Prevalence of Atrial Fibrillation on a 24-hour Holter in Adult Indians.

OBJECTIVE: To evaluate paroxysmal atrial fibrillation (AF) prevalence in Indian adults who completed 24-Hour Holter monitoring. METHODS: A total of 23,847 patients (36.9% women) were analyzed for AF duration using using a software algorithm. RESULTS: AF was diagnosed in 4,153 (17.4%) patients with a median AF duration of 13 minutes and 55 seconds. CONCLUSION: AF prevalence was high and largely untreated. The short duration of AF episodes indicates a low likelihood of detection during clinical visits, highlighting its potential underestimation in Indian healthcare.

Cardiovascular Compatibility of Proton Pump Inhibitors: Practice Recommendations.

This manuscript aims to critically evaluate the current evidence regarding adverse cardiovascular effects associated with proton pump inhibitors (PPIs) in patients with coronary artery disease (CAD). It also provides guidance for the selection of the most appropriate PPI within the context of cardiovascular polypharmacy and emphasizes the importance of establishing consensus among clinicians on the need to prescribe PPIs with limited cytochrome P450 (CYP450) enzyme inhibition to reduce the risk of drug interactions. PPIs are among the most widely used drugs for the treatment of gastroesophageal reflux disease (GERD) and the prevention of gastrointestinal (GI) bleeding. The manuscript reports the proceedings from the first practice recommendations meeting on the cardiovascular compatibility of PPIs in an Indian setting. A panel of eight Indian experts in cardiology and gastroenterology reviewed 14 consensus statements. Available literature was searched and summarized, and after multiple rounds of review, consensus was achieved for these statements. Based on the available evidence, the consensus panel highlights that a PPI with minimal drug-drug interaction (DDI) is recommended, especially in patients requiring clopidogrel or polypharmacy. Rabeprazole appears to be a good option in cases where co-prescription is indicated, owing to its optimal acid suppression and minimal drug interaction profile.

Practical Recommendations for the Use of Angiotensin Receptor-Neprilysin Inhibitors (ARNI) in Heart Failure: Insights from Indian Cardiologists.

Heart failure is a significant public health concern characterized by notable rates of morbidity and mortality. Despite the presence of guideline-directed medical therapy (GDMT), its utilization remains inadequate. This practical recommendation paper focuses on the utilization of angiotensin receptor-neprilysin inhibitor (ARNI) as a pivotal treatment for heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with improved ejection fraction (HFimpEF). The recommendations presented in this paper have been developed by a group of cardiologists in India who convened six advisory board meetings to discuss the utilization of ARNI in the management of heart failure. The paper emphasizes the importance of accurate biomarkers for diagnosing heart failure, particularly N-terminal pro-B-type natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP), which are commonly used. Additionally, the paper advocates the use of imaging, specifically echocardiography, in diagnosing and monitoring heart failure patients. Moreover, the paper highlights the role of ARNI in heart failure management, with numerous clinical trials that have demonstrated its effectiveness in reducing cardiovascular death or heart failure hospitalization, enhancing quality of life, and diminishing the risk of ventricular arrhythmias. This practical recommendation paper offers valuable insights into the utilization of ARNI in the management of heart failure, aiming to enhance the implementation of GDMT and ultimately alleviate the burden of heart failure on society.

Clinical Decision Pathway for the Use of Fondaparinux in the Management of Acute Coronary Syndrome (ACS) in Hospitals with and Without Catheter Laboratories: An Expert Opinion from India.

The current recommendations by Indian experts who are focused on the challenges in the management of patients with acute coronary syndrome (ACS) in rural areas, due to limited catheterization (CATH) lab facilities and interventional cardiologist coverage across the country, are described. 120 cardiologist experts drafted recommendations during ten advisory board meetings conducted from April to May 2022. Experts framed statements based on experience, collective clinical judgment from practical experience, and available scientific evidence regarding ACS. The consensus positioned fondaparinux as highly useful in non-CATH-lab-based hospitals for patients diagnosed with non-ST elevation acute coronary syndrome (NSTE-ACS) and ST elevation acute coronary syndrome (STE-ACS) patients who cannot be shifted to percutaneous coronary intervention (PCI)-capable centres, or for patients who are thrombolysed at peripheral centres.

Bempedoic Acid for Lipid Management in the Indian Population: An Expert Opinion.

