Pulmonary Hypertension Association Research Articles

Association of Pulmonary Hypertension With End-Stage Renal Disease Among the Obese Population.

IntroductionPulmonary hypertension (PH) is a known complication that occurs in patients of end-stage renal disease (ESRD) that have an arteriovenous fistula (AVF) for hemodialysis (HD). It is defined as pulmonary artery pressure (PAP) of greater than 30 mmHg on echocardiography. The presence of PH in ESRD is an independent risk factor and decreases the survival likelihood among HD patients. Unexplained PH is frequently seen in ESRD following AVF.Obesity can lead to various complications, such as sleep apnea, cardiac complications, pulmonary hypertension, and mortality. Data on the prevalence of coexisting PH and obesity are scarce.Obese patients often have increased albumin excretion rates (AER) that can lead to early renal impairment and an increase in intraglomerular pressure, which may increase the risk of cardiovascular (CV) morbidity and mortality.Therefore, the study aimed to evaluate and compare the associated PH and obesity separately and collectively among ESRD patients.MethodsThis comparative cross-sectional study was conducted in a tertiary care public sector hospital with the approval of the medical ethics review board committee.The study enrolled all consecutive patients with ESRD as defined by having an estimated glomerular filtration rate (GFR) of <15 mL/min/1.7 3 m2 from April 2017 till March 2019, who presented to our facility. These patients underwent dialysis twice or thrice a week, each session lasting three to four hours approximately. On initial encounter, trans-thoracic echocardiography (TTE) was done by the cardiologist to diagnose pulmonary hypertension.In addition, body mass index (BMI) was calculated for all patients, and the patients were categorized into underweight, normal, overweight, or obese. All patients underwent post-dialysis TTE at one hour or when patients were at the optimal dry weight. Systolic PAP and ejection fraction were measured, and pulmonary hypertension was defined as a PAP of 30 mmHg or greater on TTE.ESRD patients that were diagnosed with PH prior to hemodialysis or had primary PH were excluded from the study. Only ESRD patients developing secondary PH after hemodialysis were included in the study.The chi-square test was used to see the correlation of gender, ambulation status, smoking status, obesity, pulmonary hypertension, body mass index (BMI), and pulmonary hypertension and obesity combined on the final outcome. A p-value of 0.05 was considered significant. Odds ratio (OR) and relative risk (RR) were calculated for pulmonary hypertension and obesity combined, obesity, and pulmonary hypertension in the final outcome.ResultsThe study enrolled 204 patients with a mean age of 46.23 (±20.45 SD) having higher female participation of 108 (52.9%), whereas 96 (47.1%) were males. The average weight of the cohort was 66.78 kg (±22.98 SD) with a mean BMI of 29.91 kg/m2 (±13.29SD), 52 (25.5%) patients were underweight, 40 (19.6%) had a normal BMI, 29 (14.2%) were overweight, and 83 (40.7%) patients were obese.Pulmonary hypertension and obesity combined were observed in 48 (23.5%) of the cases and there was a 4.60 relative risk of death among these individuals, with an odds ratio of 13.35 and a p-value of 0.00.ConclusionThe study shows a strong synergistic effect of pulmonary hypertension and obesity towards the final survival outcome in ESRD patients who are on hemodialysis.

The Association of Pretransplant Pulmonary Hypertension With Patient and Graft Survival After Kidney Transplantation: A Retrospective Cohort Study

BackgroundPulmonary hypertension (PH) has been well characterized in end-stage kidney disease and carries a grave prognosis. Its relationship to kidney transplantation outcomes is uncertain. The purpose of the present study was to characterize PH in kidney transplant candidates and to evaluate the relationship of PH to post-transplantation outcomes. MethodsA retrospective review of medical records and echocardiographic findings in all patients listed and transplanted at a large urban academic medical center from 2010 to 2015 was undertaken. PH (defined as echocardiographic evidence of pulmonary artery systolic pressure ≥ 35 mm Hg) was assessed along with demographics, and comorbidities for its relationship to patient, and graft survival by univariable and multivariable analysis. ResultsOf 733 patients, 15.6% (115) had PH. PH in this population was primarily due to left ventricular (LV) diastolic dysfunction. Patient survival (78.3% vs 89.6%, P = .02) and the composite of patient and graft survival (70.7% vs 85.0%, P = .04) was reduced at 5 years in patients with PH as compared to patients with No PH, respectively. However, multivariable analysis suggested that age at presentation, race, and left ventricular systolic function but not PH were significantly associated with patient mortality or graft loss. ConclusionReduced patient and graft survival seen in patients with pulmonary hypertension appears to be related to risk factors other than the pulmonary hypertension itself; therefore, pretransplant PH should not be considered as a barrier to kidney transplantation.

Author rebuttal to response regarding "Letter to the Editor regarding 'Could pulmonary arterial hypertension patients be at lower risk from severe COVID-19?'".

