagy (Figure 1A-C) and induced senescence (Figure 1D), an effect further potentiated by HG and HM. Treatment with A in N and H significantly reversed the effect of HG but not HM on autophagy (Figure 1A-C) and senescence (Figure 1D). H increased the abundance of antiapoptotic miR124-3, compared to N in vehicle (V)-treated hPAEC (p=0.008) (Figure 2A), and induced a similar effect on antiapoptotic and proliferative miR191-3p, although not statistically significant (Figure 2B). In N, A potentiated the expression of both miR124-3p (p=0.007) and miR191-3p (p=0.02) in HG-treated hPAEC, and only miR191-3p in HM-treated hPAEC (p=0.01). A induced a similar effect on miR191-3p in hPAEC exposed to H+HG (p=0.02), with a non-statistically significant trend on miR124-3p. Conclusions In hPAEC exposed to H, A retains its pro-autophagic and antisenescent effects in an in vitro model mimicking diabetes. miR124-3p and miR191-3p may act as biomarkers of disease and treatment response to specific drugs in patients with PAH.Figure 1:autophagy and senescenceFigure 2:miRNA expression

Effects of sodium-glucose cotransporter 2 inhibitors on pulmonary hemodynamics in chronic heart failure patients with a pulmonary artery pressure sensor

Abstract Background Approximately 50% of patients with chronic heart failure (HF), either with preserved or reduced left ventricular ejection fraction (LVEF), have secondary pulmonary hypertension, which results in poorer prognosis. In previous studies, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown a reduction in cardiovascular death, HF hospitalization and pulmonary artery pressure (PAP) in patients with HF, regardless of LVEF, but exact mechanisms remain unclear. Purpose The main objective of this study is to analyse effects of SGLT2i on PAP in patients with chronic HF followed by a PAP sensor (CardioMEMS HF system). The secondary objective is to analyse effects in subgroups of LVEF. Methods We included chronic HF patients (regardless of LVEF) with previously implanted a PAP sensor, from July 2019 to February 2023. SGLT2i had been added in fourth position in patients with reduced LVEF, since they were previously on optimal HF treatment as chronic patients. Changes in PAP, renal function and N-terminal pro B-type natriuretic peptide (NTproBNP) were compared between two periods of time: "30 days before" and "30 days after" SGLT2i initiation. Patients were then classified in two groups: group 1 (LVEF ≤40%) and group 2 (LVEF >40%) and repeated same analyses. Results Overall, 61 patients were screened, and 17 finally were included, mean age 71.7 ± 9.6 years, 64.7% were men, mean LVEF was 49.4 ± 17.5%, 23.5% had ischaemic aetiology and 64.7% were in NYHA class III (Table 1). There were more men in group 1 than in group 2 (p=0.043), without other differences in basal characteristics between groups (Table 1). Dapagliflozin (10mg daily) was initiated in 14 patients (82.4%), 5 from group 1 and 9 from group 2 (p=1.000), and empagliflozin (10mg daily) in 3 patients (17.6%), 1 from group 1 and 2 from group 2 (p=1.000). Before SGLT2i, mean diastolic PAP (dPAP) was 17.3 ± 5.6 mmHg and median NTproBNP was 2841.5 (289-10515) pg/mL. SGLT2i significantly reduced dPAP; average dPAP ("30 days after" period) was 1.5 mmHg lower (95% CI, 0.26-2.74; p=0.021) compared to "30 days before" period (Figure 1). SGLT2i also reduced systolic PAP (-2.2 mmHg), mean PAP (-1.7 mmHg), NTproBNP (-183 pg/mL) and creatinine (-0.2 mg/dL), but not statistically significant. SGLT2i reduced PAP, NTproBNP and creatinine too in group 1 (6 patients), but did not achieve statistical significance. Reductions were as well observed in group 2 (11 patients), and SGLT2i significantly reduced dPAP (-2.04 mmHg) (95% CI, 0.31-3.77; p=0.025). Conclusions In patients with chronic HF and a PAP sensor, SGLT2i, added to previous HF treatment, significantly reduced dPAP. PAP reductions were observed regardless LVEF, but results were more robust in patients with LVEF >40%.Figure 1

Suppression of Fibulin 5 Attenuated Pulmonary Arterial Hypertension Associated with Congenital Heart Disease via Mitigating Pulmonary Arterial Smooth Muscle Cell Dysfunction

