Increase In Mean Pulmonary Arterial Pressure Research Articles

Evaluation of Pre and Post-operative Pulmonary Artery Pressures in Children with Adenotonsillar Hypertrophy and Correlation with Chronicity: A Prospective Study on 50 Children.

Children with grade III or IV of adenotonsillar hypertrophy especially of a longer duration, may show cardiovascular changes due to mouth breathing. These changes can be detected on doppler echocardiocardiography which can be used as a screening tool. Fifty paediatric patients of grade 3 and 4 adenotonsillar hypertrophy underwent adenotonsillar resection after a pre-operative work up which included doppler echocardiography to measure pulmonary artery pressures. A post-operative doppler echocardiography was done after three months. 11 children (22%) showed deranged pulmonary artery pressure values with increased mean pulmonary artery pressure (MPAP) and pulmonary artery systolic pressure (PSAP) on preoperative doppler echocardiography, and 2 out of these 11 children had Pulmonary Artery Hypertension. A significant (p < 0.001) improvement was noted in pulmonary artery pressure values (MPAP and PSAP returned to normal) after adenotonsillectomy in 3-month postoperative echocardiography. Also, a statistically significant correlation was obtained between chronicity of symptoms and raised pulmonary artery pressures. Our study concluded that these children with chronic untreated upper airway obstructive symptoms get predisposed to potential cardiac complications. And these grave consequences can be easily prevented by a timely intervention.

Increased NT-proBNP levels and cardiac ventricular function during aortic valve replacement (pilot study)

The objective was to study the relationship between the increased preoperative N-terminal segment of B-type natriuretic peptide precursor (NT-proBNP) blood levels and the parameters of the heart ventricles function, as well as the conditions for coronary perfusion of their myocardium before and after on-pump aortic valve replacement.Materials and methods. The study involved 27 patients aged 57.7±2.5 years who underwent aortic valve replacement. NT-proBNP blood level was determined before surgery. The level of NT-proBNP &gt; 1000 pg/ml was considered increased. Invasive hemodynamics, including the data of the right ventricle thermodilution volumetry, and transesophageal echocardiography data were analyzed at the stages: the 1st – after anesthesia induction, the 2nd – at the end of surgery. Logistic regression and ROC analysis were used for data processing.Results. Preoperative blood levels of NT-proBNP &gt; 1000 (3163.0[2507.25–7319]) pg/ml were recorded in 55.6% of patients. At the 1st stage, the biomarker increased level was associated with increased index of left ventricular end-systolic volume (OR 1.0955, 95% CI 1.0097–1.1885, p = 0.028, AUC 0.903), decreased left ventricular ejection fraction (OR 0, 9447, 95% CI 0.8949–0.9973, p = 0.040, AUC 0.753) and area contraction fraction (OR 0.8868, 95% CI 0.8086–0.9726, p = 0.011, AUC 0.890), increased mean pulmonary artery pressure (OR 1.1824, 95% CI 1.0020–1.3952, p = 0.047, AUC 0.722), and increased transpulmonary gradient (OR 1.4497, 95% CI 1.0103–2.0802, p = 0.044, AUC 0.810), increased right ventricular stroke work index (OR 1.5151, 95% CI 1.0319–2.2246, p = 0.034, AUC 0.761), and decreased coronary perfusion gradients of the left (OR 0.8961–0.9241, 95% CI 0.8229–0.9459 – 0.8630–0.9896, p = 0.012–0.024, AUC 0.793–0.861) and right (OR 0.9519, 95% CI 0.9136–0.9918, p = 0.019, AUC 0.847) ventricles. At the 2nd stage, NT-proBNP blood values &gt; 1000 pg/ml were associated with impaired left ventricular function, decreased mean arterial pressure (OR 0.9066, 95% CI 0.8264–0.9946, p = 0.038, AUC 0.761), and the vasopressor and inotropic support (OR 8.4000, 95% CI 1.2584–56.0694, p = 0.028, AUC 0.710).Conclusions. Prior to aortic valve replacement, the blood level of NT-proBNP &gt; 1000 pg/ml is associated with a moderate decrease in the left ventricular ejection fraction and area contraction fraction, an increased left ventricular end-systolic volume with a normal end-diastolic volume, an increased index of right ventricular stroke work in combination with moderately increased mean pulmonary artery pressure and increased transpulmonary gradient, as well as a decreased coronary perfusion gradients. At the end of operations, increased NT-proBNP blood level is associated with signs of impaired left ventricular contractility, a tendency to arterial hypotension, and the vasopressor and inotropic support. Increased preoperative NT-proBNP blood level are not associated with right ventricular volumes and ejection fraction both before and after on-pump aortic valve replacement.

