Pulmonary arterial hypertension with below threshold pulmonary vascular resistance.

Pulmonary vascular resistance (PVR) >3 Wood units is a criterion of the haemodynamic definition of pulmonary arterial hypertension (PAH). However, this cut-off is conservative and arbitrarily defined. Data is lacking on the natural history, response to therapy and survival of patients diagnosed with precapillary pulmonary hypertension (PH) with mild or borderline elevation of PVR.In Australia, PAH therapy could be prescribed solely on mean pulmonary arterial pressure (PAP) and pulmonary arterial wedge pressure (PAWP) criteria. Using the Australian and New Zealand Pulmonary Hypertension Registry, we aimed to study a population diagnosed with PAH between January 2004 and December 2017 with the pre-defined haemodynamic characteristics of mean PAP ≥25 mmHg, PAWP ≤15 mmHg and PVR <3 Wood units.Eighty-two patients met the pre-defined haemodynamic inclusion criteria (mean age 63±11 years; 67 females). Underlying aetiologies included idiopathic disease (n=39), connective tissue disease (CTD; n=42) and HIV infection (n=1). At diagnosis, mean PAP was 27 mmHg (interquartile range (IQR) 25-30 mmHg), PAWP 13 mmHg (IQR 11-14 mmHg) and PVR 2.2 Wood units (IQR 1.9-2.7 Wood units). Baseline 6-min walk distance (6MWD) was 352 m (IQR 280-416 m) and 77% of subjects were in New York Heart Association (NYHA) functional class 3 or 4. All patients were commenced on initial monotherapy with an endothelin receptor antagonist (ERA; n=66) or phosphodiesterase type-5 inhibitor (PDE5i; n=16). At first re-evaluation, 6MWD increased by 46 m (IQR 7-96 m) and 35% of subjects demonstrated improvement in NYHA functional class. After a median follow-up of 65 months (IQR 32-101 months), 18 out of 82 subjects (22.0%) had died, with estimated 1-year and 5-year survival rates of 98% and 84%, respectively. Death attributed to PAH occurred in six out of these 18 patients (33.3%, 7% of total cohort).Patients with precapillary PH and "borderline" PVR falling outside the current definition have adverse outcomes. Such patients appear to respond to PAH therapy; however, this requires further study in randomised trials.

Clinical Utility of Stress Echocardiography in Remote Indigenous and Non-Indigenous Populations: A 10-Year Study in Central Australia.

BACKGROUND: Remote Central Australia has a large Indigenous population and a significant burden of cardiovascular disease. Stress echocardiography has been previously validated as a useful investigation for long-term prognostication. However, there are no prior studies assessing its utility in remote or Indigenous populations. METHOD: Consecutive individuals undergoing stress echocardiography in Central Australia between 2007 and 2017 were included. Stress echocardiography was performed and reported via standard protocols. Individuals were followed up for all-cause mortality. RESULTS: One-thousand and eight patients (1,008) (54% Indigenous Australian) were included. After a mean follow-up of 3.5±2.4 years, 54 (5%) patients were deceased. Overall, 797 (79%) patients had no abnormalities during rest or stress echocardiography, with no difference according to ethnicity (p>0.05). In patients with a normal test, annual mortality averaged 1.3% over 5 years of follow-up, with annual mortality significantly higher in Indigenous compared to non-Indigenous individuals (1.8% vs 0.6% respectively). In those with an abnormal test, annual mortality was 4.4% vs 1.3% in Indigenous and non-Indigenous individuals respectively. Increasing age, Indigenous ethnicity and cardiometabolic comorbidities were associated with mortality in univariate analyses (p<0.05 for all). In multivariate models, only chronic kidney disease remained predictive of mortality, with other associations (including Indigenous ethnicity) becoming attenuated. CONCLUSION: This is the first study to report on the use of stress echocardiography in a remote or Indigenous population. A normal stress echocardiogram in remote Indigenous individuals was able to identify a lower risk group of patients in this setting. Although Indigenous individuals with a normal test still had a higher annual rate of mortality compared to non-Indigenous individuals, this association appeared to be mediated by cardiometabolic comorbidities.

Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability.