In response to comments published by Timothy Fernandes et al. to our Letter to the Editor titled “Could pulmonary arterial hypertension patients be at a lower risk from severe COVID-19?,”1 we believe it is critical to provide additional information and perspective. Fernandes et al. expressed concern that our survey data of pulmonary arterial hypertension (PAH) and CTEPH patients represented only a snapshot early in the COVID-19 pandemic when the U.S. was at the beginning stages of disease acceleration, and testing was limited. We agree with this observation and have extended our survey window through 6 May 2020, past the peak of COVID activity in much of the U.S. At the end of the survey period, we received a total of 86 responses by PH health care providers, with 66% estimating that their sites had more than 100 PAH and CTEPH patients strengthening our conclusions. From our survey responses, 16 PAH/CTEPH patients were reported as testing positive for COVID-19, 11 (58%) were hospitalized, and 6 (55%) of those hospitalized required intubation. Given the timing of survey response, we acknowledge that these reports also reflect a time when PCR testing was limited in most regions to patients sick enough to require hospitalization. At the end of the survey period, 60% of responders who had hospitalized COVID-19-positive PAH/CTEPH patients indicated that they had patients discharged. Of the 16 PAH/CTEPH COVID-19-positive patients, three deaths were reported. We agree with Fernandes et al.1 that there are limitations to surveys such as ours and that exact incidence, hospitalization, and mortality numbers cannot be determined. However, with this broader reach of our survey that included centers with larger numbers of PAH patients, the fact that 16 PAH and CTEPH patients were reported to be COVID-19 positive suggests that severe infection requiring hospitalization is reassuringly similar to the general population and presumably lower than what was widely feared. Moreover, the overall mortality was 19% in this high-risk group with severe underlying cardiopulmonary co-morbidities. Fernandes et al.1 expressed concern that our Letter to the Editor may be misinterpreted by the PH community and could lead to less stringent adherence to precautions taken by PH patients, such as social distancing and wearing masks, to protect against SARS-CoV-2 infection. We, along with the Pulmonary Hypertension Association, strongly advocate that all patients and their families, caregivers, and friends follow strict social distancing and all other infection protection measures recommended by the Centers for Disease Control. Our patients are more accustomed to social distancing and excruciating attention to avoiding at high-risk situations. We specifically hypothesized in our Letter to the Editor that perhaps lower numbers of COVID-19-positive PAH/CTEPH patients may be a result of early implementation by the PH community of social distancing and other protective measures. Our preliminary observations are hypothesis generating and in no way minimize our recommendations to the PH community. There is still much unknown about COVID-19 and the impact on PH patients. Additional studies will need to test hypotheses to understand the science and optimize patient care. A recent NEJM article adds to this unusual endothelial pathology with further hypothesis generating ideas that could be pertinent to PAH.2 Our initial letter was never intended to suggest that PAH patients lessen their self-discipline and intense protective measures, as we still consider them to be a high-risk cohort. Erika B. Rosenzweig https://orcid.org/0000-0003-4849-214X

Psychosocial and Financial Burden of Therapy in USA Patients with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating disease with significant morbidity and mortality. There are many psychosocial and financial implications of this disease; however, little is known how this affects the treatment of PAH patients. A questionnaire-based prospective cohort study was performed on 106 PAH patients from a Pulmonary Hypertension Center and the Pulmonary Hypertension Association national conference in 2018. The demographic, treatment, psychosocial, employment, financial impact on treatment data was obtained. The majority of patients had cardiopulmonary symptoms despite treatment. The symptoms affected their social and work lives, with about one in three applying for disability because of their PAH. The majority of PAH patients had insurance coverage, but still noted a significant financial burden of the disease, with nearly a half who needed financial assistance to pay for their PAH medications. Thirty (28.3%; 95% CI, 20.6–37.5%) patients mentioned they changed their medication regimen, with some skipping doses outright (28 [26.4%; 95% CI, 19–35.6%]) in order to save money. PAH continues to cause significant psychosocial and financial burden on patients despite advances in medications. This impact ranged from dissatisfaction with quality of life, to unemployment, to altering their medication regimen to save money.

Characteristics and Prognostic Associations of Echocardiographic Pulmonary Hypertension With Normal Left Ventricular Systolic Function in Patients ≥90 Years of Age

The high prevalence of pulmonary hypertension (PH) in elderly patients is well known. However, much remains unknown about those population. We sought to find the clinical characteristics of echocardiographic PH and the prognostic factors in patients ≥90 years of age. We retrospectively reviewed 310 patients ≥90 years of age (median age 92 years, 64% women) diagnosed as echocardiographic PH (peak systolic pulmonary arterial pressure ≥40 mm Hg) with normal left ventricular systolic function. We defined left heart disease (LHD) as significant left-sided valve diseases, left ventricular hypertrophy and left ventricular diastolic dysfunction by using echocardiography. The endpoint was all-cause death at 2,000 days after diagnosis. LHD was found in 92% of patients. During the median follow-up of 367 days (interquartile range, 39-1,028 days), 151 all-cause deaths (49%) occurred. Multivariable Cox regression analysis demonstrated that right ventricular fraction area change <35% (adjusted hazard ratio [HR]: 2.31; p <0.001), pericardial effusion (adjusted HR: 2.28; p <0.001), serum albumin <3.5 g/dL (adjusted HR: 1.76; p = 0.001), chronic obstructive pulmonary disease (adjusted HR: 1.93; p = 0.001) and New York Heart Association (NYHA) class ≥II (adjusted HR: 1.73; p = 0.004) were associated with mortality after adjusted for age. In conclusion, LHD was significantly associated with echocardiographic PH in most patients ≥90 years of age. Also, the co-morbid factors at diagnosis (right ventricular systolic dysfunction, pericardial effusion, hypoalbuminemia, chronic obstructive pulmonary disease, and NYHA class ≥II) were independently associated with mortality.