Pulmonary hypertension: calcium channel-mediated signaling, present and future pharmacological targets

Pulmonary arterial hypertension is characterized by increased mean pulmonary arterial pressure, resistance, and pathological remodeling of pulmonary arteries. Calcium entry from the extracellular to the intracellular space through voltage-dependent and -independent channels play a major role in the increase of contractility of pulmonary arteries and in the loss of regulation of the proliferative behavior of the cells from the different layers of the pulmonary arterial wall. In doing so, these channels contribute to enhanced vasoconstriction of pulmonary arteries and their pathological remodeling. This review aims to summarize the evidence obtained from animal and cellular models regarding the involvement of the main plasma membrane calcium channels in these key pathophysiological processes for pulmonary arterial hypertension, discussing the potential value as pharmacological targets for therapies in the present and the future.

Naples Prognostic Score and Clinical Outcomes in Pulmonary Arterial Hypertension Patients.

Pulmonary arterial hypertension (PAH) is a specific form of pulmonary hypertension characterized by an increased mean pulmonary arterial pressure. Risk stratification is crucial in managing PAH, using various clinical, laboratory, and imaging parameters. The Naples prognostic score (NPS), incorporating nutritional and inflammatory markers, has demonstrated prognostic value in other conditions but not in PAH. The goal of this study was to appraise the importance of NPS as a prognostic indicator for patients with PAH. This retrospective study involved 101 PAH patients. Echocardiographic, laboratory, and right heart catheterization data were collected. Statistical analyses compared variables between survivors and non-survivors, and multivariate logistic regression identified mortality risk factors. Among the 101 patients, 18 died within the follow-up period. The mortality group showed elevated levels of B-type natriuretic peptide (BNP) and significantly higher median NPS. Patients were categorized based on their NPS scores, revealing higher mortality in Group 2. Multivariate logistic regression identified age and BNP levels as independent predictors of mortality. The inclusion of NPS in the model further reinforced its association with mortality. The study suggests that NPS is linked to poor outcomes in PAH patients. NPS, a straightforward and easily calculated score, holds the potential to predict the clinical trajectory of PAH, offering advantages for risk assessment in this population.

Computational modelling of multi-temporal ventricular-vascular interactions during the progression of pulmonary arterial hypertension.

A computational framework is developed to consider the concurrent growth and remodelling (G&R) processes occurring in the large pulmonary artery (PA) and right ventricle (RV), as well as ventricular-vascular interactions during the progression of pulmonary arterial hypertension (PAH). This computational framework couples the RV and the proximal PA in a closed-loop circulatory system that operates in a short timescale of a cardiac cycle, and evolves over a long timescale due to G&R processes in the PA and RV. The framework predicts changes in haemodynamics (e.g. 68.2% increase in mean PA pressure), RV geometry (e.g. 38% increase in RV end-diastolic volume) and PA tissue microstructure (e.g. 90% increase in collagen mass) that are consistent with clinical and experimental measurements of PAH. The framework also predicts that a reduction in RV contractility is associated with long-term RV chamber dilation, a common biomarker observed in the late-stage PAH. Sensitivity analyses on the G&R rate constants show that large PA stiffening (both short and long term) is affected by RV remodelling more than the reverse. This framework can serve as a foundation for the future development of a more predictive and comprehensive cardiovascular G&R model with realistic heart and vascular geometries.

