Citations

Introduction: The prevalence of acute vasodilator response (AVR) to inhaled NO (defined as a reduction in mPAP ≥ 10 mmHg with an absolute value of mPAP ≤ 40 mmHg with increased/unchanged CO) is reported to be around 12% in incident patients with idiopathic PAH (IPAH). The prevalence of AVR, however, is reportedly lower in other disease-associated PAH in Group 1, such as connective tissue disease (CTD). Furthermore, the prevalence of AVR for combined inhaled NO and oxygen, and in patients on PAH therapy (prevalent cohort), is less known. Hypothesis: We hypothesized there would be differences in the prevalence of AVR in PAH subgroups in the large PVDOMICS cohort of incident and prevalent patients. Methods: Group 1 PAH patients enrolled in PVDOMICS underwent right heart catheterization for baseline measurements. AVR was then measured in response to 100% inhaled oxygen (O 2 ) and 100% O 2 plus NO at 40 ppm (O 2 +NO) for 5 min each before hemodynamic measurements. Details of the PVDOMICS methodology and core adjudication of hemodynamic measurements were reported previously. Rates of AVR to 100% O 2 and 100% O 2 +NO were compared between incident and prevalent patients in each PAH subgroup. Results: 351 patients, mostly female (73%), average age of 52.9 years, with mostly prevalent disease (87%) and an average of 4 years from PAH diagnosis, underwent AVR assessment. A positive AVR was found in 0.6% of patients in response to 100% oxygen and 6% of patients in response to 100%+NO for the overall cohort. AVR was similar in incident and prevalent IPAH patients (6 and 6.9%, respectively). It was, however, 0% and 6.9%, in incident vs. prevalent CTD-PAH patients, respectively. There were no responders to either challenge in any other PAH subgroup. Conclusions: The prevalence of AVR is relatively rare in IPAH and CTD-PAH (~ 6%) and absent in other subgroups. There was no response to 100% O2 alone, suggesting specificity of AVR to NO in PAH. AVR is more common than previously reported in CTD-PAH, but only in prevalent disease. Whether the latter is related to long-term PAH therapy affecting pulmonary vasomotor response and/or vascular remodeling in these patients would warrant further studies.

Intro: Recent World Symposium of Pulmonary Hypertension (WSPH) Group 1 data indicate significant racial and ethnic disparities in disease severity and mortality. It is unclear if these differences extend to other forms of PH and if they are a reflection of comorbidities. The PVDOMICS program incorporates deep phenotyping across all WSPH groups allowing for a first-time side-by-side comparison. The aims of this study are to evaluate inter-racial/ethnic factors of disease severity and comorbidities among patients with PH. Methods/Results: Participants in PVDOMICS prospectively underwent comprehensive testing for echocardiography, PFT, chest imaging, 6-minute walk, cardiac MRI, and hemodynamics with provocation. WSPH group assignment was assessed according to guideline recommendations. Race and ethnicity were self-reported. Statistical testing and sample sizes are described in the Table . In 692 PH participants, Non-Hispanic whites (NHW) were older and more often male than non-Hispanic African American (AA) and Hispanic patients. WSPH Group 1 was less but Groups 4 and 5 more common in AA than NHW. There were no inter-race/ethnicity differences in the percent of PH patients on PH therapy (range 53-63%, p=0.23). Comorbidities such as diabetes and lung disease were more common in AA vs. NHW. Hispanics showed lower left atrial (LA) volume on echo, LA filling pressures with exercise, as well as increased cardiac index relative to NHW. Right ventricular function on cardiac MRI was similar between groups ( Table ). When WSPH Group 1 was analyzed separately, inter-racial/ethnic comparisons were generally similar. Conclusions: Significant inter-racial/ethnic differences are evident across all WSPH groups. Comorbidities appear to drive part of the differences among AA patients while Hispanic patients exhibit factors that may prove beneficial. How these differences contribute to varying disease risk and outcomes across race and ethnicity remain to be seen.