Age-related differences in hemodynamics and functional status in pulmonary arterial hypertension: Baseline results from the Pulmonary Hypertension Association Registry

The age of patients with pulmonary arterial hypertension (PAH) has increased, with registries now reporting mean ages of 50 to 65 years old. Limited data exist on age-related differences in hemodynamic and functional assessments in PAH. Adults with PAH in the Pulmonary Hypertension Association Registry were divided into 3 groups (18-50, 51-65, and >65 years old). Analysis of variance and chi-square testing were used to assess for baseline differences. Linear regression was used to examine the association of age with continuous hemodynamic and functional variables. A total of 769 patients with mean age of 56 ± 16 years were included. Older patients had more connective tissue disease-associated PAH and less drug-associated PAH. In linear regression models, each year of increased age was associated with shorter 6-minute walk distance (-3.37 meters; 95% CI, -3.97 to -2.76), lower mean pulmonary arterial pressure (-0.21 mmHg; 95% CI, -0.27 to -0.15), and lower pulmonary vascular resistance (-0.06 Wood units; 95% CI, -0.09 to -0.04). Pulmonary arterial compliance, cardiac index, right ventricular stroke work index, and percent predicted 6-minute walk distance were unrelated to age; resistance-compliance time was negatively related to age (-3 milliseconds per year; 95% CI, -4 to -2). Relative to their pulmonary vascular resistance, older patients have lower pulmonary artery compliance and worse right ventricular performance. Based on these findings, we suspect that age influences right ventricular loading conditions and the response of the right ventricle to increased afterload.

Association of pulmonary hypertension and right ventricular function with exercise capacity in heart failure.

AimRelationships of pulmonary artery systolic pressure (PASP) and right ventricular (RV) dysfunction with exercise capacity are understudied. To assess the relationship of PASP and RV function with functional capacity and ventilatory efficiency in heart failure (HF) with a wide range of left ventricular ejection fraction (LVEF).Methods and resultsFive hundred thirty‐two consecutive HF patients referred for cardiopulmonary exercise testing [percent predicted peak VO2 (ppVO2), VE/VCO2 slope] and echocardiography [LVEF, PASP, and RV fractional area change (RVFAC)] were studied. Associations of PASP and RVFAC with ppVO2 and VE/VCO2 slope were assessed by multivariable linear regression and restricted cubic splines. Associations with composite of death, heart transplant, and LV assist device (median 3.9 year follow‐up) was assessed using multivariable Cox proportional hazard models.Mean age was 56 ± 14 years and mean LVEF was 35 ± 15%. Mean PASP was 34 ± 12 mmHg, RVFAC was 41 ± 13%, ppVO2 was 60 ± 21%, and VE/VCO2 slope was 35 ± 12. After adjusting for demographics, co‐morbidities, LVEF, mitral regurgitation severity, and left atrial volume index, higher PASP was associated with worse ppVO2 (P = 0.004) and was more robust in patients with LVEF ≥45% vs. <45% (P interaction = 0.006). Lower RVFAC was associated with both worse ppVO2 (P = 0.002) and higher VE/VCO2 slope (P = 0.002). Higher PASP and lower RVFAC were both associated with heightened risk of composite endpoint (HR 1.07 per 5 mmHg increase, P = 0.03; HR 1.17 per 5% decrease, P <0.001, respectively).ConclusionsIn HF across wide range of LVEF, greater PASP and worse RV function predict worse functional capacity and greater respiratory inefficiency, independent of LV structure and function.

Letter to the Editor regarding "Could pulmonary arterial hypertension patients be at lower risk from severe COVID-19?"