Chronic thromboembolic pulmonary hypertension and mortality after venous thromboembolism: a nationwide population-based cohort study

Abstract Background One of the ultimate long-term complications of venous thromboembolism (VTE) is chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a condition defined as an increased mean pulmonary arterial pressure of at least 25 mmHg at rest and abnormal pulmonary artery resistance measured by right heart catheterization. To our knowledge, no study has compared mortality in VTE patients developing CTEPH to those who do not. Purpose We aimed to investigate the influence of CTEPH on long-term VTE mortality, by examining how receiving any pulmonary hypertension (PH) diagnosis following VTE influenced mortality. Methods We conducted a population-based cohort study of all adult Danish patients with an incident in or outpatient VTE diagnosis from 1995 through 2016. We excluded patients with a previous PH diagnosis. We defined CTEPH as receiving any PH diagnosis within two years following VTE. We categorized VTE by type (deep venous thrombosis [DVT] or pulmonary embolism [PE]) and provoking risk factors. We followed patients from two years after VTE until the first of death, emigration, or 31 December 2016. We calculated mortality rates and standardized mortality rate ratios (SMRs) of the association between PH and all-cause mortality and cause-specific mortality due to cancer and cardiovascular diseases. We also stratified the analyses by baseline presence of comorbidity (congestive heart failure, chronic pulmonary disease, and/or interstitial pulmonary disease). Results In 89,062 VTE patients alive two years after their VTE, 724 developed PH. The mortality rate per 1,000 person-years was 121 (95% confidence interval [CI]: 110–134) in patients with PH and 48 (95% CI: 47–48) in patients without PH. The SMR was 2.05 (95% CI: 1.77–2.37) for all VTE patients, 2.20 (95% CI: 1.53–3.16) for DVT patients, and 1.72 (95% CI: 1.47–2.01) for PE patients. The SMR was 1.79 (95% CI: 1.28–2.51) in VTE patients with a provoking VTE risk factor and 2.15 (95% CI: 1.83–2.53) in VTE patients without a provoking VTE risk factor. PH was associated with increased cause-specific mortality due to cardiovascular diseases (SMR=2.31, 95% CI: 1.75–3.06), but not cancer (SMR=0.94, 95% CI: 0.64–1.38). The SMR was 2.36 (95% CI: 2.06–2.71) in patients with comorbidity and 1.80 (95% CI: 1.45–2.24) in patients without comorbidity. Conclusion Development of PH, as a measure of CTEPH, within two years following incident VTE was associated with two-fold increased mortality in two-year VTE survivors. The increase in mortality was driven by cardiovascular causes. Funding Acknowledgement Type of funding sources: None.

Platelet-leukocyte aggregate formation and inflammation in patients with pulmonary arterial hypertension and CTEPH

Pulmonary hypertension (PH) is defined by increased mean pulmonary artery pressure, and the clinical classification includes five etiologies, of which we investigated subgroup 1, pulmonary arterial hypertension (PAH) and subgroup 4, chronic thrombotic and/or embolic disease (CTEPH). Platelets participate in both innate and adaptive immune responses and could possibly contribute to the suggested systemic inflammation associated with PAH. In this study, we utilized flow cytometry to analyze platelet activation and platelet-monocyte (PMA) and granulocyte (PGA) aggregates in PAH and CTEPH patients and healthy control subjects. The plasma concentration of proinflammatory cytokines was measured by multiplex electrochemiluminescence. Our main finding is that circulating platelets are activated in the circulation and form aggregates with both monocytes and granulocytes in patients with idiopathic PAH (IPAH), associated PAH (APAH) and pulmonary hypertension due to CTEPH. There was a strong correlation between the platelet activation, assessed as P-selectin, and the number of aggregates formed. IL-6, IL-8, IL-10 and TNF-α were increased in all PH subgroups as compared to healthy controls, and PMAs were associated with circulating IL-6, IL-8 and IL-10, whereas PGAs were associated with IL-6. The increased concentrations of platelet-leukocyte aggregates found in PAH/CTEPH patients might thus contribute to the inflammatory state in PH.