Left atrial (LA) size and function is recognized as a cumulative index of pulmonary capillary wedge pressure (PCWP) and an index of left heart disease (LHD). While anticipated that LA features contribute to LHD-associated pulmonary hypertension (PH), we hypothesized that LA abnormalities (LAA) may exist in other WSPH groups. Therefore, we examined LA structure and function in the PVDOMICS cohorts. PVDOMICS enrolled 1097 total subjects with PH (mPA > 25 mmHg) and at-risk disease comparators (mPA<25 mmHg) for each of the WSPH groups. Patients with WSPH Groups 1, 3, 4, and 5 [non-Group 2] (n=618) were younger (56.2 ± 14.5 vs 60.1 ± 12.7 yrs, p<.02) and had less hypertension (38.6% vs 51.5 %, p<.02) than their non-Group 2 comparators (n=204). They also had less hypertension, diabetes, and a lower BMI than WSPH Group 2 (n=145), whereas WSPH Group 2 and its comparator Group 2 (n=130) were similar. LA area by echo was greater in WSPH Group 2 compared to non-Group 2 (22.8 ± 6.6 vs 16.9 ± 5.0 cm 2 , p<.02), in the comparator Group 2 vs. non-Group 2 comparators (22.7 ± 7.9 vs 16.4 ± 4.7 cm 2 , p<.02) but similar between WSPH group 2 and its comparator. MRI LA ejection fraction was lowest in Group 2 (33.2 ± 17.7%) and comparator Group 2 (38.9 ±16.7%, p=ns), significantly lower than WSPH non-Group 2 (45.9 ±14.7%, p<.02) which was lower than comparator non-Group 2 (50.9 14.6%, p<.02) which was lower than normal controls (n=96) (58.4 ±1.7%, p<.02). At right heart catheterization, whereas mPA pressures were similar between WSPH non-Group 2 and Group 2, resting PCW (11.1± 5.3 vs 20.3 5.6 mm Hg, p<0.02) was lower in WSPH non-Group 2 , PVR was higher (5.5[3.3, 8.7] vs. 3.7[7.2, 5.7] WU, p<0.02), and cardiac output was higher (5.4 ± 1.9 vs. 4.9 ± 1.6 L/min, p<0.02). Following a fluid challenge, PCW remained lower (14.9 ± 5.8 vs 20.7 ± 4.5 mm Hg, p<0.02) and PVR higher (5.2[3.1, 7.8] vs. 3.2[2.3, 5.5] WU, p<0.02). PCW and PVR at rest were lower in the comparator non-Group 2 vs WSPH non-Group 2 (8.9 ± 4.1 vs 11.1± 5.3 mm Hg, p<.02) and 1.7[1.2, 2.3] vs 5.5[3.3, 8.7] WU, p<.02. Thus, while LAA are most notable in WSPH and comparator Group 2’s, LAA differ between WSPH non-Group 2 and its non-Group 2 comparators. The role of LAA as predictors of PH outcomes remains to be determined.

Introduction: Previous reports have shown that atrial and ventricular arrhythmias (VA) are common in all forms of pulmonary hypertension (PH) with prevalence of supraventricular arrhythmias ranging from 13-25% and VA 27%. Arrhythmias are also associated with clinical worsening events. Reports have limited numbers of patients with a variety of forms of PH and limited data comparing the prevalence of atrial arrhythmias across WSPH groups and whether advancing age, WHO FC, echocardiographic, exercise capacity and hemodynamic patterns are associated with a higher prevalence of atrial arrhythmias. Methods: As part of the PVDOMICS program, we enrolled 1195 PH participants, controls and PH comparators and prospectively collected electrocardiograms (ECGs) at enrollment for 1147 of them. Comparisons across participants with and without atrial fibrillation/atrial flutter (afib/flutter) used analysis of variance (ANOVA) or Kruskal-Wallis test in continuous variables based on distribution with statistics presented as mean + SD or median [P25, P75] respectively. Pearson’s chi-square test was used for categorical variables. Results: Of 732 PH participants (467F) who had ECGs available at baseline, 527 (72.0%) were in normal sinus rhythm and 62 had afib/flutter (8.5%). Afib/flutter participants were older (75 + 8 vs 57 + 14 years; p<0.001), most commonly in WSPH group 2 (28.1%) vs. WSPH 1 (3.3%), WSPH 3(6.5%) and WSPH group 4 (3.7%), had predominantly WHO FC II/III symptoms (89.5%), higher RAP (12.6 + 5 vs.7.8 + 5mmHg; p<0.001) and PCWPm (17.8 + 5.8 vs. 12.3 + 6.2mmHg; p<0.001) and lower CO (4.3+ 1.5 vs. 5.2 +1.8L/min;p<0.001). Participants with afib/flutter had lower 6MWD 277 + 117 vs.356 + 134meters (p<0.001) than PH participants without. Echocardiography demonstrated increase in LA volume index (mL/m2), RA volume (mL) and tricuspid regurgitation severity with reduced TAPSE and LVEF (54 + 10 vs. 61 + 10%;p<0.001). ProBNP was higher in afib/flutter participants 2029 [1073, 2964] vs.268 [100, 1074]pg/ml; P<0.001) Conclusions: In this analysis of atrial arrhythmias in a large cohort of PH participants across all WSPH groups, afib/flutter was present most often in older WSPH group 2 patients who demonstrated clinical and hemodynamic features of worse heart failure.