Abstract Backgrounds: The specific molecular pathogenesis of pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) and the reversal still remain elusive. Fibulin 5 was involved in the regulation of cardiovascular system while little is known about the expression and functions of fibulin 5 in the development of CHD-PAH. This study aimed to investigate the role of fibulin 5 in the pathogenesis of the disease. Methods Lung samples were obtained both from patients with CHD-PAH and aortocaval shunt-associated PAH rat models. TGF-β1was used to induce human pulmonary artery smooth muscle cells (hPASMCs) dysfunction and lentiviruses were responsible for alteration of fibulin 5 expression. In an effort to explore the specific role of fibulin 5, an inhibitor of phosphatidylinositol-3-kinases (PI3K) /protein-serine-threonine kinase (AKT) which was defined as the TGF-β1-related downstream signaling was applied for further exploration. Results Fibulin 5 was pronouncedly elevated in the PASMCs of the remodeled pulmonary arterioles from patients with CHD-PAH and shunt-associated PAH rats. We found that over-expression of fibulin 5 could promote hPASMCs dysfunction induced by TGF-β1 and it could be reversed by the PI3K/AKT inhibitor LY294002 suggesting the essential role of TGF-β1/PI3K/AKT signaling activation in phenotypic switch, proliferation and migration of PASMCs. Moreover, an adeno-associated virus vector encoding fibulin 5 by intratracheally instillation with rats improve the hemodynamic parameters in shunt-associated PAH rats and its related pulmonary artery remodeling. Conclusion Over-expression of fibulin 5 could significantly promote hPASMCs dysfunction and pulmonary artery remodeling via reinforcing TGF-β1/PI3K/AKT signaling activation, which highlighted the potential valuable pharmacological target for the treatment of CHD-PAH.Fibulin 5 was over-expressed in PAHInhibition of fibulin 5 attenuated PAH

Improved prognosis prediction of idiopathic pulmonary arterial hypertension using targeted plasma proteomics in disease management

Abstract Background Idiopathic pulmonary arterial hypertension (IPAH), a special subgroup of PAH with unclear etiology, is characterized by rapid progression and poor prognosis underscoring the need for optimization of IPAH management and the accurate prediction of prognosis. However, it is disappointing that specific plasma biomarkers for IPAH management and prognosis are lacking in clinical practice. Up to date, the plasma biomarkers used for assessment of IPAH severity and prognosis are relied solely on indicators such as N-terminal prohormone of brain natriuretic peptide, or brain natriuretic peptide, which could reflect cardiac function but fail to promptly response to the dynamic change of disease condition due to the complexity of IPAH pathogenesis. Purpose We evaluated the prognostic value of plasma proteins in addition to current clinical predictors for prognosis prediction of IPAH. Methods Olink Immune-Response panel was used to measure 92 plasma proteins in a prospective IPAH cohort with 169 patients and a mean follow-up period of 2.4 ± 0.9 years. Six machine learning methods were used to construct predictive models, including plasma proteins-based Olink models, clinical parameters-based clinical models, and integrative models. Results A total of 18 proteins showed differential expression between patients with or without adverse clinical outcomes. Three proteins (STC1, CXADR, and IL6) were strongly correlated with clinical indicators of IPAH severity and their concentrations showed upward trends along with increased risk stratification. Elevated levels of STC1, CXADR, and IL6 are all associated with an increased risk of adverse clinical events, indicated by survival analysis, restricted cubic splines, and multivariable Cox regression analysis (STC1 HR=3.474, 95%CI: 1.129-10.692, P=0.030; CXADR: HR=1.602, 95%CI: 1.074-2.387, P=0.021; IL6: HR=1.883, 95%CI: 1.376-2.576, P<0.001). The inclusion of these three proteins into the predictive model could significantly increase the predictive power on the basis of the clinical model (AUC: 0.746 vs 0.626). Conclusions High levels of STC1, CXADR, and IL6 in plasma were associated with severe clinical phenotype and increased risk of adverse clinical events in patients with IPAH. These plasma proteins could significantly improve the prognostic performance of pre-existing clinical models, facilitating the clinical management of IPAH patients.The predictive efficient of models