Abstract 12205: A New Mouse Model of Myocardial Lipids, Fibrosis, Arrhythmia and Diastolic Dysfunction Induced by Hyperlipidemia and Cardiac LDLR

Background: Hyperlipidemia is a major risk factor for CVD. Patients with HF with preserved ejection fraction (HFpEF) have more myocardial lipid accumulation than patients with reduced EF (HFrEF). RNASeq data from cardiac biopsies showed downregulation of the gene for lipoprotein lipase (LPL) that degrades triglycerides, in HFpEF patients compared to healthy and HFrEF controls. Poloxamer-407 (p407) induces hyperlipidemia by blocking LPL and subsequent increase in plasma triglycerides and low-density lipoprotein (LDL) cholesterol. We hypothesized that mice treated with p407 and cardiac LDL-Receptor (LDLR) over-expression (OE) develop hyperlipidemia, myocardial lipid accumulation, and diastolic dysfunction resulting in HFpEF and arrhythmias. Methods: Baseline cardiac function was assessed by echo for male and female C57Bl6 mice (n=9) for 2 groups: 4wk biweekly i.p. p407-injections with (n=4) or without (n=3) single i.v. injection with AAV9-cTnT-LDLR. Cardiac function was assessed by echocardiography at 3 and 4 wks. Blood Pressure (BP) and Whole Body Plethysmography (WBP) were assessed during wk4. Ttest was used for statistics. PR and ORO staining and telemetry were performed at wk4. Results: At wk3, P407 and LDLR OE led to alterations in diastolic function (increased IVCT, IVRT, MV E/E’, MPI, and NFT) and increased LV wall thickness, p&lt;0.05. At wk4, there was pulmonary hypertension (increased mean pulmonary arterial pressure, decreased pulmonary acceleration time p &lt;.05).Histology showed excessive myocardial lipids and fibrosis, and telemetry showed incidents of second-degree and higher-degree AV block. The group injected solely with p407 show e d alterations in diastolic function (increased IVCT, IVRT, NFT, LVMPI, LVMPI NFT p&lt;.05 ) and decreased EDV, ESV, EDLVM, ESLVM, p&lt;.05 at wk4. All groups had preserved %EF and no abnormalities in BP or WBP. Conclusions: P407 and cardiac LDLR OE induce a drastic decline in cardiac diastolic function over a shorter period of time compared to p407 alone. Diastolic dysfunction was observed in wk3 followed by pulmonary hypertension, arrhythmia, myocardial lipid accumulation and fibrosis in wk4. This new model may allow for more rapid investigations of cardiac abnormalities seen in HFpEF patients.

Prognostic value of the combination of pulmonary-systemic pressure ratio and a new systemic inflammation-nutrition index in patients admitted for acute decompensated heart failure

Abstract Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced HF. On the other hand, systemic inflammation plays a critical role in the outcomes of heart failure, and malnutrition is also associated with poor outcome in heart failure patients It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index × serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. However, there is no information available on the prognostic value of the combination of MPS ratio and ALI in patients with acute decompensated HF (ADHF). Methods and results We studied 219 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. During a follow up period of 5.1±4.2 yrs, 57 had cardiovascular death (CVD). MPS ratio was significantly greater (0.401±0.107 vs 0.346±0.105, p=0.0009) and ALI was significantly smaller (34.2±18.7 vs 52.0±27.1, p&amp;lt;0.0001) in patients with than without CVD At multivariate Cox analysis, MPS ratio and ALIwere significantly associated with CVD, independently of eGFR and prior heart failure hospitalization, after the adjustment with left ventricular end-diastolic dimension and serum sodium level. The patients with both greater MPS ratio&amp;gt;0.350 (AUC 0.652 [0.569–0.735]) and smaller ALI &amp;lt;35.767 (AUC 0.714 [0.636–0.792]) had a significantly increased risk of CVD than those with either greater MPS or smaller ALI and none of them (67% vs 22% vs 11%, p&amp;lt;0.0001, respectively). Conclusion The combination of MPS ratio and ALI might be useful for stratifying ADHF patients at higher risk for CVD. Funding Acknowledgement Type of funding sources: None.

Abstract P428: A New Mouse Model Of Myocardial Lipids, Fibrosis, Arrhythmia And Diastolic Dysfunction Induced By Hyperlipidemia And Cardiac LDLR