BACKGROUND: Massively parallel genetic sequencing allows rapid testing of known intellectual disability (ID) genes. However, the discovery of novel syndromic ID genes requires molecular confirmation in at least a second or a cluster of individuals with an overlapping phenotype or similar facial gestalt. Using computer face-matching technology we report an automated approach to matching the faces of non-identical individuals with the same genetic syndrome within a database of 3681 images [1600 images of one of 10 genetic syndrome subgroups together with 2081 control images]. Using the leave-one-out method, two research questions were specified: 1) Using two-dimensional (2D) photographs of individuals with one of 10 genetic syndromes within a database of images, did the technology correctly identify more than expected by chance: i) a top match? ii) at least one match within the top five matches? or iii) at least one in the top 10 with an individual from the same syndrome subgroup? 2) Was there concordance between correct technology-based matches and whether two out of three clinical geneticists would have considered the diagnosis based on the image alone? RESULTS: The computer face-matching technology correctly identifies a top match, at least one correct match in the top five and at least one in the top 10 more than expected by chance (P < 0.00001). There was low agreement between the technology and clinicians, with higher accuracy of the technology when results were discordant (P < 0.01) for all syndromes except Kabuki syndrome. CONCLUSIONS: Although the accuracy of the computer face-matching technology was tested on images of individuals with known syndromic forms of intellectual disability, the results of this pilot study illustrate the potential utility of face-matching technology within deep phenotyping platforms to facilitate the interpretation of DNA sequencing data for individuals who remain undiagnosed despite testing the known developmental disorder genes.

Association of Pulmonary Artery Pressures With Mortality in Adults With Reduced Left Ventricular Ejection Fraction.

BACKGROUND: The independent effect of pulmonary hypertension (PHT) severity on mortality in those with reduced left ventricular ejection fraction (LVEF) is not well known. OBJECTIVES: The authors aimed to examine the prognostic impact of increasingly elevated pulmonary pressures in a large clinical cohort of adults with reduced LVEF. METHODS: The authors analyzed data from the National Echocardiography Database of Australia, a large clinical registry linking routine echocardiographic investigations to mortality. In 23,675 adults with a recorded tricuspid regurgitation peak velocity (TRV) and reduced LVEF (<50%), the authors evaluated the relationship between conventional thresholds of increasing risk of PHT and mortality during median follow-up of 2.9 years (Q1-Q3: 1.0-5.4 years). RESULTS: Mean age was 70 ± 15 years, and 7,498 (31.7%) individuals were female. Overall, 8,801 (37.2%) had normal (TRV <2.5 m/s), 7,061 (29.8%) had borderline (2.5-2.8 m/s), 5,676 (24.0%) intermediate (2.9-3.4 m/s), and 2,137 (9.0%) individuals had high-risk PHT (>3.4 m/s). With increasing risk of PHT, 1- and 5-year actuarial mortality increased from 13.3% and 43.8% to 41.5% and 81.4%, respectively (P < 0.0001) from normal to severely elevated TRV. The adjusted HR of mortality increased by 1.31-fold (95% CI: 1.23-1.38), 1.82-fold (95% CI: 1.72-1.93), and 2.38-fold (95% CI: 2.21-2.56) in those with borderline, intermediate, and high risk of PHT respectively, compared with normal TRV. Further analyses suggested a distinctive threshold with a TRV reached >2.41 m/s (adjusted HR: 1.18 [95% CI: 1.04-1.33]). CONCLUSIONS: The authors demonstrate the prevalence and negative prognostic impact of increasingly elevated TRV levels in individuals with reduced LVEF, with a threshold for mortality lying within the range of "borderline risk" PHT.

Prevalence of pulmonary hypertension in mitral regurgitation and its influence on outcomes.