Proteomics in low CVD risk black women living with HIV: H-ART to Heart Study

Abstract Background 39 million people worldwide are living with HIV (human immunodeficiency virus), acquired immune deficiency syndrome (AIDS)-related deaths have reduced by 51% since the peak in 2004. BWLWH represent 42% of those infected but only 9% are represented in clinical trials. HIV/AIDS has been shown to be associated with the development of heart failure, pulmonary hypertension and myocarditis. Previous studies in asymptomatic PLWH have revealed a high burden of underlying CVD and subclinical disease. The H-ART to Heart study is designed to examine potential signals and pathways of cardiovascular disease (CVD) in asymptomatic BWLWH with no traditional CV risk factors compared to HIV negative controls (-). Methods A cross-sectional study comparing asymptomatic BWLWH aged 35-55yrs (diagnosed >10 yrs, with undetectable viral loads) to HIV negative controls. Black African/Caribbean women without known CV risk factors (hypertension, hyperlipidaemia, diabetes, smoking, inflammatory arthritis, depression, severe mental illness) or hepatitis co-infection were included. Assessment included blood pressure (BP), 10yr CVD risk calculation % (Q-Risk 3), bloods including lipids. A targeted discovery proteomics approach was used to evaluate 92 unique proteins using the O-link Target 96 Cardiovascular II panel. Results 48 participants were recruited (23 BWLWH; 25 controls), mean duration of HIV was 17.6 years, mean duration of ART was 11.5 years, demographic details - Age 47.7± 44.7±; p=0.06, BP 125/77 v 123/79 ; p=0.89; BMI (kg/m²) 30.1±5.1 v 28.51±4.27 p=0.25; cLDL 3.49±1.22 v 2.42±0.74 p<0.02; Total Chol:HDL ratio 3.01±0.98 v 2.77±0.56 p=0.353; Q-Risk 3 1.92%±1.27 v 1.49%±1.12 p=0.219; There were no significant differences in baseline data apart from higher mean cLDL in BWLWH. Of the 92 proteins tested, 9 were significant in BWLWH (Figure 1). As demonstrated by the Heat map. Conclusion Data from our study of asymptomatic low risk BWLWH with no CVD risk factors indicates several pathways (Figure 2.) for further investigation in this previously under investigated vulnerable patient sub group. Whether this finding is of importance in CV risk assessment of BWLWH remains to be seen.

Development and validation of a predicting model for risk of rehospitalization within 30 days in heart failure patients with preserved ejection fraction

Abstract Objective This study aimed to develop and validate a predicting model for risk of rehospitalization within 30 days post discharge in patients diagnosed with Heart Failure with Preserved Ejection Fraction (HFpEF). Methods Clinical data of 9555 HFpEF patients registered in the heart failure registry from 2014 to 2022 at our hospital were analyzed. A total of 8160 patients (from 2014-2021) were designated as the training set, and 1395 patients (from 2022) as the validation set. A predictive model was established based on risk factors associated with 30-day rehospitalization due to heart failure identified by the Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression analysis. The model's stability was ensured through Bootstrap internal validation and Temporal validation external validation. Results LASSO and logistic regression analyses identified eight risk factors associated with increased risk of 30-day rehospitalization, including New York Heart Association (NYHA) classification, albumin, c-reactive protein, N-terminal pro b-type natriuretic peptide (NT-proBNP) divided by 100, anemia, pleural effusion, atrial fibrillation, and pulmonary hypertension. The established predictive model demonstrated good discriminative ability in the internal validation with an Area Under the Curve (AUC) value of 0.714, and a 95% confidence interval (CI) of 0.693-0.736 after 500 Bootstrap replicates. In the Temporal validation external validation, the model exhibited robust stability with an AUC value of 0.740 and a 95% CI of 0.693-0.781. When compared to analogous models from prior studies, present model showcased superior predictive accuracy in that both Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) values were positive and within their respective 95% confidence intervals (P-values <0.05). Conclusion This study successfully developed and validated a predictive model for 30-day rehospitalization due to heart failure in patients diagnosed with HFpEF. This model might allow the timely identification of high-risk HFpEF patients for 30-day rehospitalization due to heart failure and optimizes the patient management accordingly.

Risk assessment using DEVI and CARPREG -1 score to predict maternal adverse cardiac cvents in pregnancies with valvular heart disease: external validation study from MPAC registry

