Pulmonary arterial hypertension in a multi-ethnic Asian population: Characteristics, survival and mortality predictors from a 14-year follow-up study.

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare and fatal disease. Data from Asia are lacking compared with the West. We aim to describe disease characteristics in an ethnically diverse South-East Asian population and assess predictors for survival. METHODS: We consecutively enrolled patients with PAH referred to our pulmonary hypertension specialty centre from January 2003 to December 2016. Baseline characteristics and survival were analysed. Based on a forward predictor selection procedure, a multi-level structural equation model was applied to identify predictors associated with mortality. RESULTS: Out of 148 patients enrolled, 77% were females and mean age was 50.8 ± 15.9 years. Racial distribution was consistent with our population census. The most common aetiologies were congenital heart disease-associated PAH (35.8%), idiopathic PAH (29.7%) and then connective tissue disease-associated PAH (24.3%). Most patients presented in World Health Organization (WHO) Functional Class (FC) II (48.6%), followed by FC III (28.8%). Majority of patients (54.1%) were on phosphodiesterase type 5 (PDE5) inhibitor monotherapy. Survival rates were 85.8% at the end of the first year, 70.9% at 3 years, 66.9% at 5 years, 61.5% at 7 years and 55.4% at 10 years. The Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) score (RS) was found to be the best predictor of mortality. A score > 6 was identified as a cut-off. Other predictors include mean right atrial pressure, heart rate, aetiology, age and N-terminal pro-brain natriuretic peptide. CONCLUSION: In this first registry study from a South-East Asian population, our survival rates are comparable with other national registries. The RS is validated in our population to be a good predictor of mortality.

Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial.

BACKGROUND: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved. METHODS: An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy. RESULTS: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%. CONCLUSIONS: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.

Refractory hypoxaemia following inferior ST-segment elevation myocardial infarction: case report of an unusual complication and review of treatment strategies.

Right ventricular (RV) infarction is not an uncommon complication of acute left ventricular infarction. It has been established that RV dysfunction post myocardial infarction (MI) is associated with increased mortality and morbidity. When RV infarction occurs in a patient with previously dormant patent foramen ovale (PFO), an unusual presentation of persistent refractory hypoxaemia ensues. We present a case of new RV infarction in a patient with underlying ischaemic cardiomyopathy, which was complicated by acute right-to-left shunting through the PFO. He was treated with percutaneous coronary intervention (PCI) and subsequent percutaneous PFO closure. We will also review the existing literature with regards to diagnostic and management strategies for patients with this unusual sequelae of MI.

Pulmonary Artery Strain Predicts Prognosis in Pulmonary Arterial Hypertension.

BACKGROUND: Current cardiac magnetic resonance (CMR) imaging in pulmonary arterial hypertension (PAH) focuses on measures of ventricular function and coupling. OBJECTIVES: The purpose of this study was to evaluate pulmonary artery (PA) global longitudinal strain (GLS) as a prognostic marker in patients with PAH. METHODS: The authors included 169 patients with PAH from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) and INITIATE (Integrated computatioNal modelIng of righT heart mechanIcs and blood flow dynAmics in congeniTal hEart disease) registries, and 82 normal controls with similar age and gender distributions. PA GLS was derived from CMR feature tracking. Right ventricular measurements including volumes, ejection fraction, and right ventricular GLS were also derived from CMR. Patients were followed up a median of 34 months with all-cause mortality as the primary endpoint. Other known risk scores were collected, including the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) 2.0 and COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) 2.0 scores. RESULTS: Of 169 patients (mean age: 57 ± 15 years; 80% female), 45 (26.6%) died (median follow-up: 34 months). Mean PA GLS was 23% ± 6% in normal controls and 10% ± 5% in patients with PAH (P < 0.0001). Patients with PA GLS <9% had a higher risk of mortality than those with PA GLS ≥9% (P < 0.001), and this was an independent predictor of mortality in PAH on multivariable analysis after adjustment for known risk factors (HR: 2.93; P = 0.010). Finally, in patients with PAH, PA GLS provided incremental prognostic value over the REVEAL 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.030) and COMPERA 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.048). CONCLUSIONS: PA GLS confers incremental prognostic utility over the established risk scores for identifying patients with PAH at higher risk of death, who may be targeted for closer monitoring and/or intensified therapy.

Prognostic Value of Left Atrial Strain in Aortic Stenosis: A Competing Risk Analysis.

BACKGROUND: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%. METHODS: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk. RESULTS: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value. CONCLUSIONS: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes.

Does pulmonary artery pulsatility index predict mortality in pulmonary arterial hypertension?