Lipid-lowering is a central theme in the management of patients with atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH), with statins being currently used as the first-line lipid-lowering agent (LLAs). Bempedoic acid (BA) has been recently approved for lipid management in ASCVD/HeFH patients. This expert opinion paper brings out the essential concept to assess the current place of BA in the Indian population. Here we highlight that the majority of the patients with clinical ASCVD may not be receiving the optimal dose of statin, thereby failing to achieve their lipid targets. The addition of BA to statin results in a significant reduction in low-density lipoprotein cholesterol (LDL-C) along with substantial reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP) levels. For patients who do not achieve LDL-C targets, BA can be an effective add-on alternative to choose among non-statin LLAs. BA is a good choice for statin-intolerant cases, especially in combination with ezetimibe. Given the lack of effect of worsening hyperglycemia or any increase in the occurrence of new-onset diabetes, BA can be used without hesitation in patients with diabetes. The small risk of hyperuricemia could be mitigated with appropriate patient selection and monitoring of serum uric acid levels in patients at high risk of hyperuricemia. We believe BA is an excellent non-statin therapy that is efficacious, well-tolerated, and cost-effective for lipid management in ASCVD, HeFH, and statin-intolerant patients in India.

Evaluation of Effectiveness and Tolerability of Fondaparinux in the Management of Symptomatic Acute Coronary Syndrome: A Real-World Evidence-Based Study on an Indian Population.

INTRODUCTION: Fondaparinux is a low molecular weight heparin anticoagulant used to manage the full spectrum of acute coronary syndrome (ACS) patients and has proved its efficacy and safety in multiple clinical trials. However, there are limited data available showing whether the same results could be reproduced in real-world practice on an Indian population. Our objective was to determine the effectiveness and tolerability of fondaparinux in the management of symptomatic ACS in real-world clinical practice. METHODS: The EMR data of hospitalized ACS patients (n = 611), from January 2015 to January 2020, representing UA or NSTEMI or STEMI and were prescribed fondaparinux (2.5 mg once daily) to manage ACS were analyzed. The effectiveness was analyzed as recurrence of ACS and tolerability as total incidence of major bleeding during hospitalization, at 30 days and 180 days. Appropriate statistical analysis was used with a statistically significance of p value < 0.05. RESULTS: The incidence of recurrent ACS was not seen during hospitalization and in the first 30 days, while in only 0.65% (n = 4) patients, ACS reoccurred within 180 days. In a mean duration of 172.75 ± 3.20 days, UA was reported in 0.49% (n = 3) patients, NSTEMI in 0.16% (n = 1) of patients, and STEMI was not documented. None of the major bleeding events occurred during the entire study period, whereas minor bleeding events were reported during hospitalization 0.98% (n = 6) and at 30 days 0.16% (n = 1). The bleeding events were statistically insignificant (p value > 0.05). No incidences of stent thrombosis were reported during the entire study period. CONCLUSIONS: In the real world, fondaparinux was found to be effective and tolerable when used to manage symptomatic ACS patients regardless of revascularization procedure with no incidence of stent thrombosis, and minimal recurrent ACS and insignificant increase in bleeding events.

A retrospective cohort study exploring diltiazem as a pharmaco-enhancer for tacrolimus, in a post-heart transplant setting.

BACKGROUND: A significant proportion of heart transplant-associated expenditure are attributable to immunosuppressants. Post-transplant hypertension adds to the pill burden and subsequent costs. In this study, we describe the effect of diltiazem-the antihypertensive and pharmaco-enhancer-on reducing the required oral dose of tacrolimus. METHODS: We included 17 recipients who had successfully undergone heart transplants but later developed post-transplant hypertension and were treated with diltiazem. Serum trough levels of the immunosuppressant tacrolimus were measured every 2 weeks. Required doses before and after the introduction of diltiazem were compared. Patients were assessed at each follow-up visit for any evidence of toxicity. Medication-related expenditure was estimated based on government-mandated standardized retail price. RESULTS: The power of the study was 98.92% at α = 0.05. The mean tacrolimus dose required prior to initiation of diltiazem was 5.85 ± 1.55 mg. After initiating diltiazem, the mean required doses reduced to 2.88 ± 1.24 mg (p < .0001). Relatively, the required doses reduced by 52.4 ± 10.9%-independently of age, sex, and dose of diltiazem. Medication-related monthly expenditure reduced by 50.3 ± 10.4%. No patient demonstrated evidence of toxicity. CONCLUSIONS: Concomitant use of diltiazem and tacrolimus can safely, effectively, and predictably reduce the required dose of tacrolimus and significantly reduce corresponding costs.