OBJECTIVE: Pulmonary hypertension (PHT) commonly coexists with significant mitral regurgitation (MR), but its prevalence and prognostic importance have not been well characterised. In a large cohort of adults with moderate or greater MR, we aimed to describe the prevalence and severity of PHT and assess its influence on outcomes. METHODS: In this retrospective study, we analysed the National Echocardiography Database of Australia (data from 2000 to 2019). Adults with an estimated right ventricular systolic pressure (eRVSP), left ventricular ejection fraction >50% and with moderate or greater MR were included (n=9683). These subjects were then categorised according to their eRVSP. The relationship between PHT severity and mortality outcomes was evaluated (median follow-up of 3.2 years, IQR 1.3-6.2 years). RESULTS: Subjects were aged 76±12 years, and 62.6% (6038) were women. Overall, 959 (9.9%) had no PHT, and 2952 (30.5%), 3167 (32.7%), 1588 (16.4%) and 1017 (10.5%) patients had borderline, mild, moderate and severe PHT, respectively. A 'typical left heart disease' phenotype was identified with worsening PHT, showing rising E:e', right and left atrial sizes increasing progressively, from no PHT to severe PHT (p<0.0001, for all). With increasing PHT severity, 1- and 5-year actuarial mortality increased from 8.5% and 33.0% to 39.7% and 79.8%, respectively (p<0.0001). Similarly, adjusted survival analysis showed the risk of long-term mortality progressively increased with higher eRVSP levels (adjusted HR 1.20-2.86, borderline to severe PHT, p<0.0001 for all). A mortality inflection was apparent at an eRVSP level >34.00 mm Hg (HR 1.27, CI 1.00-1.36). CONCLUSIONS: In this large study, we report on the importance of PHT in patients with MR. Mortality increases as PHT becomes more severe from an eRVSP of 34 mm Hg onwards.

Prevalence of pulmonary hypertension in aortic stenosis and its influence on outcomes.

OBJECTIVE: The significance of pulmonary hypertension (PHT) complicating aortic stenosis (AS) is poorly characterised. In a large cohort of adults with at least moderate AS, we aimed to describe the prevalence and prognostic importance of PHT in such patients. METHODS: In this retrospective study, we analysed the National Echocardiography Database of Australia (data from 2000 to 2019). Adults with an estimated right ventricular systolic pressure (eRVSP), left ventricular ejection fraction (LVEF) >50% and with moderate or greater AS were included (n=14 980). These subjects were then categorised according to their eRVSP. The relationship between PHT severity and mortality outcomes were evaluated (median follow-up of 2.6 years, IQR 1.0-4.6 years). RESULTS: Subjects were aged 77±13 years and 57.4% were female. Overall, 2049 (13.7%), 5085 (33.9%), 4380 (29.3%), 1956 (13.1%) and 1510 (10.1%) patients had no (eRVSP<30.00 mm Hg), borderline (30.00-39.99 mm Hg), mild (40.00-49.99 mm Hg), moderate (50.00-59.99 mm Hg) and severe PHT (>60.00 mm Hg), respectively. An echocardiographic phenotype was evident with worsening PHT, showing rising E:e' ratio and right and left atrial sizes(p<0.0001, for all). Adjusted analyses showed that the risk of long-term mortality progressively rose as eRVSP level increased (HR 1.14-2.94, borderline to severe PHT, p<0.0001 for all). A mortality threshold was identified in the 4th decile of eRVSP categories (35.01-38.00 mm Hg; HR 1.19, 95% CI 1.04 to 1.35), with risk progressively increasing through to the 10th decile (HR 2.86, 95% CI 2.54 to 3.21). CONCLUSIONS: In this large cohort study, we find that PHT is common in ≥moderate AS and mortality increases as PHT becomes more severe. A threshold for higher mortality lies within the range of 'borderline-mild' PHT. TRIAL REGISTRATION NUMBER: ACTRN12617001387314.

Prevalence of pulmonary hypertension in aortic regurgitation and its influence on outcomes.

OBJECTIVE: Aortic regurgitation (AR) can lead to pulmonary hypertension (PHT). There is a paucity of data on the prognostic importance of PHT in these patients. We therefore aimed to describe the prevalence and prognostic importance of PHT in such patients. METHODS: In this retrospective study, we analysed the National Echocardiography Database of Australia (data from 2000 to 2019). Adults with an estimated right ventricular systolic pressure (eRVSP), left ventricular ejection fraction (LVEF) >50% and with moderate or greater AR were included (n=8392). These subjects were then categorised according to their eRVSP. The relationship between PHT severity and mortality outcomes were evaluated (median follow-up of 3.1 years, IQR 1.5-5.7 years). RESULTS: Subjects were aged 74±14 years and 58.4% (4901) were female. Overall, 1417 (16.9%) had no PHT, and 3253 (38.8%), 2249 (26.9%), 893 (10.6%) and 580 (6.9%) patients had borderline, mild, moderate and severe PHT, respectively. Mean eRVSP was slightly higher in females than males (41±13 vs 39±12 mm Hg, p<0.0001) and increased with age in both sexes. After adjustment for age and sex, the risk of long-term mortality increased as eRVSP increased (adjusted HR (aHR) 1.20, 95% CI 1.06 to 1.36 in borderline PHT, to aHR 3.32, 95% CI 2.85 to 3.86 in severe PHT, p<0.0001). There was a mortality threshold seen from mild PHT onwards (eRVSP 41.36-44.15 mm Hg; aHR 1.41, 95%CI 1.17 to 1.68). CONCLUSIONS: In this large cohort study, we characterise the relationship between AR and PHT in adults. In patients with ≥moderate AR, PHT is associated with a progressive risk of mortality, even at mildly elevated levels.

