Collagen 18A1/Endostatin Expression in the Progression of Right Ventricular Remodeling and Dysfunction in Pulmonary Arterial Hypertension.

Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII α 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure-volume loops in patients with PAH to assess RV-pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV-pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increases early in disease development in the RV and implicates COL18A1/ES in pathologic RV dysfunction in PAH.

Aberrant long-chain fatty acid metabolism associated with evolving systemic sclerosis-associated pulmonary arterial hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n = 22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared with metabolites assayed in matched SSc patients who did not develop PAH (n = 22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 yr) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to 2 yr before clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including before clinical diagnosis and in mild disease.NEW & NOTEWORTHY Abnormal lipid metabolism is evident across time in the development of SSc-PAH, and dysregulated long-chain fatty acid metabolism predicts overt PAH.

Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry.

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.

Cardiorenal syndrome in heart failure with preserved ejection fraction-an under-recognized clinical entity.

Cardiorenal syndrome (CRS) results from the complex and bidirectional interaction between the failing heart and the kidneys. Limited information exists about the pathophysiology and treatment options for worsening kidney function in the setting of heart failure with preserved ejection fraction (HFpEF). This review summarizes the salient pathophysiological pathways in CRS in patients with HFpEF, with emphasis on type 1 and type 2 phenotypes, and outlines diagnostic and therapeutic strategies that are applicable in this population. Elevated central venous and intra-abdominal pressure, left ventricular hypertrophy, LV strain, RAAS activation, oxidative injury, pulmonary hypertension, and RV dysfunction play key roles in the pathogenesis of CRS in the backdrop of HFpEF. The availability of biomarkers of renal and cardiac injury offer a new dimension in accurately diagnosing and quantifying end organ damage in CRS and will improve the accuracy of goal-directed therapies in this population. Novel targeted therapies such as the development of angiotensin/neprilysin inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer new territory in realizing potential benefits in reduction of cardio-renal adverse outcomes in this population. Future studies focusing exclusively on renal outcomes in patients with HFpEF are crucial in delivering optimal therapies in this subset of patients.

Frequency of acute vasodilator response (AVR) in incident and prevalent patients with pulmonary arterial hypertension: Results from the pulmonary vascular disease phenomics study.

The prevalence of acute vasodilator response (AVR) to inhaled nitric oxide (iNO) during right heart catheterization (RHC) is 12% in idiopathic pulmonary arterial hypertension (IPAH). AVR, however, is reportedly lower in other disease-associated pulmonary arterial hypertension (PAH), such as connective tissue disease (CTD). The prevalence of AVR in patients on PAH therapy (prevalent cases) is unknown. We sought to determine AVR prevalence in Group 1 PH in the PVDOMICS cohort of incident and prevalent patients undergoing RHC. AVR was measured in response to 100% O2 and O2 plus iNO, with positivity defined as (1) decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to a value ≤40 mmHg, with no change or an increase in cardiac output (definition 1); or (2) decrease in mPAP by ≥12% and pulmonary vascular resistance by ≥30% (definition 2). AVR rates and cumulative survival were compared between incident and prevalent patients. In 338 mainly prevalent (86%) patients, positive AVR to O2-only was <2%, and 5.1% to 16.9%, based on definition 1 and 2 criteria, respectively; following O2 + iNO. IPAH AVR prevalence (4.1%-18.7%) was similar to prior reports. AVR positivity was 7.7% to 15.4% in mostly CTD-PAH prevalent cases, and 2.6% to 11.8% in other PAH groups. Survival was 89% in AVR responders versus 77% in nonresponders from PAH diagnosis, and 91% versus 86% from PVDOMICS enrollment (log-rank test p = 0.04 and p = 0.05, respectively). In conclusion, AVR in IPAH patients is similar to prior studies. AVR in non-IPAH patients was higher than previously reported. The relationship between PAH therapy, AVR response, and survival warrants further investigation.

Risk Stratification of Patients with Pulmonary Arterial Hypertension: The Role of Echocardiography.