SUPPORT-1 (Subjects Undergoing PCI and Perioperative Reperfusion Treatment): A Prospective, Randomized Trial of CMX-2043 in Patients Undergoing Elective Percutaneous Coronary Intervention.

OBJECTIVE: The natural molecule α-lipoic acid has been shown to be partially cytoprotective through antioxidant and antiapoptotic mechanisms. To obtain an initial assessment of the safety and potential efficacy of a synthetic derivative, CMX-2043, in preventing ischemic complications of percutaneous coronary intervention (PCI) we conducted the Subjects Undergoing PCI and Perioperative Reperfusion Treatment (SUPPORT-1) trial, the first patient experience with this agent. METHODS AND RESULTS: SUPPORT-1 was a phase 2a, 6-center, international, placebo-controlled, randomized, double-blind trial. A total of 142 patients were randomized to receive a single intravenous bolus dose of drug or placebo administered 15-60 minutes before PCI. Cardiac biomarker assessments included serial measurements of creatine kinase myocardial band (CK-MB) at 6, 12, 18, and 24 hours after PCI and a single measurement of troponin T (TnT) at 24 hours. Peak concentrations of CK-MB and TnT were significantly reduced in the 2.4 mg/kg group compared with placebo (P = 0.05 and 0.03, respectively). No subject administered 2.4 mg/kg of CMX-2043 had an increase of CK-MB to ≥3X upper limit of normal versus 16% for placebo (P = 0.02); 16% of the 2.4-mg/kg dose group developed an elevation of TnT to ≥3X upper limit of normal versus 39% in the placebo group (P = 0.05). No drug-related serious adverse events were observed in any group. CONCLUSION: These data suggest that CMX-2043 may reduce PCI periprocedural myonecrosis and support further clinical evaluation of this novel agent for its potential cytoprotective effects.

Self-blood pressure measurement as compared to office blood pressure measurement in a large Indian population; the India Heart Study.

OBJECTIVE: India Heart Study (IHS) is aimed at investigating the agreement between office blood pressure measurement (OBPM) and self (S)BPM in a hypertension-naive population. METHODS: A total of 18 918 individuals (aged 42.6 ±â€Š11.7 years, 62.7% men), visiting 1237 primary care physicians across India, underwent OBPM. They performed SBPM for a period of 1 week using a validated oscillometric BP monitor that was preprogrammed to adhere to a guideline-based SBPM-schedule and blinded to the results. Thereafter, individuals underwent a second OBPM. Available laboratory results were obtained. Thresholds for elevated OBPM and SBPM were 140/90 and 135/85 mmHg, respectively. RESULTS: On the basis of first-visit OBPM and SBPM, there were 5787 (30.6%) individuals with normotension; 5208 (27.5%) with hypertension; 4485 (23.7%) with white-coat hypertension (WCH) and 3438 (18.2%) with masked hypertension. Thus, a diagnosis contradiction between SBPM and first-visit OBPM was seen in 9870 (41.9%) individuals. On the basis of second-visit OBPM, the normotension, hypertension, WCH and masked hypertension prevalence values were 7875 (41.6%); 4857 (25.7%); 2397 (12.7%) and 3789 (20.0%). There was poor agreement (kappa value 0.37) between OBPM of visit 1 and 2 with a diagnosis difference in 6027 (31.8%) individuals. The majority of masked hypertension and WCH individuals had BP values close to thresholds. CONCLUSION: There was a poor agreement between OBPM of visit1 and visit 2. Likewise, the agreement between OBPM at both visits and SBPM was poor. SBPM being considered to have a better correlation with patient prognosis should be the preferred method for diagnosing hypertension.

Usefulness of ambulatory blood pressure measurement for hypertension management in India: the India ABPM study.

