Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases.

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.

Microcirculatory Disease in Patients after Heart Transplantation.

Although the treatment and prognosis of patients after heart transplantation have significantly improved, late graft dysfunction remains a critical problem. Two main subtypes of late graft dysfunction are currently described: acute allograft rejection and cardiac allograft vasculopathy, and microvascular dysfunction appears to be the first stage of both. Studies revealed that coronary microcirculation dysfunction, assessed by invasive methods in the early post-transplant period, correlates with a higher risk of late graft dysfunction and death during long-term follow-up. The index of microcirculatory resistance, measured early after heart transplantation, might identify the patients at higher risk of acute cellular rejection and major adverse cardiovascular events. It may also allow optimization and enhancement of post-transplantation management. Moreover, cardiac allograft vasculopathy is an independent prognostic factor for transplant rejection and survival rate. The studies showed that the index of microcirculatory resistance correlates with anatomic changes and reflects the deteriorating physiology of the epicardial arteries. In conclusion, invasive assessment of the coronary microcirculation, including the measurement of the microcirculatory resistance index, is a promising approach to predict graft dysfunction, especially the acute allograft rejection subtype, during the first year after heart transplantation. However, further advanced studies are needed to fully grasp the importance of microcirculatory dysfunction in patients after heart transplantation.

Impact of the COVID-19 Pandemic on Pulmonary Hypertension Patients: Insights from the BNP-PL National Database.

We aimed to evaluate the clinical course and impact of the SARS-CoV-2 pandemic on the rate of diagnosis and therapy in the complete Polish population of patients (pts) with pulmonary arterial hypertension (PAH-1134) and CTEPH (570 pts) treated within the National Health Fund program and reported in the national BNP-PL database. Updated records of 1704 BNP-PL pts collected between March and December 2020 were analyzed with regard to incidence, clinical course and mortality associated with COVID-19. Clinical characteristics of the infected pts and COVID-19 decedents were analyzed. The rates of new diagnoses and treatment intensification in this period were studied and collated to the proper intervals of the previous year. The incidence of COVID-19 was 3.8% (n = 65) (PAH, 4.1%; CTEPH, 3.2%). COVID-19-related mortality was 28% (18/65 pts). Those who died were substantially older and had a more advanced functional WHO class and more cardiovascular comorbidities (comorbidity score, 4.0 ± 2.1 vs. 2.7 ± 1.8; p = 0.01). During the pandemic, annualized new diagnoses of PH diminished by 25-30% as compared to 2019. A relevant increase in total mortality was also observed among the PH pts (9.7% vs. 5.9% pre-pandemic, p = 0.006), whereas escalation of specific PAH/CTEPH therapies occurred less frequently (14.7% vs. 21.6% pre-pandemic). The COVID-19 pandemic has affected the diagnosis and treatment of PH by decreasing the number of new diagnoses, escalating therapy and enhancing overall mortality. Pulmonary hypertension is a risk factor for worsened course of COVID-19 and elevated mortality.

Neopterin as a predictive biomarker of postoperative atrial fibrillation following coronary artery bypass grafting.

BACKGROUND: The pathophysiology of postoperative atrial fibrillation (POAF) is multifactorial. Inflammation and increased oxidative stress play a significant role in POAF development. Neopterin, a biomarker of cellular immune response that enhances oxidative stress and increases the cytotoxic potential of activated macrophages and dendritic cells, was recently found as an independent predictive biomarker of non-operative atrial fibrillation. However, as far as we know, neopterin has never been investigated in POAF. AIMS: The study aimed to assess neopterin concentration as a prognostic biomarker of POAF following coronary artery bypass grafting (CABG). METHODS: One hundred one patients (80.2% males, 85% off-pump, 15% on-pump) were included. Blood samples were taken from patients for analysis of serum neopterin and high-sensitive C-reactive protein (hs-CRP) at three time points: (1) before operation (NP0); (2) on the first day after operation (NP1); and (3) between the fifth and eighth day after the procedure (NP5-8). All factors (preoperative, echocardiographic, and surgical), significant in univariate analysis, were included in a multivariable logistic regression analysis. RESULTS: POAF occurred in 30 patients (30%). In the analyzed multivariable logistic regression models, the independent predictors of POAF occurrence were: higher NP0 concentration (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.02-1.38 for continuous and OR, 3.75; 95% CI, 1.39-10.1 for NP0 cut-off >8.7 nmol/l), higher body mass index (OR, 1.15; 95% CI 1.02-1.29), history of pulmonary disease (OR, 6.72; 95% CI 1.57-28), increased diastolic thickness of the interventricular septum (OR, 1.45; 95% CI, 1.14-1.83), and duration of operation (OR, 1.01; 95% CI, 1.03-1.36). CONCLUSIONS: We found that elevated neopterin concentration before CABG may be a predictive biomarker of POAF.