AIMS: Pulmonary artery pulsatility index (PAPi), defined as [(pulmonary artery systolic pressure - diastolic pulmonary artery pressure)/mean right atrial pressure], is a novel haemodynamic index that predicts right ventricular failure after myocardial infarction and left ventricular assist device implantation. We analysed if a low PAPi is associated with death in our 14 - â€‹year pulmonary arterial hypertension (PAH) registry. METHODS: Consecutive patients with newly diagnosed PAH and complete haemodynamic data were prospectively enrolled into our standing registry between January 2003 and December 2016. PAPi was calculated from baseline invasive right heart catheterization data. A prognostic cut-off value was determined with a decision tree. Baseline characteristics of 'high' and 'low' PAPi groups based on this cut-off were compared, as well as odds of death and time-to-death. RESULTS: One hundred and two patients were included. Mean age was 53 years, and 77% were women. Our multi-ethnic cohort was 64% Chinese, 23% Malay, and 10% Indian. The aetiologies were idiopathic (33%), connective tissue disease (31%), congenital heart disease (24%), and others (12%). The low PAPi group (<5.3) had a greater age (56 years vs. 49 years), lower pulmonary artery systolic pressure (71 mmHg vs. 85 mmHg), and higher mean right atrial pressure (14 mmHg vs. 6 mmHg). Mortality risk was higher in the low PAPi group (adjusted odds ratio: 2.98 and adjusted hazard ratio: 2.23). Mean right atrial pressure was the strongest predictor (hazard ratio 1.114, P = 0.009) when components of PAPi were analysed. CONCLUSIONS: Pulmonary artery pulsatility index was found to be predictive of mortality in PAH and may be a valuable marker for risk stratification. Its prognostic strength may be driven by mean right atrial pressure.

Echocardiographic Global Longitudinal Strain Is Associated With Myocardial Fibrosis and Predicts Outcomes in Aortic Stenosis.

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF.

Mortality and hospitalization outcomes of interstitial lung disease and pulmonary hypertension in the Singapore systemic sclerosis cohort.

OBJECTIVES: We compared mortality and hospitalization rates in four groups of patients with systemic sclerosis (SSc) [isolated pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD), concomitant ILD-pulmonary hypertension (PH), and no/mild pulmonary involvement]. METHODS: In the Systemic Sclerosis Cohort Singapore (SCORE), ILD was diagnosed by HRCT and significant ILD was defined by forced vital capacity <70% predicted. Patients were classified as PAH if echocardiographic systolic pulmonary artery pressure (sPAP) ≥50 mmHg or right heart catheterization (RHC) mean PAP ≥25 mmHg. Multivariable regression analyses were performed to determine factors associated with mortality and hospital admissions per year. Cox proportional hazard model was used to analyze survival. RESULTS: Of 490 SSc patients, 50 patients had PAH, 92 patients had ILD and 43 patients had ILD-PH. Of 93 patients with PAH or ILD-PH, 56 were based on echocardiography and 37 on RHC. Patients with ILD-PH (HR 3.77, 95% CI: 2.05-6.93) had the highest risk of death, followed by PAH (HR 3.03, 95% CI: 1.60-5.76) and ILD (HR 1.84, 95% CI: 1.04-3.28). After adjustment for confounders, PAH (HR 2.39, 95% CI: 1.13-5.07) remained independently associated with mortality, but not ILD-PH or ILD. Other factors associated with mortality were male gender, age at SSc diagnosis, malabsorption and digital ulcer/ gangrene. Increased hospitalization rate was associated with renal crisis, right heart failure and PAH medications, but not SSc groups. CONCLUSION: PAH is an independent risk factor of mortality in SSc. Increased hospitalization rate was not associated with SSc groups. Other factors associated with increased mortality and hospital admissions were identified.

Echocardiographic left ventricular mass in a multiethnic Southeast Asian population: proposed new gender and age-specific norms.