Background: Hyperlipidemia is a major risk factor for CVD. Patients with HF with preserved ejection fraction (HFpEF) have more myocardial lipid accumulation than patients with reduced EF (HFrEF). RNASeq data from cardiac biopsies showed downregulation of the gene for lipoprotein lipase (LPL) that degrades triglycerides, in HFpEF patients compared to healthy and HFrEF controls. Poloxamer-407 (p407) induces hyperlipidemia by blocking LPL and subsequent increase in plasma triglycerides and low-density lipoprotein (LDL) cholesterol. We hypothesized that mice treated with p407 and cardiac LDL-Receptor (LDLR) over-expression (OE) develop hyperlipidemia, myocardial lipid accumulation, and diastolic dysfunction resulting in HFpEF and arrhythmias. Methods: Baseline cardiac function was assessed by echo for male and female C57Bl6 mice (n=9) for 2 groups: 4wk biweekly i.p. p407-injections with (n=4) or without (n=3) single i.v. injection with AAV9-cTnT-LDLR. Cardiac function was assessed by echocardiography at 3 and 4 wks. Blood Pressure (BP) and Whole Body Plethysmography (WBP) were assessed during wk4. Ttest was used for statistics. PR and ORO staining and telemetry were performed at wk4. Results: At wk3, P407 and LDLR OE led to alterations in diastolic function (increased IVCT, IVRT, MV E/E’, MPI, and NFT) and increased LV wall thickness, p&lt;0.05. At wk4, there was pulmonary hypertension (increased mean pulmonary arterial pressure, decreased pulmonary acceleration time p &lt;.05).Histology showed excessive myocardial lipids and fibrosis, and telemetry showed incidents of second-degree and higher-degree AV block. The group injected solely with p407 show e d alterations in diastolic function (increased IVCT, IVRT, NFT, LVMPI, LVMPI NFT p&lt;.05 ) and decreased EDV, ESV, EDLVM, ESLVM, p&lt;.05 at wk4. All groups had preserved %EF and no abnormalities in BP or WBP. Conclusions: P407 and cardiac LDLR OE induce a drastic decline in cardiac diastolic function over a shorter period of time compared to p407 alone. Diastolic dysfunction was observed in wk3 followed by pulmonary hypertension, arrhythmia, myocardial lipid accumulation and fibrosis in wk4. This new model may allow for more rapid investigations of cardiac abnormalities seen in HFpEF patients.

Mechanistic insights into cell-free hemoglobin-induced injury during septic shock.

Cell-free hemoglobin (CFH) levels are elevated in septic shock and are higher in nonsurvivors. Whether CFH is only a marker of sepsis severity or is involved in pathogenesis is unknown. This study aimed to investigate whether CFH worsens sepsis-associated injuries and to determine potential mechanisms of harm. Fifty-one, 10-12 kg purpose-bred beagles were randomized to receive Staphylococcus aureus intrapulmonary challenges or saline followed by CFH infusions (oxyhemoglobin >80%) or placebo. Animals received antibiotics and intensive care support for 96 h. CFH significantly increased mean pulmonary arterial pressures and right ventricular afterload in both septic and nonseptic animals, effects that were significantly greater in nonsurvivors. These findings are consistent with CFH-associated nitric oxide (NO) scavenging and were associated with significantly depressed cardiac function, and worsened shock, lactate levels, metabolic acidosis, and multiorgan failure. In septic animals only, CFH administration significantly increased mean alveolar-arterial oxygenation gradients, also to a significantly greater degree in nonsurvivors. CFH-associated iron levels were significantly suppressed in infected animals, suggesting that bacterial iron uptake worsened pneumonia. Notably, cytokine levels were similar in survivors and nonsurvivors and were not predictive of outcome. In the absence and presence of infection, CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. In the presence of infection alone, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation, a known consequence of clinical septic shock, adversely impacts sepsis outcomes through more than one mechanism, and is a biologically plausible, nonantibiotic, noncytokine target for therapeutic intervention.NEW & NOTEWORTHY Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.

Oxygen Therapy Lowers Right Ventricular Afterload in Experimental Acute Pulmonary Embolism.