It was with great interest and some concern we read the recently published paper “Could pulmonary arterial hypertension (PAH) patients be at lower risk from severe COVID-19.”1 In this paper, the authors quote an electronic survey of the Pulmonary Hypertension Association (PHA) centers conducted in March 2020, which only yielded 13 confirmed cases of COVID-19 in known PAH patients. Based on these results, they speculate that PAH patients may have an attenuated COVID-19 course due to potential protective features of PAH-targeted therapies (endothelin receptor antagonists, phosphodiesterase type 5 inhibitor (PDE) inhibitors or prostanoids). We are concerned about the possible detrimental effects misinterpretation of this message could have to the PAH community. These assumptions were based on little data at an early stage of the pandemic in the US, and the resulting speculations could mislead and put PAH patients at higher risk. SARS-CoV2 and its related illness can have devastating effects on those with pre-existing medical conditions including PAH, and assuming protective effects of their medical therapy may lead PAH patients to altering their behavior by providing a false sense of security. A closer look at the data that was presented underscores that PAH patients are not at lower risk for severe COVID-19 and may even carry a risk for more severe illness. The authors' methodology of collecting survey results is subject to response bias as it is unclear how many centers responded and how many PAH patients were included to find the 13 COVID-19 positive patients. Additionally, this survey was conducted at a time in March when many centers were constrained in their ability to test patients with symptoms of COVID-19 and the US was only at the beginning of the disease acceleration. Some speculate that the number of COVID-19 cases identified may only represent a fraction of the total infections circulating.2 As serologic tests become widely available, we hope to better approximate the total number of infections including those with mild or no symptoms. Furthermore, based on the data presented in the paper, 53.8% of the patients with PAH and COVID-19 required hospitalization, 23.1% required intubation and 7.7% died. Compared to the early data from China, these estimates are actually higher in this report of PAH patients than what was observed in the general population in Wuhan (2.3% of all laboratory confirmed cases required intubation and case-fatality rate was 1.4%).3 In comparison, reports from Italy note 5.0% of all patients having critical illness with a 7.2% case-fatality rate.4 Moreover, in this very limited sample of PAH patients, there are large error bars around the estimates and there is little to no evidence supporting the speculation that PAH patients could be protected from COVID-19. Although the authors provide speculation into the downstream effects of various PAH medications which may be protective against Acute respiratory distress syndrome (ARDS), they did not mention potential harms. A significant concern with the use of PAH-targeted therapies in patients with severe COVID-19-associated ARDS is the potential for worsening ventilation/perfusion (V/Q) matching and obliterating the hypoxemic vasoconstrictive response to areas of infiltrated lung parenchyma, as was seen with the use of sildenafil in patients with COPD-associated pulmonary hypertension.5 In PAH patients with COVID-19 infection, worsening hypoxemia has potential for real harm as many with severe hypoxemia will require intubation. In conclusion, although this is clearly a time that some speculation and assumptions are important to pose better questions, advance knowledge and push COVID19-related research forward, we must be careful not to confuse this with over-reaching conclusions. The language we use and the uncontrolled, retrospective data we present in the literature can be misconstrued and have the opposite effects of what was expected. In the era of social media and massive dissemination of information, opinions, assumptions and speculation (even admitted by the authors in this case) if not presented appropriately have serious potential for harm. There is potential for this information to be misunderstood by a lay patient as to mean PAH patients can be reassured of a lower risk for severe COVID-19 than the general population. Such an interpretation may result in less stringent social distancing or hand hygiene practices. The unified message from all PAH providers should be that there is little data on the effects of PAH or related therapies on COVID-19 and until we have such data, all efforts should be focused on avoiding infection through social distancing and good hygiene. The author(s) declare that there is no conflict of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Could pulmonary arterial hypertension patients be at a lower risk from severe COVID-19?

The COVID-19 pandemic now impacts over 1.2 million individuals worldwide with higher risk comorbidities including age, cardiac and pulmonary diseases. Pulmonary hypertension (PH) centers prepared for the worst for their high-risk pulmonary arterial hypertension (PAH) patients. However, providers have been surprised thus far by the paucity of hospitalized PAH–COVID-19 patients, generally tolerable symptoms in those affected, and their relatively early recovery. In late March 2020, experts from over 32 U.S. PH Centers responded to a Pulmonary Hypertension Association (PHA) query. Only 13 COVID-19 cases were reported, with one death (Table 1), prompting us to ask, why have there been so few catastrophic COVID–PAH patient events? At the outset of the pandemic, PAH patients were warned to self-isolate, something that they may be more accustomed to than the general population, and that may be the simple answer. However, paradoxically could the pre-existing pulmonary vasculopathy and/or PAH-specific medications somehow be protective for these otherwise high-risk patients? Could PH-specific medications (endothelin receptor antagonists (ERA), phosphodiesterase-5 (PDE5) inhibitors, inhaled nitric oxide (iNO) and prostacyclins) protect against some cardiopulmonary manifestations of COVID-19? Might there be an altered pulmonary endothelial response due to lack of ability to mount a florid inflammatory response, relative hypoxemia and possible effect on viral replication, efficacy of the nitric oxide/cyclic GMP pathway, antiplatelet effect of prostacyclins and/or use of anticoagulants in WSPH Group 1 PAH patients? In influenza-mediated cytokine storm1 pulmonary endothelial cells are central to innate cell recruitment and cytokine/chemokine production independent of inflammatory cell infiltration. An autopsy of a COVID-19 patient without PAH also revealed microvascular endotheliitis mimicking capillaritis (personal communication, Steven P. Salvatore, MD), leading us to ask key questions: Could vascular remodeling and/or altered lymphocyte subsets render the vasculature too “exhausted” to manifest endotheliitis and launch the cytokine release syndrome? Angiotensin-converting-enzyme 2 (ACE2) is a membrane-bound cellular receptor for SARS-CoV-2.2 Whether increasing ACE2 permits more viral entry in vivo, or whether soluble ACE 2 “binds the virus” is unclear. In some studies, lung injury is protected by the angiotensin II antagonist losartan and generation of angio 1-7. ERAs and a particularly selective endothelin A receptor antagonist (ETa) may synergistically inhibit angiotensin II (Ang II).3 There is also evidence that donor-specific ETa and anti-angiotensin II antibodies may lead to antibody-mediated rejection in renal, cardiac, and most recently, a fulminant post-lung transplant-associated capillaritis.4 We speculate that there be a favorable interaction of ERAs or Ang II receptor blockade with such antibodies should they exist. Last, in models of acute inflammatory pancreatitis, ERAs are beneficial by counteracting endothelin-mediated stimulation of NFKB, IL-2 and IL-6.5 PAH patients are also chronically treated with PDE-5 inhibitors and/or prostanoids, and iNO when they become ill, which have all been used (off-label) in ARDS, and there may be alternative benefits even if mechanistically independent of an endotheliitis/capillaritis. Nitric oxide is being explored as an experimental treatment for COVID-19. It is possible that these PAH-specific medications that mediate pulmonary vasodilatation, anti-proliferation and are antithrombotic may offer a protective benefit. While we speculate about plausible pathobiological mechanisms and await further data (and move to generate a PH specific registry), if the expected poor prognosis for COVID-19 in PAH patients is truly attenuated, then therein may lie new clues to the pathogenesis and mitigation of severe COVID-19. Erika B Rosenzweig https://orcid.org/0000-0003-4849-214X