The present paper reports differences between office blood pressure (BP) measurement (OBPM) and ambulatory blood pressure measurement (ABPM) in a large multi-centre Indian all comers' population visiting primary care physicians. ABPM and OBPM data from 27,472 subjects (aged 51 ± 14 years, males 68.2%, treated 45.5%) were analysed and compared. Patients were classified based on the following hypertension thresholds: systolic BP (SBP) ≥ 140 and/or diastolic BP (DBP) ≥90 mmHg for OBPM, and SBP ≥ 130 and/or DBP ≥ 80 mmHg for 24-h ABPM, and SBP ≥ 120 and/or DBP ≥ 70 mmHg for night-time ABPM and SBP ≥ 135 and/or DBP ≥ 85 mmHg for daytime ABPM, all together. White coat hypertension (WCH) was seen in 12.0% (n = 3304), masked hypertension (MH) in 19.3% (n = 5293) and 55.5% (n = 15,246) had sustained hypertension. Isolated night-time hypertension (INH) was diagnosed in 11.9% (n = 3256). Untreated subjects had MH relatively more often than treated subjects (23.0% vs. 14.8%, p < 0.0001; respectively). Females had higher relative risk (RR) of having WCH than males (RR 1.16 [CI 95, 1.07-1.25], p < 0.0001). Whereas, males had higher RR of MH than females (RR 1.09 [CI 95, 1.02-1.17] p < 0.01). INH subjects had lower average systolic and diastolic dipping percentages (0.7 ± 6.6/ 2.2 ± 7.9 vs. 9.0 ± 7.3/11.9 ± 8.5, p < 0.001) than those without INH. In conclusion, for diagnosis of hypertension there was a contradiction between OBPM and ABPM in approximately one-third of all patients, and a substantial number of patients had INH. Using ABPM in routine hypertension management can lead to a reduction in burden and associated costs for Indian healthcare.

Blood pressure related to age: The India ABPM study.

The present paper reports trends in office blood pressure (BP) measurement (OBPM) and ambulatory blood pressure measurement (ABPM) with age in a large multi-center Indian all comers' population visiting primary care physicians. ABPM and OBPM data from 27 472 subjects (aged 51 ± 14 years, males 68.2%, treated 45.5%) were analyzed and compared. Individual differences between OBPM and ABPM patterns were compared for patients according to 10-year age categories. Results showed that systolic (S) BP values started to increase with age from the age of 40, BP variability (SD) increased from the age of 30 years. Diastolic (D) BP values started to decrease from the age of 50 years. Mean OBPM values were higher than daytime ABPM values (all P < .001) in all age-groups. The prevalence of white coat hypertension (WCH) and masked hypertension (MH) was based on OBPM and daytime, 24-hour, and nighttime average BPs together. WCH decreased with age from 15.1% and 12.4% in treated and untreated subjects at the youngest age to 7.2% and 6.9% in the oldest age, respectively. MH prevalence was higher for untreated than for treated subjects but remained similar for all age-groups (range of 18.6%-21.3%). The prevalence of reverse dippers increased with age from the youngest to oldest group with 7.3%-34.2% (P < .001 for trend). Dippers prevalence decreased from 42.5% to 17.9% from the youngest to oldest age-groups, respectively (P < .001 for trend). These findings confirm that BP patterns show clear differences in trends with age, particularly regarding nighttime BP.

S-Amlodipine: An Isomer with Difference-Time to Shift from Racemic Amlodipine.

Calcium channel blockers are among the first-line drugs for treatment of hypertension (HTN). S-amlodipine (S-AM), an S-enantiomer of amlodipine, is available in India and in other countries like China, Korea, Russia, Ukraine, and Nepal. Being clinically researched for nearly two decades, we performed in-depth review of S-AM. This review discusses clinical evidence from total 42 studies (26 randomized controlled trials, 14 observational studies, and 2 meta-analyses) corroborating over 7400 patients treated with S-AM. Efficacy and safety of S-AM in HTN in comparison to racemic amlodipine, used as monotherapy and in combination with other antihypertensives, efficacy in angina, and pleiotropic benefits with S-AM, are discussed in this review.

Subject Profile Assessment of Cases Recommended with Nutritional Supplement Containing Red Yeast Rice, Grape Seed Extract and Black Pepper Extract: A Prospective, Multicentric, Post-marketing Study.