AbstractBackground/ObjectivesTo determine the role of sex in port‐wine stain (PWS) distribution and describe the epidemiologic and anatomic differences between syndrome‐associated and non‐syndrome‐associated PWS using modern criteria.MethodsA retrospective review of PWS patients aged 18 years and younger from 1995 to 2018 seen in the Department of Dermatology at an academic tertiary referral center. Cases were reviewed for sex, anatomic location, and presence of associated syndrome. 4,527 records were reviewed on the basis of ICD billing codes for congenital vascular malformations, with 516 meeting inclusion criteria.Results516 patients were included in the analysis: 234 (45.4%) men and 282 (54.6%) women. A female preponderance of Sturge‐Weber syndrome (18 of 23, 78%, P = .03) and a trend toward more female‐isolated PWS (149 of 269, 55%, P = .72) were found. No lateral predominance observed for isolated PWS was found: 112(41.6%) limited left‐side lesions and 113(42%) limited right‐side lesions (P = .41). A trend toward Klippel‐Trenaunay syndrome (KTS)‐associated PWS occurring more commonly isolated to the left side (76 (45.5%) vs 59 (35.12%) P = .29) was found. Nine percent of SWS patients had a PWS on the body. Five percent of KTS patients had a facial PWS. The lower limb was the most common location overall of body PWS with 33.8% of isolated PWS and 81.5% of KTS patients having a lower limb lesion.ConclusionsFemale children were more likely to be diagnosed with SWS, and a trend toward more isolated PWS in women was found. No lateral predominance of isolated PWS was found, but KTS‐associated PWS was more common on the left. A considerable proportion of lesions do not appear in anatomic locations traditionally considered typical in the setting of associated syndromes, which underscores the importance of conducting a complete physical examination and adhering to diagnostic criteria for those syndromes.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Introduction: Racial disparities in outcomes of acute myocardial infarction (AMI) and cardiac arrest (CA) exist. This study assessed the racial differences in the management and outcomes of CA complicating AMI to better inform clinical care. Hypothesis: We hypothesized that racial minorities would have worse outcomes with AMI-CA as compared to white patients. Methods: During 2012-2017, AMI admissions with a concomitant diagnosis of CA were identified from the National Inpatient Sample. Race was classified as white, black and others (Hispanic, Asian or Pacific Islander, Native American, Others). The primary outcome was racial disparities in in-hospital mortality. Secondary outcomes included racial disparities in invasive procedures and hospitalization characteristics. Results: We identified 3,504,225 admissions for AMI in the study period, of which 182,750 (5.2%) were complicated by CA. 74.8% were white, 10.7% were black and 14.5% belonged to other races. Black and other race AMI-CA admissions received less frequent early coronary angiography (41.4% vs 50.2% vs 52.8%), coronary angiography (61.9% vs 70.2% vs. 73.1% %), PCI (44.6% vs 53.0% vs 58.1%), CABG and mechanical circulatory support compared to white and other races. The mean time to coronary angiography was highest among blacks (3.4 ± 4.2 days) and lowest among whites (3.0 ± 3.7 days). Black and other races had significantly higher unadjusted mortality, however in a multivariable logistic regression analysis with white race as referent, black race was associated with lower in-hospital mortality (OR 0.95 [95% CI 0.91-0.99]; p =0.007) whereas other races had higher in-hospital mortality (OR 1.11 [95% CI 1.08-1.15]; p <0.001) compared to white race. AMI-CA admissions of black race had longer length of hospital stay, higher rates of palliative care consultation, less frequent DNR status use, and fewer discharges to home. Admissions of other races had higher use of DNR status and higher hospitalization costs compared to whites and blacks. Conclusions: Significant racial disparities exist in in-hospital mortality among AMI admissions complicated with CA. Further quantitative and qualitative research into the equitable care of racial minorities with AMI-CA is needed to address this disparity.