Background: Given the morbidity and mortality associated with pulmonary arterial hypertension (PAH), risk stratification approaches that guide therapeutic management have been previously employed. However, most patients remain in the intermediate-risk category despite initial therapy. Herein, we sought to determine whether echocardiographic parameters could improve the risk stratification of intermediate-risk patients. Methods: Prevalent PAH patients previously enrolled in observational studies at 3 pulmonary hypertension centers were included in this study. A validated PAH risk stratification approach was used to stratify patients into low-, intermediate-, and high-risk groups. Right ventricular echocardiographic parameters were used to further stratify intermediate-risk patients into intermediate-low- and intermediate-high-risk groups based on transplant-free survival. Results: From a total of 146 patients included in our study, 38 patients died over a median follow-up of 2.5 years. Patients with intermediate-/high-risk had worse echocardiographic parameters. Tricuspid annular plane systolic excursion (TAPSE) and the degree of tricuspid regurgitation (TR) were highly associated with survival (p < 0.01, p = 0.04, respectively) and were subsequently used to further stratify intermediate-risk patients. Among intermediate-risk patients, survival was worse for patients with TAPSE < 19 mm compared to those with TAPSE ≥ 19 mm (estimated one-year survival 74% vs. 96%, p < 0.01) and for patients with moderate/severe TR compared to those with no/trace/mild TR (estimated one-year survival 70% vs. 93%, p < 0.01). Furthermore, among intermediate-risk patients, those with both TAPSE < 19 mm and moderate/severe TR had an estimated one-year survival (56%) similar to that of high-risk patients (56%), and those with both TAPSE ≥ 19 mm and no/trace/mild TR had an estimated one-year survival (97%) similar to that of low-risk patients (95%). Conclusions: Echocardiography, a routinely performed, non-invasive imaging modality, plays a pivotal role in discriminating distinct survival phenotypes among prevalent intermediate-risk PAH patients using TAPSE and degree of TR. This can potentially help guide subsequent therapy.

Causes and outcomes of ICU hospitalisations in patients with pulmonary arterial hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a rare disease characterised by limited survival despite remarkable improvements in therapy. The causes, clinical burden and outcomes of patients admitted to the intensive care unit (ICU) remain poorly characterised. The aim of this study was to describe patient characteristics, causes of ICU hospitalisation, and risk factors for ICU and 1-year mortality. Methods: Data from patients enrolled in the Johns Hopkins Pulmonary Hypertension Registry were analysed for the period between January 2010 and December 2020. Clinical, functional, haemodynamic and laboratory data were collected. Measurements and main results: 102 adult patients with 155 consecutive ICU hospitalisations were included. The leading causes for admission were right heart failure (RHF, 53.3%), infection (17.4%) and arrhythmia (11.0%). ICU mortality was 27.1%. Mortality risk factors included Na <136 mEq·mL-1 (OR: 3.10, 95% CI: 1.41-6.82), elevated pro-B-type natriuretic peptide (proBNP) (OR: 1.75, 95% CI: 1.03-2.98), hyperbilirubinaemia (OR: 1.40, 95% CI: 1.09-1.80), hyperlactaemia (OR: 1.42, 95% CI: 1.05-1.93), and need for vasopressors/inotropes (OR: 5.29, 95% CI: 2.28-12.28), mechanical ventilation (OR: 3.76, 95% CI: 1.63-8.76) and renal replacement therapy (OR: 5.57, 95% CI: 1.25-24.76). Mortality rates at 3, 6 and 12 months were 17.5%, 27.6% and 39.0%, respectively. Connective tissue disease-associated PAH has lower 1-year survival compared to idiopathic PAH (51.4% versus 79.8%, log-rank test p=0.019). Conclusions: RHF is the most common cause for ICU admission. In-hospital and 1-year mortality remain exceedingly high despite improved ICU care. Recognising specific risk factors on admission can help identifying patients at risk for poor outcomes.

Systemic Sclerosis-Associated Pulmonary Hypertension: Spectrum and Impact.

Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a catastrophic complication of one of the most common and devastating autoimmune diseases. Once diagnosed, it becomes the leading cause of mortality among this patient population. Screening modalities and risk assessments have been designed and validated by various organizations and societies in order to identify patients early in their disease course and promptly refer them to expert centers for a hemodynamic assessment and formal diagnosis. Moreover, several large multicenter clinical trials have now included patients with SSc-PAH to assess their response to therapy. Despite an improved understanding of the condition and significant advances in supportive and targeted therapy, outcomes have remained far from optimal. Therefore, rigorous phenotyping and search for novel therapies are desperately needed for this devastating condition.

Inflammatory Mechanisms in the Pathogenesis of Pulmonary Arterial Hypertension: Recent Advances.

Inflammatory processes are increasingly recognized in the pathogenesis of the vascular remodeling that characterizes pulmonary arterial hypertension (PAH). Chronic inflammation may contribute to disease progression or serve as a biomarker of PAH severity. Furthermore, inflammatory pathways may represent possible therapeutic targets for novel PAH-specific drugs beyond the currently approved therapies targeting the endothelin, nitric oxide/cyclic GMP, and prostacyclin biological pathways. The main focus of this article is to provide recent advances in the understanding of the role of inflammatory pathways in the pathogenesis of PAH from preclinical studies and current clinical data supporting chronic inflammation in PAH patients and to discuss emerging therapeutic implications. © 2021 American Physiological Society. Compr Physiol 11:1805-1829, 2021.