OBJECTIVE: To assess the profile and general health indices in subjects prescribed with a nutritional supplement containing red yeast rice, grape seed extract and black pepper extract (NS-YGP; PreLipid®; Abbott Healthcare Pvt. Ltd.) in routine clinical setting in India. METHODS: In this prospective, postmarketing observational study, consecutive subjects recommended NS-YG at their outpatient department were recruited from 39 sites in India. The primary outcome of interest was to identify the profiles of subjects recommended with NS-YGP. The secondary outcome measures were to evaluate the changes in lipid profile from baseline to 3 and 6 months and assess the safety of NS-YGP. RESULTS: A total of 573 subjects were enrolled, of which 527 (92%) completed the study. Majority of subjects receiving NS-YGP were males (76.6%), non-obese (85.9%) and had borderline dyslipidemia (87.3%) at the time of enrolment. There was a significant improvement in lipid profile over a period of 6 months; with a significant decline in the levels of total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides from baseline to month 3 and 6 (p < 0.0001 for each parameters). Furthermore, HDL-C level significantly improved from baseline till month 6 (p = 0.0007). There was a significant change in levels of other laboratory parameters, including creatine phosphokinase, serum creatinine, hemoglobin and white blood cells from baseline to 3 and 6 months (p< 0.05). No adverse events were reported in the study. CONCLUSION: Most of the subjects prescribed with NS-YG had borderline elevated lipid levels. NS-YGP significantly improved lipid profile and was safe, well-tolerated and can be recommended in the primordial prevention of borderline dyslipidemia.

Pharmacological Reperfusion Therapy with Tenecteplase in 7,668 Indian Patients with ST Elevation Myocardial Infarction - A Real World Indian Experience.

OBJECTIVE: This real-world, observational, prescription event monitoring study was conducted to evaluate safety and efficacy of indigenous tenecteplase (TNK-tPA) in Indian patients presenting with ST elevation myocardial infarction (STEMI). METHODS: This is a multi-centric, observational, prescription event monitoring study. Data was collected for 7,668 patients from 1,307 investigator sites across India from January 2011 to February 2016. RESULTS: Overall, 76.71% patients were hypertensive, 47.97% patients were diabetic, 42.01% had dyslipidemia, 24.35% had ischemic heart disease and 40.82% patients were smokers. The overall rate for achieving clinically successful thrombolysis by TNK was 93.34%. Delayed administration of tenecteplase yielded lower success rate (84.66%) as against those patients who received tenecteplase within 3 hours of symptoms (94.34%). 93.2% patients had chest pain resolution after pharmacological fibrinolysis. Overall 91.1% patients had 50% resolution of ST elevation at 90 minutes and mean time for 50% ST resolution was 72.06 minutes. Overall 53 patients died (mortality of 0.69%) before discharge. The incidence of bleeding (excluding stroke) was 1.77%, any stroke without ICH was 0.18% and any ICH was 0.38%. CONCLUSION: The findings of this study further reinforce the safety and efficacy of indigenous TNK-tPA in Indian patients presenting with STEMI, including high-risk sub-groups. The study also highlights the importance of early reperfusion therapy.

Current Practice of Hypertension in India: Focus on Blood Pressure Goals.

INTRODUCTION: Recommended Blood Pressure (BP) goals in elderly and those with co-morbid conditions like Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD) vary in different Hypertension (HTN) management guidelines. AIM: To understand currently followed BP goals and practices among the physicians involved in management of HTN in India. MATERIALS AND METHODS: A cross-sectional, observational survey was conducted at 66th annual conference of Cardiological Society of India (CSICON-2014, Hyderabad). A structured questionnaire related to the BP goals and HTN practices was provided and responses from voluntarily participating physicians were collected. Data was analysed with descriptive statistics. RESULTS: Two-hundred sixty physicians completed this survey. In their routine clinical practice, physicians most frequently referred to Joint National Committee (JNC) guidelines (63.85%) followed by Indian guidelines on HTN (14.23%). In patients aged 60 years and above, BP goal <140/90mmHg and <150/90mmHg was aimed by 43.46% and 33.85% of the physicians respectively. In HTN with Type 2 DM (T2DM), most physicians (61.92%) had a BP goal of <130/80mmHg. A target BP <130/80mmHg was aimed by 48.08% physicians in CKD without proteinuria and 68.85% physicians in CKD with proteinuria. In newly diagnosed hypertensives, treatment modification was practiced after 15, 20 and 30 days by 37.31%, 16.15% and 35.77% of the physicians respectively. Beta-blockers were considered as third-line agents in HTN without co-morbidities by 45% physicians. Ambulatory BP Monitoring (ABPM) is practiced only in few patients (<5%) by most (71.93%) physicians. CONCLUSION: In practice, Indian physicians follow lower BP goals when compared to the recommendations from the most referred JNC guidelines. Increasing physicians' awareness to the changes in recommendations is the need.