CaMKII is Necessary for Proliferation and Migration of Pulmonary Arterial Smooth Muscle Cells

ObjectiveCa2+/calmodulin‐dependent protein kinase II (CaMKII) is a calcium‐ and oxidation‐activated serine/threonine kinase, with four known isoforms. CaMKII has been shown to be necessary for remodeling involving smooth muscle cell proliferation and migration in response to injury in the systemic vasculature. However, the role of CaMKII in pulmonary arterial smooth muscle cell (PASMC) function remains unknown.MethodsPASMCs were isolated from male Wistar rats and expanded in culture. In cell lysates, mRNA expression of CaMKII isoforms was measured by real‐time quantitative reverse transcription PCR; protein expression was assessed via immunoblot. PASMC proliferation was measured via BrdU incorporation. PASMC migration was assessed by the Transwell assay. PASMCs were treated with 10 μM KN‐93 in vitro to inhibit CaMKII or with either vehicle or 10 μM KN‐92 (an inactive analog of KN‐93) for control experiments. To deplete CaMKIIδ protein, PASMCs were treated with 100nM siRNA targeted to CaMKIIδ while PASMCs treated with scrambled siRNA were used for control experiments.ResultsThe CaMKIIδ and CaMKIIγ isoforms showed mRNA and protein expression in rat PASMCs. Both proliferation and migration of rat PASMCs were inhibited by pharmacologic inhibition of CaMKII using KN‐93, but were not inhibited by the inactive analog KN‐92. siRNA‐mediated knockdown of CaMKIIδ resulted in reduction of CaMKIIδ protein expression but did not have an effect on either PASMC proliferation or migration.ConclusionsCaMKII activity is necessary for PASMC proliferation and migration. As the CaMKIIδ isoform is not required for these functions, future work will examine the role of the CaMKIIγ isoform.Support or Funding InformationFunding SourcesNIH K08HL133475 &amp; Pulmonary Hypertension Association K08 Supplement

Differences in right ventricular dysfunction in patients with idiopathic pulmonary hypertension versus secondary pulmonary hypertension.

Right ventricular (RV) function in the setting of pulmonary hypertension based on different etiologies has not been well studied. In this study, we evaluated the RV function in patients with idiopathic pulmonary hypertension (IPH) versus secon-dary pulmonary hypertension (SPH) due to congestive heart failure. Forty-five patients with pulmonary hypertension and New York Heart Association (NYHA) functional class II or III were enrolled. Of these, 22 were diagnosed with IPH and 23 with SPH. Echocardiographic data, including Doppler and Doppler based strain, were assessed according to the American Society of Echocardiography (ASE) guidelines for detailed evaluation of RV function in these two groups. Mean PAP was 60 ± 14.5 mm Hg in patients with IPH versus 43 ± 11.5 mm Hg in patients with SPH (p = 0.001). Considering conventional indexes of RV function, only Sm and dp/dt were significantly better in the first group compared with the second group (p-value for Sm = 0.042 and for dp/dt = 0.039). RV end diastolic dimension was significantly higher in the IPH group (p = 0.013). Using deformation indexes of RV function, the basal and mid portion of RV free wall strain and basal RV strain rates were significantly worse in the chronic systolic heart failure (PH-HF) group in comparison to the IPH group (p < 0.001 in basal RV strain, p = 0.034 in mid RV strain and p = 0.046 in basal RV strain rate respectively). IPH has less impact on RV function in comparison to PH-HF. Considering both entities are in the category of RV pressure overload, we conclude that the etiology of pulmonary hypertension also plays an important role in RV function in addition to pressure overload.