Association of Electrocardiographic Signs of Right Ventricular Hypertrophy and Clot Localization in Chronic Thromboembolic Pulmonary Hypertension.

The role of electrocardiography (ECG) in chronic thromboembolic pulmonary hypertension (CTEPH) diagnosis and prognosticating has not been yet established. We aimed to assess the relationships of the recommended ECG criteria of right ventricular hypertrophy (RVH) with clot localization in CTEPH patients. ECG patterns of RVH according to the American College of Cardiology Foundation were assessed in patients with newly diagnosed CTEPH. We enrolled 58 (45.3%) patients with proximal and 70 (54.7%) with distal CTEPH. Receiver-operating characteristics curves analysis indicated that the following ECG abnormalities predicted proximal CTEPH localization: RV1 > 6 mm-AUC 0.75 (CI: 0.66-0.84, p < 0.00001); SV6 > 3 mm-AUC 0.70 (CI: 0.60-0.79, p < 0.00001); SI > RI wave-AUC 0.67 (CI: 0.58-0.77, p = 0.0004); RV1:SV1 > 1.0-AUC 0.66 (CI: 0.56-0.76, p = 0.0009); RV1 peak > 0.035 s (QRS < 120 ms)-AUC 0.66 (CI: 0.56-0.75, p = 0.0016); RV1:SV1 > RV3(V4):SV3(V4)-AUC-0.65 (CI: 0.54-0.75, p = 0.0081); RaVR > 4 mm-AUC 0.62 (CI: 0.52-0.71, p = 0.002) and PII > 2.5 mm-AUC 0.62 (CI: 0.52-0.72, p = 0.00162). Pulmonary vascular resistance significantly correlated with amplitudes of RV1 (r = 0.34, p = 0.008), SV6 (r = 0.53, p = 0.000027) and PII (r = 0.44, p = 0.00007). In patients with CTEPH, only 8 out of 23 ECG RVH criteria were useful for differentiating between proximal and distal CTEPH localization and we found that RV1 and SV6 may contribute as potential discriminators.

Implementation of a regional multidisciplinary pulmonary embolism response team: PERT-POZ initial 1-year experience.

BACKGROUND: Pulmonary embolism (PE) is the third most common potentially life­threatening cardiovascular disease. A new approach of pulmonary embolism response teams (PERTs) has been introduced to provide rapid multidisciplinary assessment and treatment of patients with PE. However, detailed data on institutional experience and clinical outcomes from such teams are missing. AIMS: The aim of this study was to report our experience with the management of PE guided by the PERT-POZ within the first year of operation. METHODS: We performed a prospective study of PERT-POZ activations at a university care center between October 2018 and October 2019. Patient characteristics, therapies, and clinical outcomes were evaluated. RESULTS: There were 86 unique PERT-POZ activations, and PE was confirmed in 80 patients including: 9 patients (11.25%) classified as low­risk PE, 19 (23.75%) as intermediate­low risk, 38 (47.5%) as intermediate­high, and 14 (17.5%) as high­risk. Sixty patients (75%) received anticoagulation only, 28 (35%) direct oral anticoagulant, 7 (8.75%) vitamin K antagonist, 23 (28.75%) low-molecular-weight heparin, and 2 (2.50%) unfractionated heparin. Ten patients (12.5%) were treated with catheter­directed thrombectomy, 6 (7.5%) received systemic thrombolysis, 2 (2.5%) underwent surgical embolectomy, 2 (2.5%) were on extracorporeal membrane oxygenation support, and 2 (2.5%) underwent pharmacomechanical venous thrombectomy. There were 7 (8.75%) in­hospital deaths, and 2 (2.5%) deaths during a 3­month follow­up. Bleeding complications were rare: only 3 patients (3.75%) had major bleeding events, but none after administration of systemic thrombolysis. CONCLUSIONS: Our study demonstrated that after the creation of PERT-POZ with a precise activation protocol, patients with intermediate and high­risk PE received most optimal treatment strategies.