Undiagnosed OSA May Significantly Affect Outcomes in Adults Admitted for COPD in an Inner-City Hospital.

BACKGROUND: COPD is the second most common cause of hospital admission in the United States. OSA is a highly prevalent and underdiagnosed condition that may affect the outcome of COPD. RESEARCH QUESTION: We hypothesized that presence of unrecognized and untreated OSA will increase hospital readmissions in patients admitted for COPD exacerbation. STUDY DESIGN AND METHODS: We reviewed patients admitted for COPD exacerbation from May 2017 through July 2018 who were also screened for previously unrecognized and untreated OSA with a sleep questionnaire, and who subsequently underwent a high-resolution pulse oximetry or portable sleep monitoring study. We compared the rates of 30-, 90-, and 180-day readmission or death across OSA categories and compared overall survival in patients with and without OSA. RESULTS: Of 380 patients admitted for COPD exacerbation, 256 were screened for OSA with a sleep questionnaire (snoring, tiredness during daytime, observed apnea, high BP). Of these, 238 underwent an overnight high-resolution pulse oximetry/portable sleep monitoring. Of the 238 total patients, 111 (46.6%) were found to have OSA; 28.6% had mild, 9.7% moderate, and 8.4% severe OSA. Baseline characteristics and demographics were compared between the cohorts of participants with OSA and without OSA and were similar except that patients with OSA had a higher mean BMI (33.9 vs 30.3 kg/m2) and an increased prevalence of heart failure (19.8% vs 7.1%). For patients with COPD and mild OSA, odds of 30-day readmission were 2.05 times higher than for patients without OSA (32.4% vs 18.9%). Additionally, odds of 30-day readmission were 6.68 times higher for patients with moderate OSA vs patients without OSA (60.9% vs 18.9%) and 10.01 times high for patients with severe OSA vs patients without OSA (70% vs 18.9%). Readmission rates were also greater at 90 and 180 days. All-cause mortality was lower for patients without OSA than for patients with OSA (P < .01). The time to hospital readmission or death was shorter with greater OSA severity (P < .01). INTERPRETATION: Patients hospitalized for COPD exacerbation and who have unrecognized OSA; 30-, 90-, and 180-day readmission rates; and 6-month mortality rates are higher than in those without OSA.

Effects of Pulmonary Hypertension and Right Ventricular Function in Short and Long-Term Kidney Function.

BACKGROUND: Pulmonary hypertension is not uncommon in patients with renal disease and vice versa; therefore, it influences treatments and outcomes. There is a large body of literature on pulmonary hypertension in patients with kidney disease, its prognostic implications, economic burden, and management strategies. However, the converse, namely the hemodynamic effects of pulmonary hypertension on kidney function (acute and chronic kidney injury) is less studied and described. There is also increasing interest in the effects of pulmonary hypertension on kidney transplant outcomes. The relationship is a complex phenomenon and multiple body systems and mechanisms are involved in its pathophysiology. Although the definition of pulmonary hypertension has evolved over time with the understanding of multiple interplays between the heart, lungs, kidneys, etc; there is limited evidence to provide a specific treatment strategy when kidneys and lungs are affected at the same time. Nevertheless, available evidence appears to support new therapeutics and highlights the importance of individualized approach. There is sufficient research showing that the morbidity and mortality from PH are driven by the influence of the pulmonary hemodynamic dysfunction on the kidneys. CONCLUSION: This concise review focuses on the effects of pulmonary hypertension on the kidneys, including, the patho-physiological effects of pulmonary hypertension on acute kidney injury, progression of CKD, effects on kidney transplant outcomes, progression of kidney disease in situations such as post LVAD implantation and novel diagnostic indices. We believe a review of this nature will fill in an important gap in understanding the prognostic implication of pulmonary hypertension on renal disease, and help highlight this important component of the cardio-reno-pulmonary axis.

Recognition and Treatment of Sleep-disordered Breathing in Obese African American Hospitalized Patients may Improve Outcome.

