A phase 1 clinical trial of SP16, a first-in-class anti-inflammatory LRP1 agonist, in healthy volunteers.

BACKGROUND: Endogenous serine protease inhibitors are associated with anti-inflammatory and pro-survival signaling mediated via Low-density lipoprotein receptor-related protein 1 (LRP1) signaling. SP16 is a short polypeptide that mimics the LRP1 binding portion of alpha-1 antitrypsin. METHODS: A pilot phase I, first-in-man, randomized, double blind, placebo-controlled safety study was conducted to evaluate a subcutaneous injection at three dose levels of SP16 (0.0125, 0.05, and 0.2 mg/kg [up to 12 mg]) or matching placebo in 3:1 ratio in healthy individuals. Safety monitoring included vital signs, laboratory examinations (including hematology, coagulation, platelet function, chemistry, myocardial toxicity) and electrocardiography (to measure effect on PR, QRS, and QTc). RESULTS: Treatment with SP16 was not associated with treatment related serious adverse events. SP16 was associated with mild-moderate pain at the time of injection that was significantly higher than placebo on a 0-10 pain scale (6.0+/-1.4 [0.2 mg/kg] versus 1.5+/-2.1 [placebo], P = 0.0088). No differences in vital signs, laboratory examinations and electrocardiography were found in those treated with SP16 versus placebo. CONCLUSION: A one-time treatment with SP16 for doses up to 0.2 mg/kg or 12 mg was safe in healthy volunteers.

Impact of Diltiazem Alone versus Diltiazem with Nitrate on Five-Year Clinical Outcomes in Patients with Significant Coronary Artery Spasm.

PURPOSE: Calcium channel blockers diltiazem and nitrate have been used as selective coronary vasodilators for patients with significant coronary artery spasm (CAS). However, no study has compared the efficacy of diltiazem alone versus diltiazem with nitrate for long-term clinical outcomes in patients with CAS. MATERIALS AND METHODS: A total of 2741 consecutive patients without significant coronary artery disease with positive CAS by acetylcholine (Ach) provocation test between November 2004 and May 2014 were enrolled. Significant CAS was defined as a narrowing of >70% by incremental intracoronary injection of 20, 50, and 100 µg of Ach into the left coronary artery. Patients were assigned to either the diltiazem group (n=842) or the dual group (diltiazem with nitrate, n=1899) at physician discretion. To adjust for potential confounders, a propensity score matching (PSM) analysis was performed using the logistic regression model. After PSM analysis, two well-balanced groups (811 pairs, n=1622, C-statistic=0.708) were generated. RESULTS: At 5 years, there were similar incidences in primary endpoints, including mortality, myocardial infarction, revascularization, and recurrent angina requiring repeat coronary angiography between the two groups. Diltiazem alone was not an independent predictor for major adverse cardiovascular events or recurrent angina requiring repeat coronary angiography. CONCLUSION: Despite the expected improvement of endothelial function and the relief of CAS, the combination of diltiazem and nitrate treatment was not superior to diltiazem alone in reducing mortality and cardiovascular events up to 5 years in patients with significant CAS.

Delayed High Output Heart Failure due to Arteriovenous Fistula Complicated with Herniated Disc Surgery.

A 36-year-old male presented with progressive exertional dyspnea over months. Physical examination showed jugular venous distension, lung crecipitations, femoral bruit and pitting pedal edema. Echocardiogram showed a dilated right ventricle with severe pulmonary hypertension and a non collapsing inferior vena cava (IVC). On right heart catheterization, IVC oxygen saturation was noted at 92% suggesting arterial mixing; a computed tomography of the abdomen showed a fistula between the right common iliac artery to the right common iliac vein at L4 level and a massive IVC; this was linked to trauma from a disectomy done 16 years ago at L4-L5 level. Endovascular sealing with a 16 × 60 mm bifurcated stent graft (S & G Biotech, Seoul, Korea) was performed which led to complete resolution of the patient's dyspnea. Iatrogenic vascular injury during lumbar disc surgery, although rare, can lead to high output cardiac failure developing over months to years.

Impact of Cigarette Smoking: a 3-Year Clinical Outcome of Vasospastic Angina Patients.

BACKGROUND AND OBJECTIVES: Cigarette smoking is a risk significant factor in coronary artery disease (CAD) and vasospastic angina (VSA). However, it is largely unknown whether smoking adds to any long-term clinical risk in VSA patients. SUBJECTS AND METHODS: A total of 2797 patients without significant CAD underwent acetylcholine (Ach) provocation test between November 2004 and October 2010. Patients were divided into three groups, based on the presence of coronary artery spasm (CAS) and smoking habits (non-CAS group: n=1188, non-smoking CAS group: n=1214, smoking CAS group: n=395). All CAS patients were prescribed with anti-anginal medications for at least 6 months. The incidence of major clinical outcomes and recurrent angina of these groups were compared up to 3 years. RESULTS: There were considerable differences in the baseline clinical and angiographic characteristics among the three groups, but there was no difference in the endpoints among the three groups (including individual and composite hard endpoints) such as death, myocardial infarction, de novo percutaneous coronary intervention, cerebrovascular accident, and major adverse cardiac events. However, there was a higher incidence of recurrent angina in both the non-smoking CAS group and smoking CAS group, as compared to the non-CAS group. In multivariable adjusted Cox-proportional hazards regression analysis, smoking CAS group exhibited a higher incidence of recurrent angina compared with the non-CAS group (hazard ratio [HR]; 2.46, 95% confidence interval [CI]; 1.46-4.14, p=0.001) and non-smoking CAS group (HR; 1.76, 95% CI; 1.08-2.87, p=0.021). CONCLUSION: Cigarette smoking CAS group exhibited higher incidence of recurrent angina during the 3-year clinical follow-up compared with both the non-CAS group and non-smoking CAS group. Quitting of smoking, paired with intensive medical therapy and close clinical follow-up, can help to prevent recurrent angina.

Impact of Statin Use on Development of New-Onset Diabetes Mellitus in Asian Population.

There have been several reports showing that the statin use is associated with new-onset diabetes mellitus (DM). The aim of the present study was to evaluate the impact of chronic statin use on development of new-onset DM in a series of Asian population. The patients were retrospectively enrolled using the electronic database of Korea University Guro Hospital from January 2004 to February 2010. A total of 10,994 patients without a history of diabetes were analyzed. Baseline lipid profiles, fasting glucose, Hemoglobin (Hb) A1c, and glucose tolerance tests were measured in all patients before statin treatment. Included patients had HbA1c ≤ 5.7% and fasting glucose level ≤ 100 (mg/dl). The patients were divided into 2 groups according to the use of statins (the statin group, n = 2,324 patients and the nonstatin group, n = 8,670 patients). To adjust baseline potential confounders, a propensity score-matched analysis was performed using logistic regression model. After propensity score matching, 2 propensity-matched groups (1,699 pairs, n = 3,398, C statistic = 0.859) were generated and analyzed. After propensity score matching, baseline characteristics of both groups were balanced except that the statin group was older and had higher rate of coronary artery disease compared with the nonstatin group. During a 3-year follow-up, the statin group had higher incidence of new-onset DM compared with the nonstatin group (hazard ratio 1.99, 95% CI 1.36 to 2.92, p <0.001), but the statin group showed lower incidence of major adverse cerebral-cardiovascular events compared with the nonstatin group (hazard ratio 0.40, 95% CI 0.19 to 0.85, p <0.001). In the present study, although the use of statins was associated with higher rate of new-onset DM, it markedly improved 3-year cardiovascular outcomes in Asian population.