Cardiac manifestations of IgG4-related disease: a case series.

Background: IgG4-related disease (IgG4-RD) is an autoimmune condition affecting almost every organ system, with an early inflammatory phase and later fibrotic consequences. Vascular manifestations, particularly, large-vessel involvement in IgG4-RD, are well described. However, important IgG4-related effects on medium-sized arteries and the pericardium are less well recognized. These less frequently reported cardiovascular effects of IgG4-RD include coronary artery stenosis, pericardial disease, cardiac masses, and valvular heart disease. Case summary: This case series focuses on three patients that demonstrate the cardiovascular effects of IgG4-RD and the pitfalls and importance of early diagnosis. Cases 1 and 2 presented with cardiac manifestations prior to more typical organ systems being affected which led to a delay in diagnosis. Case 1 presented with an acute myocardial infarction secondary to IgG4-RD of the coronary arteries and Case 2 presented with pericarditis which progressed to pericardial constriction due to IgG4-RD. Case 3 already had a diagnosis of IgG4-RD from a prior renal biopsy which raised the index of suspicion that his pericardial disease and thoracic mass were also related to IgG4-RD. Discussion: Cardiac manifestations of IgG4-RD remain under-recognized and include coronary artery and pericardial disease. These manifestations often precede more typical manifestations in other organ systems. Recognizing cardiac manifestations of IgG4-RD on cardiac imaging can raise clinical suspicion and act as a catalyst to ascertain a confirmatory diagnosis. Early diagnosis and treatment are crucial to prevent potentially fatal outcomes and irreversible fibrosis.

Case report: A patient with transient sigmoid septum in takotsubo syndrome with left ventricular outflow tract obstruction.

Left ventricular outflow tract obstruction is now recognized as a common complication of takotsubo syndrome, resulting in more serious acute and long-term outcomes. We describe a case of takotsubo syndrome where a transient sigmoid septum produced left ventricular outflow obstruction and explore the mechanisms leading to this occurring. This phenomenon has not been previously described. .

Relation of Body Mass Index to Outcomes in Acute Coronary Syndrome.

We assessed the association of BMI with all-cause and cardiovascular (CV) mortality in a contemporary acute coronary syndrome cohort. Patients from the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events and Global Registry of Acute Coronary Events between 2009 and 2019, were divided into BMI subgroups (underweight: <18.5, healthy: 18.5 to 24.9, overweight: 25 to 29.9, obese: 30 to 39.9, extremely obese: >40). Logistic regression was used to determine the association between BMI group and outcomes of all cause and CV death in hospital, and at 6 months. 8,503 patients were identified, mean age 64 ± 13, 72% male. The BMI breakdown was: underweight- 95, healthy- 2,140, overweight- 3,258, obese- 2,653, extremely obese- 357. Obese patients were younger (66 ± 12 vs 67 ± 13), with more hypertension, diabetes, and dyslipidemia vs healthy (all p < 0.05). Obese had lower hospital mortality than healthy: all-cause: 1% versus 4%, aOR (95% CI): 0.49(0.27, 0.87); CV: 1% versus 3%, 0.51(0.27, 0.96). At 6-month underweight had higher mortality than healthy: all-cause: 11% versus 4%, 2.69(1.26, 5.76); CV: 7% versus 1%, 3.54(1.19, 10.54); whereas obese had lower mortality: all-cause: 1% versus 4%, 0.48(0.29, 0.77); CV: 0.4% versus 1%, 0.42(0.19, 0.93). When BMI was plotted as a continuous variable against outcome a U-shaped relationship was demonstrated, with highest event rates in the most obese (>60). In conclusion, BMI is associated with mortality following an acute coronary syndrome. Obese patients had the best outcomes, suggesting persistence of the obesity paradox. However, there was a threshold effect, and favorable outcomes did not extend to the most obese.