High geographic prevalence of pulmonary artery hypertension: associations with ethnicity, drug use, and altitude.

While estimates of pulmonary arterial hypertension incidence and prevalence commonly range from 1–3/million and 15–25/million, respectively, clinical experience at our institution suggested much higher rates. We sought to describe the disease burden of pulmonary arterial hypertension in the geographic area served by our Pulmonary Hypertension Clinic and compare it to the REVEAL registry. Our secondary objectives were to document pulmonary arterial hypertension prevalence in minorities underrepresented in REVEAL (Hispanics and Native Americans) and to address the association of pulmonary arterial hypertension with exposure to drugs and moderately increased residential altitude in this population. Retrospective review of pulmonary arterial hypertension clinic patients alive during 2016 identified 154 patients. Hispanic patients made up 35.7% of the cohort, a much greater percentage than REVEAL, p < .001 but smaller than the percentage of Hispanic patients (48.4%) in geographic area served by the clinic. Pulmonary arterial hypertension due to drug exposure was more common and idiopathic pulmonary arterial hypertension was less common than in REVEAL (p < .001). Overall, pulmonary arterial hypertension incidence was 14 cases per million, greater than the REVEAL registry, odds ratio 6.3 (95% CI: 4.2–9.5), (p < .001). Annual period prevalence of pulmonary arterial hypertension was 93 cases per million, also greater than the REVEAL, odds ratio = 7.5 (95% CI: 6.4–8.8) and remained greater when the clinic cohort was constrained to patients with hemodynamic severity comparable to REVEAL, odds ratio = 3.8 (95% CI: 3.0–4.6), (p < .001). There was a strong association between pulmonary arterial hypertension prevalence and residence at altitude > 4000 ft, odds ratio = 26.6 (95% CI: 8.5–83.5), p < .001; however, this was potentially confounded by pulmonary arterial hypertension treatment referral patterns. These findings document a much higher local pulmonary arterial hypertension incidence and prevalence than previously reported in REVEAL. While population ethnicity differed markedly from REVEAL, the disease burden was not driven by these differences. The possible association of moderately increased residential altitude with pulmonary arterial hypertension warrants further evaluation.

The Association of Autoantibodies in Hyperthyroid Heart Disease Combined with Pulmonary Hypertension.

Hyperthyroidism is a clinical state that results from increased thyroid hormone levels which has a significant impact on cardiac function and structure. Graves' disease is the most common cause of hyperthyroidism in iodine-replete areas. Hyperthyroid heart disease may be associated with pulmonary hypertension in patients who have overt hyperthyroidism. To investigate the association of pulmonary hypertension induced by hyperthyroid heart disease and autoantibody, one hundred and one cases with hyperthyroid heart disease who were consecutively admitted to the inpatient department of endocrinology and metabolism of the Shandong Provincial Hospital between November 2014 and April 2018 were collected and analyzed statistically. According to the Independent samples T-test, variance analysis, chi-square test, Pearson linear correlation analysis, and logistic regression, there was a good correlation between pulmonary artery systolic pressure and thyroid stimulating hormone (TSH) and receptor antibodies (TRAb) (r = 0.264, P=0.025) (OR = 1.037, P=0.029), but there was no significant correlation between the pulmonary artery systolic pressure and other thyroid-related parameters (FT3, FT4, TSH, anti-TPO, and anti-TG). Based on variance analysis, PASP rose as the level of TRAb gets higher. What is more, patients with HHD combined with PH showed a significantly higher serum level of TRAb; moreover, serum TRAb concentration was remarkably correlated with the PASP level. Therefore, TRAb participates in the process of pulmonary hypertension caused by hyperthyroid heart disease.

Association of Pulmonary Hypertension With Clinical Outcomes of Transcatheter Mitral Valve Repair