Abstract Background Even though many risk assessment tools in pregnant women with valvular heart disease (VHD) are available, validation studies are few that assess their performance in diverse settings, which is needed prior to the application of routine clinical practice. Objectives To validate and establish the clinical utility of two risk stratification tools – DEVI (VHD-specific tool) and CARPREG-I in predicting adverse cardiac events in pregnant patients with VHD. Methods This cohort study involved consecutive pregnancies complicated with VHD enrolled in the prospective MPAC registry from July 2016 to December 2019(1). The ability to discriminate those with and without adverse cardiac outcomes was assessed using the area under the curve for both the DEVI and CARPREG-1 scores. Performance was assessed through discrimination and calibration characteristics. Clinical utility was evaluated with Decision Curve Analysis. Results Among 1029 pregnancies complicated with heart disease in the MPAC registry cohort, 604(52.3%) with valvular heart disease were included in this analysis. One or more composite adverse cardiac events occurred in 70 (11.6%) pregnancies during antenatal or the early postpartum period. Mitral regurgitation was the most common lesion (67.7%). In assessing the pregnancy outcomes, those who continued past 20 weeks were included, with the majority (92.0%) delivered at term, and the cesarean rates were 33.6% (n=203). The most common adverse event was heart failure (n=32, 5.3%), most of which (68.6%) occurred in the postnatal period. There were 11 maternal deaths (1.8%) during the study period, six among those with mechanical heart valves (four prosthetic valve thrombosis), two among those with severe mitral stenosis and pulmonary hypertension and two with severe mitral regurgitation and infective endocarditis. The area under the receiver operating characteristic curve (AUC) was 0.766, with 95% confidence intervals (CI) 0.703- 0.828 for DEVI and 0.703 (95%CI 0.644- 0.763) for CARPREG-I models. Calibration plots suggested that the DEVI score overestimates risk at higher probabilities, whereas the CARPREG-I score underestimates the risk at most probabilities. Decision curve analysis demonstrated that both models were useful across predicted probability thresholds between 10% and 60%. Conclusion In this external validation study in pregnant women with primary rheumatic VHD, DEVI and CARPREG-I scores showed good discrimination ability and clinical utility across various probabilities. Both can be used to classify those who develop adverse cardiac outcomes during pregnancy and childbirth. However, both models need recalibration to improve the agreement between the predicted and observed events prior to routine application in diverse clinical settings.Figure 1.a and b ROC and Decision Curves

MELHORES ELEIÇÕES PARA DIAGNÓSTICO E TRATAMENTO DA HIPERTENSÃO PULMONAR ASSOCIADA A DOENÇA CARDÍACA ESQUERDA

Pulmonary hypertension associated with left heart disease (PH-LHD) is the most prevalent form of pulmonary hypertension, affecting patients with heart failure and valvular disease. Divided into isolated post-capillary and combined pre-capillary, PH-LHD is characterized by a challenging prognosis, due to the difficulty in identifying the factors that contribute to its progression. Early diagnosis is essential and can be aided by imaging tests and procedures such as cardiac catheterization, with volume testing being an important tool to differentiate the types of PH. The management of PH-LHD involves symptom control and treatment of the underlying heart failure. Although there are no specific therapies to significantly improve the prognosis, diuretics and selective pulmonary vasodilators are used, with surgical interventions in more severe cases. Recent research has investigated treatments such as phosphodiesterase-5 inhibitors, which have shown some hemodynamic improvement, and pulmonary artery denervation, a promising technique, but still in the investigational phase. Despite advances, PH-DCE remains associated with high mortality, especially in patients with progressive elevation of pulmonary vascular resistance. Treatment should focus on managing underlying cardiac diseases and seeking new therapeutic approaches.

An elevated mPAP over CO slope by exercise echocardiography predicts outcome in unexplained dyspnea

Abstract Background Exercise pulmonary hypertension, defined by a slope of mean pulmonary artery pressure (mPAP) over cardiac output (CO) >3 mmHg/L/min, measured by invasive exercise hemodynamics, is associated with worse event-free survival in patients with unexplained dyspnea. Whether non-invasive techniques yield similar results has yet to be tested. Purpose To investigate the prognostic value of an mPAP/CO slope > 3 mmHg/L/min determined by exercise echocardiography in suspected heart failure with preserved ejection fraction (HFpEF). Methods This prospective cohort study included patients with unexplained dyspnea defined as dyspnea with an ejection fraction ≥50%. Patients with more than mild valvular heart disease, more than mild pulmonary disease, a history of heart failure, and myocardial or pericardial disease were excluded. A positive HFpEF score was defined as either an HFA-PEFF score of ≥5, including the diastolic stress test and exercise tricuspid regurgitation velocity, or a H2FPEF score of ≥6. The mPAP and CO were obtained by Doppler echocardiography. The primary outcome was the composite endpoint of unplanned cardiovascular hospitalisation (CVH) or all-cause mortality. Results Among the 1922 patients studied (median age 66 [56 to 74] years, 48% women), 39% (n=721) had exercise pulmonary hypertension. After a median follow-up of 14 (10-34) months; 57(3%) patients died and 235 (12%) had at least 1 unplanned CVH. A mPAP/CO slope >3 mmHg/L/min predicted death or unplanned CVH with an odds ratio of 1.51(1.11-2.07) when adjusted for age, sex and pulmonary pressures at rest (Figure 1). The mPAP/CO slope had incremental prognostic value irrespective of whether patients had a positive HFpEF score or not (increase in χ² from 19 to 29; p =0.002) (Figure 2). Conclusion Exercise pulmonary hypertension determined by exercise echocardiography is prognostically relevant as it predicts death and unplanned CVH in patients with unexplained dyspnea. These findings were independent of age, sex, pulmonary hypertension at rest and both the HFpEF scores with the diastolic stress test included.KM exPHTKM exPHT and HFpEF score