To investigate if oxygen could unload the right ventricle and improve right ventricle function in a porcine model mimicking intermediate-high risk acute pulmonary embolism. Controlled, blinded, animal study. Tertiary university hospital, animal research laboratory. Female, Danish pigs (n = 16, approximately 60 kg). Acute autologous pulmonary embolism was induced until doubling of baseline mean pulmonary arterial pressure. Group 1 animals (n = 8) received increasing Fio2 (40%, 60%, and 100%) for time intervals of 15 minutes returning to atmospheric air between each level of Fio2. In group 2 (n = 8), the effects of Fio2 40% maintained over 75 minutes were studied. In both groups, pulmonary vasodilatation from inhaled nitric oxide (40 parts per million) was used as a positive control. Effects were evaluated by biventricular pressure-volume loop recordings, right heart catheterization, and arterial and mixed venous blood gasses. Pulmonary embolism increased mean pulmonary arterial pressure from 15 ± 4 to 33 ± 6 mm Hg (p = 0.0002) and caused right ventricle dysfunction (p < 0.05) with troponin release (p < 0.0001). In group 1, increasing Fio2 lowered mean pulmonary arterial pressure (p < 0.0001) and pulmonary vascular resistance (p = 0.0056) and decreased right ventricle volumes (p = 0.0018) and right ventricle mechanical work (p = 0.034). Oxygenation was improved and pulmonary shunt was lowered (p < 0.0001). Maximal hemodynamic effects were seen at Fio2 40% with no additional benefit from higher fractions of oxygen. In group 2, the effects of Fio2 40% were persistent over 75 minutes. Supplemental oxygen showed the same pulmonary vasodilator efficacy as inhaled nitric oxide (40 parts per million). No adverse effects were observed. In a porcine model mimicking intermediate-high risk pulmonary embolism, oxygen therapy reduced right ventricle afterload and lowered right ventricle mechanical work. The effects were immediately present and persistent and were similar to inhaled nitric oxide. The intervention is easy and safe. The study motivates extended clinical evaluation of supplemental oxygen in acute pulmonary embolism.

Prognostic value of pulmonary-systemic pressure ratio and fibrosis-4 index in patients admitted for acute decompensated heart failure

Abstract Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. An increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is reported to be associated with worse clinical outcomes in patients with advanced HF. On the other hand, cardiohepatic interactions have been a focus of attention in HF, and liver dysfunction in HF patients is caused by liver congestion, which is related to liver stiffness. It has been recently shown that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4 (FIB4) index predicts the mortality in HF patients. However, there is no information available on the prognostic value of the combination of MPS ratio and FIB4 index in patients with acute decompensated heart failure (ADHF). Methods and results We studied 238 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. MPS ratio was obtained at the admission. FIB4 index was calculated by the formula: age (yrs) × AST [U/L] / (platelets [103/μL] × √(ALT[U/L])). FIB4 index &amp;gt;2.67 was defined as abnormal, as previously reported. During a follow up period of 5.2±4.4 yrs, 93 patients died. At multivariate Cox analysis, MPS ratio (p=0.01) and FIB4 index (p=0.01) were significantly associated with the total mortality, independently of creatinine level and prior heart failure hospitalization, after the adjustment with hemoglobin, albumin levels and body mass index. The patients with both MPS ratio ≥0.388 (determined by ROC analysis; AUC 0.613 [0.541–0.687]) and abnormal FIB4 index had a significantly increased risk of the total mortality than those with either greater MPS or abnormal FIB4 index and none of them (52% vs 40% vs 28%, p=0.0068, respectively). Conclusion The combination of MPS ratio and FIB4 index might be useful for stratifying ADHF patients at higher risk for the total mortality. Funding Acknowledgement Type of funding source: None

Long-term prognostic value of the combination of malnutrition and pulmonary-systemic pressure ratio in patients admitted with acute decompensated heart failure

Abstract Background Malnutrition is associated with increased mortality risk in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of malnutrition and MPS ratio in pts admitted for ADHF. Methods and results We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. Malnutrition was assessed by geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). During a mean follow-up period of 5.2±4.4 yrs, 62 pts had cardiovascular death (CVD). MPS ratio was significantly greater in pts with than without CVD (0.408±0.114 vs 0.347±0.102, p=0.0001). GNRI and PNI were significantly lower, CONUT was significantly greater in pts with than without CVD. At multivariate Cox regression analysis, GNRI and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia, although PNI and CONUT showed the association with CVD at unvariate analysis. Pts with malnutrition (GNRI≤median value=96.5) and greater MPS ratio (≥median value=0.346) had a significantly higher CVD risk than those with either and none of them (51% vs 20% vs 12%, p&amp;lt;0.0001, respectively). Conclusions The combination of malnutrition and MPS ratio might be useful for stratifying pts at risk for CVD in patients with ADHF. Funding Acknowledgement Type of funding source: None