Pulmonary hypertension (pHTN) is associated with increased risk of mortality after mitral valve surgery for mitral regurgitation. However, its association with clinical outcomes in patients undergoing transcatheter mitral valve repair (TMVr) with a commercially available system (MitraClip) is unknown. To assess the association of pHTN with readmissions for heart failure and 1-year all-cause mortality after TMVr. This retrospective cohort study analyzed 4071 patients who underwent TMVr with the MitraClip system from November 4, 2013, through March 31, 2017, across 232 US sites in the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy registry. Patients were stratified into the following 4 groups based on invasive mean pulmonary arterial pressure (mPAP): 1103 with no pHTN (mPAP, <25 mm Hg [group 1]); 1399 with mild pHTN (mPAP, 25-34 mm Hg [group 2]); 1011 with moderate pHTN (mPAP, 35-44 mm Hg [group 3]); and 558 with severe pHTN (mPAP, ≥45 mm Hg [group 4]). Data were analyzed from November 4, 2013, through March 31, 2017. Patients were stratified into groups before TMVr, and clinical outcomes were assessed at 1 year after intervention. Primary end point was a composite of 1-year mortality and readmissions for heart failure. Secondary end points were 30-day and 1-year mortality and readmissions for heart failure. Linkage to Centers for Medicare & Medicaid Services administrative claims was performed to assess 1-year outcomes in 2381 patients. Among the 4071 patients included in the analysis, the median age was 81 years (interquartile range, 73-86 years); 1885 (46.3%) were women and 2186 (53.7%) were men. The composite rate of 1-year mortality and readmissions for heart failure was 33.6% (95% CI, 31.6%-35.7%), which was higher in those with pHTN (27.8% [95% CI, 24.2%-31.5%] in group 1, 32.4% [95% CI, 29.0%-35.8%] in group 2, 36.0% [95% CI, 31.8%-40.2%] in group 3, and 45.2% [95% CI, 39.1%-51.0%] in group 4; P < .001). Similarly, 1-year mortality (16.3% [95% CI, 13.4%-19.5%] in group 1, 19.8% [95% CI, 17.0%-22.8%] in group 2, 22.4% [95% CI, 18.8%-26.1%] in group 3, and 27.8% [95% CI, 22.6%-33.3%] in group 4; P < .001) increased across pHTN groups. The association of pHTN with mortality persisted despite multivariable adjustment (hazard ratio per 5-mm Hg mPAP increase, 1.05; 95% CI, 1.01-1.09; P = .02). These findings suggest that pHTN is associated with increased mortality and readmission for heart failure in patients undergoing TMVr using the MitraClip system for severe mitral regurgitation. Further efforts are needed to determine whether earlier intervention before pHTN develops will improve clinical outcomes.

Association of Mild Echocardiographic Pulmonary Hypertension With Mortality and Right Ventricular Function

Current guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk. To determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) function and increased risk of mortality. In this cohort study, electronic health record data of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 and had recorded estimates of RVSP values were studied. Data were analyzed from February 2017 to May 2019. Mild ePH was defined as an RVSP value of 33 to 39 mm Hg. Right ventricular function was assessed using tricuspid annular plane systolic excursion (TAPSE), and RV-pulmonary arterial coupling was measured using the ratio of TAPSE to RVSP. Associations of mild ePH with mortality adjusted for relevant covariates were examined using Cox proportional hazard models with restricted cubic splines. Of the 47 784 included patients, 26 758 of 47 771 (56.0%) were female and 6040 of 44 763 (13.5%) were black, and the mean (SD) age was 59 (18) years. Patients with mild ePH had worse RV function compared with those with no ePH (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P < .001) and nearly double the prevalence of RV dysfunction (32.6% [92 of 282] vs 16.7% [170 of 1015]; P < .001). Compared with patients with RVSP less than 33 mm Hg, those with mild ePH also had reduced RV-pulmonary arterial coupling (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P < .001). An increase in adjusted mortality began at an RVSP value of 27 mm Hg (hazard ratio, 1.32; 95% CI, 1.02-1.70). Female sex was associated with increased mortality risk at any given RVSP value. Mild ePH was associated with RV dysfunction and worse RV-pulmonary arterial coupling in a clinical population seeking care. Future studies are needed to identify patients with mild ePH who are susceptible to adverse outcomes.

Lower Socioeconomic Status Associated with Decreased Completion of Exercise Rehabilitation in Patients with Pulmonary Hypertension

Purpose Patients with pulmonary hypertension (PH) who concurrently have low socioeconomic status (SES) present with more advanced illness and have increased risk of death. Exercise rehabilitation is an underutilized therapy that improves exercise capacity and quality of life. Whether disparities in rehabilitation completion exist is unknown. Methods We performed a cross-sectional survey of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) who attended the PH Association (PHA) Research Room during the biennial conference. Participants completed a survey of demographic and clinical characteristics that inquired about prior referral and completion of rehabilitation and the MacArthur Scale of Subjective Social Status (MSSS). The MSSS is a validated survey of SES that asks participants to rate where they are on a ladder ranging from 1-10 in regards to income, occupation, or education compared to other people in the US. The primary outcome was completion of rehabilitation defined as attendance at >75% of sessions. The primary predictor was SES as measured by the MSSS grouped in tertiles. Multivariable logistic regressions performed to examine association between SES and rehabilitation completion adjusted for age and WHO functional class. Using the final model, the predicted probability of completion by SES tertile was estimated. Results We enrolled 62 participants with a mean age of 51.5 (± SD; 15.1) years, of whom 87% (n =52) were female. 48.4% (n = 30) had never been referred, 4.8% (n = 3) were referred and didn't complete, and 51.6% (n = 32) had completed rehabilitation. In the multivariable analysis, participants in the lowest SES tertile had greater than 80% lower odds of being referred and completing rehabilitation than participants in the highest SES tertile (OR 0.17, 95% CI 0.04 - 0.78; p value = 0.22). Using the final model, only 25.5% (95% CI, 9.3 - 41.6) of participants in the lowest SES tertile were predicted to complete rehabilitation compared to 63.0% (38.4 - 87.6) in the highest SES tertile. Conclusion Lower SES participants with PAH and CTEPH were less likely to complete exercise rehabilitation. Decreased access to effective therapies could account for some of the excess risk seen by lower SES patients with PAH. Policies to enable equity of access to exercise rehabilitation should be explored.