The Polish adaptation of the CAMbridge Pulmonary Hypertension Outcome Review (CAMPHOR).

BACKGROUND: Pulmonary hypertension (PH) results in severely impaired quality of life (QoL) in people with this condition. The CAMbridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the only questionnaire providing a disease-specific measurement of symptoms, functioning and QoL in PH patients. It has already been adapted for use in several countries. The aim of this study was to adapt and validate CAMPHOR for the Polish-speaking population. METHODS: Two panels (bilingual and lay) were conducted to translate CAMPHOR into Polish. This new version was then tested by cognitive debriefing interviews with 15 patients. Finally, a postal validation survey was conducted with 56 patients on two occasions 2 weeks apart to assess its psychometric properties. RESULTS: No problems were experienced in producing a Polish translation of CAMPHOR. Interviewees responded well to the Polish CAMPHOR, finding it relevant, comprehensible and easy to complete. For all three CAMPHOR scales (Symptoms, Activity, QoL), The Cronbach alpha coefficients were above 0.8 at both time points, indicating high internal consistency. Test-retest reliability for the three scales achieved a value above 0.80. Predicted correlations with the Nottingham Health Profile provided evidence of the construct validity of CAMPHOR scales. The Polish CAMPHOR could distinguish between patients who differed according to their perceived general health and perceived disease severity. No significant differences in scores were found between participants grouped by gender or age. CONCLUSIONS: The Polish version of CAMPHOR demonstrated good psychometric properties and is recommended for use in clinical practice.

Prognostic Value of Oxidative Stress Markers in Patients with Pulmonary Arterial or Chronic Thromboembolic Pulmonary Hypertension.

Oxidative stress is regarded to play a crucial role in the pathophysiology of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). This study evaluated the prognostic value of serum oxidative stress markers (malondialdehyde (MDA), total antioxidant capacity (TAC), catalase activity (CAT), and superoxide activity (SOD)) in patients with PAH and CTEPH (n = 45). During 13 months of follow-up (median 9 months), clinical deterioration occurred in 14 patients (including 2 deaths). On the Cox regression analysis, MDA, TAC, and CAT were associated with clinical deterioration (p = 0.0068, HR = 1.42, 95% CI: 1.10-1.82; p = 0.0038, HR = 0.033, 95% CI: 0.0032-0.33; and p = 0.046, HR = 0.20, 95% CI: 0.04-0.98, respectively). There was no significant difference in SOD (p = 0.53, HR = 0.97, 95% CI: 0.87-1.08). The cut-off value derived from ROC curve analysis was 3.79 µM (p = 0.0048, AUC = 0.76, 95% CI: 0.62-0.91) for MDA, 0.49 mM (p = 0.027, AUC = 0.71, 95% CI: 0.18-0.47) for TAC, and 1.34 U/L (p = 0.029, AUC = 0.71, 95% CI: 0.55-0.86) for CAT. MDA in the group with deterioration was higher (p = 0.0041), while TAC as well as CAT were lower (p = 0.027 and p = 0.028, respectively) when compared to stable patients. Survival without clinical deterioration was significantly longer in patients with lower MDA (p = 0.037, HR = 0.37, 95% CI: 0.12-1.14, log-rank), higher TAC (p = 0.0018, HR = 0.19, 95% CI: 0.06-0.60, log-rank), and higher CAT (p = 0.044, HR = 0.31 95% CI: 0.11-0.88, log-rank). Markers of oxidative stress such as MDA, TAC, and CAT were associated with adverse clinical outcomes in patients with PAH and inoperable or residual CTEPH.