Hybrid procedure.

With increase in aging population and increased prevalance of coronary risk factors including diabetes mellitus, more people with multivessel coronary artery disease are diagnosed. Many of these patients undergo coronary angioplasty or bypass graft surgery (CABG). Hybrid coronary revascularisation may be preferred in multivessel CAD patients with technical limitations to PCI or CABG and in whom minimising invasiveness of CABG is preferred. Our case highlights patient selection and procedure for this new modality of coronary artery disease treatment.

Blood pressure control with a single-pill combination of indapamide sustained-release and amlodipine in patients with hypertension: the EFFICIENT study.

OBJECTIVE: Despite antihypertensive treatment, most hypertensive patients still have high blood pressure (BP), notably high systolic blood pressure (SBP). The EFFICIENT study examines the efficacy and acceptability of a single-pill combination of sustained-release (SR) indapamide, a thiazide-like diuretic, and amlodipine, a calcium channel blocker (CCB), in the management of hypertension. METHODS: Patients who were previously uncontrolled on CCB monotherapy (BP≥140/90 mm Hg) or were previously untreated with grade 2 or 3 essential hypertension (BP≥160/100 mm Hg) received a single-pill combination tablet containing indapamide SR 1.5 mg and amlodipine 5 mg daily for 45 days, in this multicenter prospective phase 4 study. The primary outcome was mean change in BP from baseline; percentage of patients achieving BP control (BP<140/90 mm Hg) was a secondary endpoint. SBP reduction (ΔSBP) versus diastolic BP reduction (ΔDBP) was evaluated (ΔSBP/ΔDBP) from baseline to day 45. Safety and tolerability were also assessed. RESULTS: Mean baseline BP of 196 patients (mean age 52.3 years) was 160.2/97.9 mm Hg. After 45 days, mean SBP decreased by 28.5 mm Hg (95% CI, 26.4 to 30.6), while diastolic BP decreased by 15.6 mm Hg (95% CI, 14.5 to 16.7). BP control (<140/90 mm Hg) was achieved in 85% patients. ΔSBP/ΔDBP was 1.82 in the overall population. Few patients (n = 3 [2%]) reported side effects, and most (n = 194 [99%]) adhered to treatment. CONCLUSION: In patients who were previously uncontrolled on CCB monotherapy or untreated with grade 2 or 3 hypertension, single-pill combination indapamide SR/amlodipine reduced BP effectively--especially SBP--over 45 days, and was safe and well tolerated. TRIAL REGISTRATION: Clinical Trial Registry-India CTRI/2010/091/000114.

Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial.

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a poorly understood and frequently lethal disease with few treatment options. METHODS: We conducted a placebo-controlled trial of intravenous treprostinil, a prostacyclin analog, in treatment-naive PAH patients. During 12 weeks of treatment with treprostinil or placebo, we quantified 6-minute walk distance (6MW), clinical symptoms and 11 cytokines/growth factors. RESULTS: Forty-two of 44 study patients had idiopathic/familial PAH in New York Heart Association (NYHA) Class III. Treprostinil increased 6MW by a placebo-corrected median of 83 meters (p = 0.008; mean increase 93 +/- 42 meters), reduced Borg score by a median 2.0 units (p = 0.02), and improved NYHA class by a median of 1.0 (p = 0.02). There was a trend toward improved survival with treprostinil (p = 0.051). Baseline plasma angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and platelet-derived growth factor (PDGF) were elevated compared with reported normal ranges. Treatment with treprostinil was associated with decreased Ang-2 levels. Improvement in 6MW distance after treatment was associated with reductions in Ang-2 and MMP-9 levels. Most of the cytokines and growth factors studied were not abnormal with disease nor did they change with treatment. CONCLUSIONS: We conclude that treprostinil treatment significantly improved exercise capacity, dyspnea and functional class. Several plasma proteins that might track disease were abnormal at baseline, and changes were associated with improved exercise capacity.