PURPOSE: The HoSMed Database recently demonstrated a high prevalence of obstructive sleep apnea (OSA) in hospitalized obese patients. Based on a long-term follow-up, this study showed an improved survival among patients who were adherent with the therapy. In this post-hoc analysis we explore the characteristics, associations, and mortality outcome of OSA in the African American (AA) population. METHODS: These subset analyses included obese AA patients screened in the hospital as high-risk for OSA. Stepwise logistic regression analysis was used to identify predictors of OSA. Patients who had polysomnography (PSG) and were initiated on positive airway pressure (PAP) therapy were followed and dichotomized to adherent versus non-adherent groups based on compliance data. Mortality rates in both groups were compared. RESULTS: Of the total of 2022 AA patients screened, 1370 (60.7% females) were identified as high risk for OSA. Of these, 279 had PSG diagnosed OSA (mean AHI = 36/hour) and were initiated on PAP therapy. Adherence in AAs was significantly lower than for Caucasians (21% versus 45%, Chi-square p < 0.0001). The following statistically significant predictors of OSA were found: heart failure, chronic kidney disease, hypertension and asthma/COPD, BMI and age. A Log-rank survival analysis of AAs on CPAP showed non-significant benefit of adherence (HR: 0.22; 95% CI 0.03-1.7, p = 0.11); a propensity analysis of AAs and Caucasians that adjusted for race and potential confounding variables found a statistically significant benefit of adherence (HR: 0.29; 0.13-0.64; p = 0.002). CONCLUSION: This large database of hospitalized patients confirms a high prevalence and lower adherence to PAP therapy in African Americans. Adherent patients, however, showed mortality benefit similar to Caucasians.

Preeclampsia as a Form of Type 5 Cardiorenal Syndrome: An Underrecognized Entity in Women's Cardiovascular Health.

BACKGROUND: Preeclampsia is a multisystem vascular disorder of pregnancy that remains a leading cause of maternal and fetal morbidity and mortality. Preeclampsia remains an underrecognized risk factor for future cardiovascular and kidney disease in women and represents the confluence of preexisting vascular risk factors with superimposed endothelial injury from placental mediated anti-angiogenic factors. SUMMARY: This review highlights the close relationship between preeclampsia and future cardiovascular and kidney disease. It describes the pathophysiology and current understanding of biomarkers that form the molecular signature for long-term endothelial dysfunction in preeclamptic women. Finally, it describes strategies for early identification and management of women with preeclampsia with elevated risk for cardiovascular and kidney disease. Key Messages: Future rigorous studies on cardiovascular risk modification in this phenotype of disease are essential to reduce the burden of cardiovascular and kidney disease, in women with preeclampsia.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Predict Acute Cellular Rejection in the Kidney Allograft.

BACKGROUND Kidney transplantation is the treatment of choice for end stage kidney disease, but acute rejection remains a limiting factor in optimizing allograft and patient survival. Needle biopsy is the current standard of care for this diagnosis. The potential for complications with repeat biopsies limits the ability to obtain temporal immune surveillance of the allograft. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be strong predictors of inflammation and of worse prognosis in a variety of conditions. MATERIAL AND METHODS This is a single center retrospective case control study which included all patients who underwent a "for -cause biopsy" of a transplanted kidney. NLR and PLR were calculated 1 month prior, at the time, and 6 months and 1 year after the biopsy. RESULTS A total of 159 biopsies were reviewed; 127 (79.9%) of these satisfied all inclusion and exclusion criteria, and 63.0% of the sample cohort (n=80) demonstrated acute cellular rejection (ACR). Patients without evidence of ACR had an average NLR of 26.8, which was approximately 7-fold greater than those patients with findings of ACR (P<0.01). A similar trend was found for PLR, where patients without ACR had a 5.5-fold greater PLR compared to those with rejection (P<0.01). The ROC showed AUC of 0.715 and 0.716 respectively. The NLR cutoff of 9.5 had a positive predictive value (PPV) of 80% and a negative predictive value (NPV) of 77.8%; the PLR cutoff of 380 had a PPV of 75% and a NPV of 100%. CONCLUSIONS This study showed that NLR and PLR are easily obtainable and reproducible predictors of ACR in the kidney allograft. Serial monitoring of these ratios will help identify subclinical inflammation before evidence of allograft dysfunction.

Cervical diffuse idiopathic skeletal hyperostosis (DISH) causing oropharyngeal dysphagia.

Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory condition characterised by calcification and ossification of the vertebral ligaments. It is most commonly seen to affect the thoracic and lumbar vertebrae and is usually seen among elderly men. The cause of this condition is unknown. Risk factors include male gender, obesity, diabetes and advancing age. The majority of these cases are found incidentally on imaging and patients are generally asymptomatic. Cervical DISH is less common than its thoracic and lumbar counterparts. When symptomatic, it can cause dysphagia or sometimes airway compromise. If this happens, surgical intervention should be performed. Although a rare cause of dysphagia, DISH is easily diagnosed with imaging. When identified, surgical decompression produces very good clinical outcomes.