Demographic, Hemodynamic, and HRQL Differences between Methamphetamine-Associated and Idiopathic PAH: The Pulmonary Hypertension Association Registry

Purpose Single-center studies previously demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We sought to use the Pulmonary Hypertension Association Registry (PHAR) to compare methamphetamine-associated (Meth-APAH) to Idiopathic Pulmonary Arterial Hypertension (IPAH) in the United States. Methods PHAR is a 32-center US-based registry of 478 PAH patients new to care at a Pulmonary Hypertension Care Center. In addition to demographics and clinical parameters, baseline health-related quality of life (HRQL) is quantified by the Medical Outcomes Study Short Form-12 (SF12-PCS - generic-physical & SF12-MCS - generic-mental; higher scores denote better HRQL) and emPHasis-10 (PAH-specific; higher scores denote worse HRQL). We included adults diagnosed with Meth-APAH and, as a control group, IPAH. Differences in demographics and clinical parameters were compared by t-tests and chi-squared tests as appropriate. We tested the association of Meth-APAH and HRQL using multivariate linear regression, adjusting for age, sex, race, and education. Results Of 278 subjects included, 58 had Meth-APAH. Subjects with Meth-APAH were younger, less likely to be insured, college graduates, or married. 83% of subjects with Meth-APAH lived in the Western US. The Meth-APAH group tended to have lower cardiac index, stroke volume index, and higher right atrial pressures. The Meth-APAH group had significantly worse SF12-MCS (-3.85, 95%CI -6.48 to -1.23) and emPHasis-10 (5.79, 95%CI 1.85 to 9.74) scores compared to the IPAH group. The groups had similar SF12-PCS scores (0.79, 95%CI -1.38 to 2.96). Results were similar in incident cases (n=132, data not shown). Conclusion Meth-APAH is an aggressive phenotype most common in the Western US. It accounts for a notable proportion of PAH in PHAR centers. Routine screening for Meth-APAH is necessary, and providers should include drug rehabilitation in their therapy plan.

Association of hyperuricemia and pulmonary hypertension: A systematic review and meta-analysis

Objectives: To investigate the association of hyperuricemia with pulmonary hypertension (PH) in term of subsequent development, severity, and prognosis of PH.Methods: The authors systematically reviewed articles from databases and conducted meta-analyses as follows: (1) association of serum uric acid (UA) levels with the presence of PH; (2) association between serum UA levels and subsequent development of PH, in terms of odds ratio of the development of PH; and (3) association of serum UA levels with severity and prognosis of PH, in terms of pulmonary arterial pressure and hazard ratio of death.Results: Twenty-six studies published between 1999 and 2017 were included. The level of serum UA was higher in subjects with PH than subjects without PH and this finding was observed regardless of status of diuretics use or renal function. The odds ratio of the development of PH was 2.32 (95% CI, 1.05–5.15) in subjects with hyperuricemia. Pulmonary arterial pressure among subjects with PH was also higher in subjects with hyperuricemia than subjects with normouricemia. There was a 19% increased hazard ratio of death (95% CI, 1.06–1.33) among patients with PH who had hyperuricemia.Conclusion: Hyperuricemia is associated with the subsequent development, worse severity and poor prognosis of PH.

Doppler-defined pulmonary hypertension in sepsis and septic shock

BackgroundThe association of pulmonary hypertension (PH) in patients with sepsis is lesser understood. MethodsThis was a retrospective study of adult patients admitted to the intensive care unit during 2007–2014 for sepsis and septic shock, with echocardiography performed <72 h. PH was defined as tricuspid regurgitation peak velocity (TRV) > 3 m/s on Doppler echocardiography. Patients with prior PH, pulmonary stenosis, or without measurable TRV were excluded. Outcomes included 28-day mortality, one-year survival and length of stay. ResultsEighty-three, of 241 (34.4%) patients included, had PH. Patients with PH were older and had greater cardiovascular comorbidity but similar illness severity, including acute respiratory distress syndrome and mechanical ventilation use. PH was an independent predictor of 28-day mortality (odds ratio 3.6 [95% confidence interval 1.1–12.5] p = .04). In a proportional hazards model, PH was an independent predictor of one-year survival (hazard ratio 1.7 [95% confidence interval 1.1–2.7]; p = .03). Severity of PH was associated with worse one-year survival but not 28-day mortality. ConclusionsIn patients with sepsis and septic shock, PH is common and is noted to be associated with higher short and long-term mortality. Further studies are needed to understand the mechanisms by which PH is associated with outcomes.

Editorial introductions

Editorial introductions