BACKGROUND: Left ventricular mass (LVM) is an independent risk factor for cardiovascular outcome. We aimed to define normal reference values of LVM/body surface area (BSA) in a multiethnic Southeast Asian population across ages, and define demographic parameters that predict LVM/BSA. METHODS: 198 subjects (44% men, mean age 40 +/- 14 years, 82% Chinese, 13% Malay and 5% Indian) with no cardiovascular comorbidity and had normal echo images for age were included in the analysis. Echo LVM was calculated as: 1.04 x[(left ventricular internal diameter at end-diastole [LVIDd]+ interventricular septal thickness at end-diastole [IVSd]+ left ventricular posterior wall thickness at end-diastole [LVPWd])(3)- LVIDd(3)x 0.8]+ 0.6(1), indexed by BSA (LVM/BSA)* and expressed as g/m(2). RESULTS: BSA and blood pressure (BP) were comparable between dichotomous age groups < or >or= 50 years within the same gender. Women aged >or= 50 years had larger IVSD, LVPWd, LVM and LVM/BSA compared to younger cohort. (p < 0.01 for all variables). The 95th percentile of LVM in men and women were 189 g and 148 g respectively; corresponding values for LVM/BSA were 106 and 96 g/m(2). These values are consistently smaller than published values from the West. Age (r = 0.27, P < 0.001), gender (r =-0.30, P < 0.001), and systolic BP (r = 0.25, P = 0.003) were significant univariate predictors of LVM/BSA. CONCLUSION: We therefore propose a different cutoff value for the diagnosis of LV hypertrophy among Southeast Asians.

Proteomics discovery of biomarkers for mitral regurgitation caused by mitral valve prolapse.

Mitral regurgitation (MR) is a common valvular lesion frequently caused by mitral valve prolapse (MVP). Surgical intervention in MVP patients with significant MR is predicated on symptoms and measures of left ventricular dysfunction. Because these indicators may be subjective or imprecise, serological biomarkers of disease could be a valuable adjunct to standard evaluation. This study aimed to identify such biomarkers by a proteomics approach. Two pooled plasma samples from 24 MVP subjects with MR (MVP/MR) and 24 non-MVP individuals were treated with the combinatorial peptide ligand library (CPLL) beads prior to iTRAQ labeling and ESI-MS/MS. Lower levels of haptoglobin, platelet basic protein (PBP), and complement component C4b were observed in the MVP/MR as compared to the control sample. These findings were verified by ELISA testing of each of the 24 paired samples, and another 42 matched cases and controls. The AUC values, sensitivities and specificities for (i) haptoglobin, (ii) PBP, (iii) C4b, and (iv) all 3 proteins in combination were (i) 0.813, 76%, 74%; (ii) 0.721, 56%, 77%; (iii) 0.689, 83%, 49%; and (iv) 0.840, 89%, 67%, respectively. In conclusion, haptoglobin, PBP, and C4b are down-regulated in MVP/MR. Their value as serological biomarkers of valvular pathology should be further explored. BIOLOGICAL SIGNIFICANCE: We report the first study that performed comparative proteomics of clinical human plasma samples to identify novel diagnostic biomarkers for mitral valve prolapse (MVP) patients with moderate to severe mitral regurgitation (MR). MR is a common valvular lesion that can be complicated by heart failure, sudden death and atrial fibrillation, yet many patients with severe MR are asymptomatic. Our results revealed reduced levels of haptoglobin, platelet basic protein (PBP), and complement component C4b in the MVP/MR patients as compared to the matched control cases. The plasma proteomics findings were subsequently confirmed by ELISA. Each of these candidate biomarkers has a putative role in the pathophysiology of MVP/MR, further supporting their roles in detection and possibly surveillance and prognostication of this disease.

Transcatheter aortic valve implantation: implications for Asian patients.

BACKGROUND: transcatheter aortic valve implantation is now an accepted therapy for patients with severe aortic valve stenosis who are deemed inoperable, and it is a reasonable alternative for patients with high surgical risk. This study assessed the clinical outcomes of this procedure and the implications of transcatheter aortic valve implantation for such patients. METHODS: 14 consecutive patients with severe aortic valve stenosis, who underwent transcatheter aortic valve implantation, were assessed. Baseline clinical characteristics, procedural information, and clinical outcomes and complications were compared at baseline and at follow-up. Thirty-day mortality was also assessed. RESULTS: the mean age of the patients was 81 ± 8 years (35% females). The mean Society of Thoracic Surgeons score was 6.8 ± 3.7. Most patients had chronic kidney disease with an estimated glomerular filtration rate of 44.5 ± 14.9 mL·kg(-1)·min(-1). The mean annulus diameter was 21.9 ± 1.7 mm, and 8 (57%) patients received 23-mm valves. After transcatheter aortic valve implantation, the mean transaortic gradient and aortic valve area improved from 42.9 ± 19.4 to 8.9 ± 3.1 mm Hg (p < 0.001) and 0.7 ± 0.1 to 1.5 ± 0.3 cm(2) (p < 0.001), respectively. The 30-day mortality for this cohort was 7%. CONCLUSION: transcatheter aortic valve implantation can be performed successfully in carefully selected Asian patients. The decision to undertake this procedure should be guided by the surgical team.