Impact of Preload on Right Ventricular Hemodynamics in Acute Pulmonary Embolism

To compare the hemodynamic effects of increased versus decreased preload in a porcine model of acute intermediate-risk pulmonary embolism. Randomized, controlled animal study. Tertiary medical center, animal research laboratory. Female, Danish slaughter pigs (n = 22, ~ 60 kg). Acute pulmonary embolism was induced by large emboli made from clotting of autologous blood. Sixteen animals were randomized to either fluid loading (n = 8, isotonic saline, 1 L/hr for 2 hr) or diuretic treatment (n = 8, furosemide, 40 mg every 30 min, total 160 mg) and compared with a vehicle group (n = 6, no treatment). Hemodynamics were evaluated at baseline, after pulmonary embolism and after each dose by biventricular pressure-volume loops, invasive pressures, diuretic output, respiratory variables, and blood analysis. Pulmonary embolism increased mean pulmonary arterial pressure (p < 0.0001), pulmonary vascular resistance (p = 0.008), right ventricular arterial elastance (p = 0.003), and right ventricular end-systolic volume (p = 0.020) while right ventricular stroke volume and right ventricular ejection fraction were decreased (p = 0.047 and p = 0.0003, respectively) compared with baseline. Fluid loading increased right ventricular end-diastolic volume (+31 ± 13 mL; p = 0.004), right ventricular stroke volume (+23 ± 10 mL; p = 0.009), cardiac output (+2,021 ± 956 mL; p = 0.002), and right ventricular ejection fraction (+7.6% ± 1.5%; p = 0.032), whereas pulmonary vascular resistance decreased (-202 ± 65 dynes; p = 0.020) compared with vehicle. Diuretic treatment decreased right ventricular end-diastolic volume (-84 ± 11 mL; p < 0.001), right ventricular stroke volume (-40 ± 6 mL; p = 0.001), cardiac output (-3,327 ± 451 mL; p = 0.005), and mean pulmonary arterial pressure (-7 ± 1 mm Hg; p < 0.001) and increased right ventricular end-systolic elastance (+0.72 ± 0.2 mm Hg/mL; p < 0.001) and systemic vascular resistance (+1,812 ± 767 dynes; p < 0.001) with no effects on mean arterial pressure. In a porcine model of acute intermediate-risk pulmonary embolism, fluid loading increased right ventricular preload and right ventricular stroke volume, whereas diuretics decreased right ventricular preload and right ventricular stroke volume without affecting mean arterial pressure.

The Myths and Realities of Portopulmonary Hypertension.

Portopulmonary hypertension (POPH), defined as an increased mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in the setting of portal hypertension, is a commonly misunderstood pulmonary vascular complication of liver disease. Recent literature has expanded our knowledge regarding disease pathogenesis, the role of pulmonary arterial hypertension (PAH) targeted therapy and liver transplantation (LT) in management, and long-term outcomes. However, many myths and misconceptions regarding POPH prognosis and treatment remain. The aim of this review is to examine the prevailing myths and current realities regarding POPH.