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disorder which leads to progressive fibrosis and lung failure within 2-5 years1,2. Approximately 30% of IPF patients develop Chronic Kidney Disease (CKD) with renal dysfunction and fibrosis3. The treatment options for IPF are still limited and the disease is an unmet clinical need. The only animal model for IPF is represented by mice treated with bleomycin, a compound used for chemotherapy which has lung toxicity as its major adverse effect, that develop progressive fibrosis. Recent data indicate that bleomycin triggers lung fibrosis by increasing the release of the pro-inflammatory cytokine TGF-β by the resident megakaryocytes (MK)4. Using these observations as foundation, we investigated whetherGata1lowmice, a model for myelofibrosis induced by a TGF-β/P-selectin (P-sel) circuitry established by the abnormal MK5, includes fibrosis in lungs and kidney and whether these traits are rescued by genetic ablation (P-selnullmutation) and antibody neutralization (by RB40.34) of P-sel. MK were observed in lungs from wild-type (WT, n=9),Gata1low(n=22),P-selnull(n=4) andP-selnullGata1low(n=10) littermates. In frequency, MK were significantly lower inGata1low andP-selnullGata1lowthan in WT andP-selnulllittermates (median=1.3-1.5 vs 3-3.7/0.144mm2, p&lt;0.003) and mostly immature. In addition, lungs and kidney fromGata1low mice, but not those from the other experimental groups, contained great levels of TGF- β (Fig.1). Interstitial pneumonia was observed in lungs from WT (n=12, age=3-13 months, males=8, females=4),P-selnull(n=9, age=3-16 months, males=4, females=5),Gata1low(n=29, age=2-24 months, males=16, females=13) andGata1lowP-selnull(n=18, age=3-16 months, males=7, females=11) mice while nephritis was observed only in kidneys fromGata1low mice. Controlling for the effects of sex, there are statistically significant differences in severity of inflammation in kidney (p=0.001) but not in lungs (p=0.86) betweenGata1low and WT mice. These results indicate that lung inflammation is a baseline condition of the CD1 background used for the study while kidney inflammation is a trait exclusive toGata1low mutants independently from their gender. Great levels of fibrosis were observed in lungs and kidney fromGata1low mice but not in those from WT littermates. There are statistically significant differences in lung (p=0.01) and kidney (p&lt;0.001) fibrosis between the two groups; these differences remained after adjusting for age or sex. By contrast, there is insufficient evidence to conclude there exists a relationship between age and fibrosis grade in the other experimental groups. Age was found to be a statistically significant effect modifier on the relationship between genotype and fibrosis in lung (p=0.024) and kidney (0.004). In addition, although there is insufficient evidence for a relationship between sex and fibrosis grade in lung (p=0.62), there is a statistically significant effect of gender in kidney fibrosis inGata1low mice (p&lt;0.001). These results indicate that fibrosis in lung and nephritis and fibrosis in kidney are novel traits ofGata1low mice developed independently from the underlying state of inflammation and which are rescued by ablation ofP-sel. To further clarify the role of P-sel in lung and kidney fibrosis, 14Gata1lowmice (7 males, 7 females) were treated with either vehicle (8 mice) or RB40.34 (30 μg/mouse/day per 3 days/week by tail vein injection as described6). Mice were sacrificed on day 5 (males) and 12 (females) and histopathology, inflammation, fibrosis and TGF-β content in lungs and kidney analyzed. Treatment with RB40.34 restored the morphology and reduced inflammation, fibrosis and TGF-β content in the lungs and in kidney with respect to vehicle (Fig.1). In conclusion, Gata1low mice are a novel animal model for IPF with CKD. The phenotype is associated with highTGF-βcontent in lung and kidney and is rescued by targeting P-sel, suggesting that treatment with antibodies against P-sel may cure IPF in man. REF: 1Richeldi et al.Lancet389: 1941, 2017; 2Hutchinson et al.EurRespirJ46, 795, 2015; 3Ikezoeet al.Respiration94: 346, 2017; 4Zhouet al.CellDeathDis10:648, 2019: 5Spangrudeet al.StemCells34: 67, 2016; 6Emburyet al.Blood104: 3378, 2004. Disclosures Migliaccio: Novartis:Research Funding.