Neopterin as a Biomarker in Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Upregulation of the immune system is regarded to play an important role in the etiopathobiology of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). To the best of our knowledge, neopterin (NP) has never been investigated in patients with PAH and CTEPH. OBJECTIVES: The aim of the study was to evaluate the concentration of NP in blood in order to examine its impact on outcome and relationship with disease severity in that population. METHODS: Serum concentration of NP was analysed prospectively in 50 patients (36 with PAH and 14 with CTEPH vs. 31 healthy controls) and assessed in relation to clinical parameters and outcome. RESULTS: NP concentration in the PAH and CTEPH groups combined was significantly higher than in the control group (8.68, 6.39-15.03 vs. 5.14, 4.16-5.98 nmol/L, p < 0.0000001). During 9 months of follow-up, clinical deterioration occurred in 18 patients (including 8 deaths), and NP concentration in this group was higher when compared to stable patients (15.6, 8.52-25.13 vs. 7.87, 6.18-9.89, p = 0.002). The cutoff value of NP derived from ROC curve analysis was 15.3 nmol/L (p = 0.002, AUC 0.77, p = 0.0004, HR = 4.35, 95% CI 1.43-13.18, log-rank test). On Cox regression analysis, NP predicted clinical deterioration (p = 0.009, 95% CI 1.01-1.06). NP correlated positively with NT-proBNP (p < 0.001), red blood cell distribution width (p < 0.001), and right atrium area (p = 0.002) and inversely with 6-min walking test (p = 0.002) and peak oxygen consumption (p = 0.001). CONCLUSIONS: NP concentration is increased in patients with PAH and inoperable CTEPH. Elevated NP concentration is associated with adverse clinical outcomes and correlates with clinical parameters.

Red Blood Cells Distribution Width as a Potential Prognostic Biomarker in Patients With Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Red blood cells distribution width (RDW) predicts survival in cardiovascular diseases. Little is known about the variability of RDW level over time among patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). To our knowledge, RDW has never been analysed as a marker of response to specific treatment. MATERIALS AND METHODS: We retrospectively analysed 77 patients for: i) RDW measured during the last hospitalisation before death or during the last follow-up (RDWlast); ii) mean RDW from all hospitalisations during the entire follow-up of the patient (RDWmean); iii) maximum RDW of all hospitalisations of each patient (RDWmax). In order to assess response to specific treatment and association with prognosis, we compared RDW levels (obtained from 56 patients) before and 3 to 6 months after introduction or intensification of treatment in both the alive and deceased group. RESULTS: Twenty-eight of 77 patients died, whereas in specific drugs treatment response analysis, 22 of 56 patients died during follow-up. The cut-off values derived from the ROC analysis and assessed using the log-rank test were significant for RDWlast (p<0.0001), RDWmean (p<0.001) and RDWmax (p=0.02). A decrease in RDW levels after introduction or intensification of specific treatment was significant (p=0.015) in survivors, whereas there was no significance (p=0.29) in decrease in RDW levels in non-survivors after change of therapy. CONCLUSIONS: Red blood cells distribution width might be a potential prognostic biomarker in patients with PAH and inoperable CTEPH. The decrease in RDW level after introduction or escalation of PAH-targeted and CTEPH-targeted drugs is associated with a good treatment response and better prognosis.

Recurrent acute myocardial infarction as an initial manifestation of antiphospholipid syndrome: treatment and management.

The antiphosholipid syndrome (APS) is an autoimmune disorder, characterized by the presence of vascular thrombosis and/or pregnancy morbidity in a patient with positive laboratory tests for antiphospholipid antibodies. The patients with APS are in the high risk of rethrombosis. We report the case of 43-year-old female presenting with recurrent acute myocardial infarction with ST-segment elevation because of recurrent coronary thrombosis in coronary left anterior descending artery (LAD) and circumflex coronary artery (Cx) resulting in four percutaneous coronary interventions (PCI), associated with the presence of plasma antiphospholipid antibodies. Patient received seven stents to LAD and the aspiration of thrombus from Cx artery was performed. Pharmacotherapy included full antithrombotic treatment consisted with antiplatelet drugs such as: aspirin, clopidogrel followed by prasugrel, glycoprotein IIb/IIIa receptor antagonists and anticoagulants such as heparin followed by warfarin as well as steroids. At 1-year follow-up, controlled coronary angiography confirmed the good effect of PCI without any signs of stenosis or rethrombosis and highlighted the important role of antithrombotic treatment in patients with APS.