Exercise Pulmonary Resistances Predict Long-Term Survival in Systemic Sclerosis

Pulmonary hemodynamics during exercise may reveal early pulmonary vascular disease and may be of clinical and prognostic relevance in systemic sclerosis (SSc). We aimed to assess the prognostic relevance of exercise pulmonary resistances in patients with SSc with no or mildly increased mean pulmonary arterial pressure (mPAP). Are pulmonary resistances at peak exercise independent predictors of mortality in systemic sclerosis? All SSc patients with resting mPAP< 25mmHg and at least one year of follow-up data who underwent symptom-limited exercise right heart catheterization between April 2005 and December 2018 were analyzed retrospectively. Age-adjusted Cox regression analysis was used to evaluate the association between pulmonary resistances and all-cause mortality. The cohort consisted of 80 patients: 73 women and 7 men with a mean age of 57 years (interquartile range [IQR], 47-67 years) and a mean follow-up time of 10.4 years (IQR, 8.5-11.8 years). At baseline, resting mPAP of≤ 20mmHg and 21 to 24mmHg was found in 68 and 12 patients, respectively. Pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR) at peak exercise were associated significantly with mortality (P= .006 [hazard ratio (HR), 2.20; 95%CI, 1.26-3.87] and P= .026 [HR, 1.56; 95%CI, 1.06-2.29]), whereas resting PVR and TPR were not (P= .087 [HR, 2.27; 95%CI, 0.89-5.83] and P= .079 [HR, 1.88; 95%CI, 0.93-3.80]). The mPAP per cardiac output (CO) and transpulmonary gradient (TPG) per CO slopes were associated significantly with mortality (P= .047 [HR, 1.14; 95%CI, 1.002-1.286] and P= .034 [HR, 1.34; 95%CI, 1.02-1.76]) as well. The area under the receiver operating characteristic curve for exercise PVR to predict 10-year mortality was 0.917 (95%CI, 0.797-1.000). PVR and TPR at peak exercise, mPAP/CO slope, and TPG/CO slope are predictors of age-adjusted long-term mortality in SSc patients with no or mildly increased pulmonary arterial pressure.

Abstract MP155: Oxidized Lipids Diet Causes Pulmonary Hypertension Through T-cell Dependent Endothelial Cell Apoptosis

Background: Pulmonary hypertension (PH) is a fatal disease characterized by an increased mean pulmonary arterial pressure above 25mmHg. This increased pressure is, at least in part, due to thickening of the distal pulmonary arteries. Recently, numerous studies demonstrated an increased plasma concentration of oxidized lipids in PH and in diseases where secondary PH developed. Furthermore, 15-hydroxyeicosatetraenoic acid (15-HETE) an oxidized lipid and a major metabolite of arachidonic acid in the lung, has been implicated in dysregulation of major biological pathways in PH. However, the mechanisms involved in the causal role of 15-HETE in pulmonary hypertension development are not known. Methods and Results: To study the role of 15-HETE in PH development, we fed C57BL6/J mice a diet supplemented with 15-HETE for 3 weeks with no other insults. After 3 weeks on the diet with added 15-HETE, C57BL6/J mice had increased concentrations of not only 15-HETE but also of other oxidized lipids (5-, 11- and 12-HETE) in plasma and lung, and they developed PH. RNA-seq analysis revealed the activation of pathways involved in antigen processing and presentation, and with evidence of T cell mediated cytotoxicity in lungs of mice fed 15-HETE. Transcriptomic profiling of lung tissues obtained from patients with pulmonary arterial hypertension (PAH) demonstrated activation of pathways similar to those seen mice. In mice fed a 15-HETE diet, there was an increase in the number of CD8/CD69 double positive cells, as well as an increase in pulmonary arterial endothelial cell (PAEC) apoptosis. Furthermore, PAEC exposed to 15-HETE were more prone to apoptosis when exposed to CD8 cells. Adding Tg6F, an apoA-I mimetic peptide to the 15-HETE diet prevented and rescued PH in C57BL6/J mice, in part, by inhibiting PAEC apoptosis. Conclusions: 15-HETE diet induced PH in C57Bl6/J mice by triggering PAEC death in a T-cell dependent mechanism. The apoA-I mimetic peptide Tg6F was able to prevent and rescue PH induced by 15-HETE.

Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell–Dependent Endothelial Cell Apoptosis

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell-mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE-fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE-fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE-induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell-dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.

Pulmonary artery hypertension patients and the coronavirus disease of 2019 (COVID-19): are they protected from severe disease?

The coronavirus disease of 2019 (COVID-19) is a current pandemic of viral infection which mainly involves respiratory system and may progress into severe multiple organ dysfunction and mortality. Pulmonary artery hypertension (PAH) is a disease marked by increased mean pulmonary artery pressure and pulmonary vascular resistance due to pulmonary panvascular remodeling. Although rare, the prevalence of PAH is currently escalating in Indonesia due to increased diagnostic capacity and referral, treatment availability and improved survival. Despite chronic cardiac and pulmonary diseases are at increased risk to develop severe COVID-19, patients with PAH are considered to be not in higher risk to develop severe COVID-19. However, whether this population is protected from severe COVID-19 is unclear. There are protective and offensive factors need to be considered in PAH patients in respect to COVID-19.