Clinical correlation of multiple biomarkers for risk assessment in patients with acute coronary syndrome.

OBJECTIVE: Biochemical markers are useful for the prediction of future cardiovascular events in patients with non-ST-segment elevation acute coronary syndrome (ACS). The independent as well as the combined prognostic value of elevated troponin-T, high-sensitivity C-reactive protein (hs-CRP), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) on the Thrombolysis In Myocardial Infarction (TIMI) risk score and on the short-term prognosis were evaluated in a cohort of ACS patients. METHODS AND RESULTS: In an unselected, heterogeneous group of 80 patients with ACS (i.e., unstable angina [USA] or non-ST-elevation myocardial infarction [NSTEMI]), the levels of troponin-T, hs-CRP, and NT-pro-BNP were analyzed. The correlation between elevation of different biomarkers with TIMI risk score and their impact on 30-day major adverse cardiac events was sought. The levels of hs-CRP were significantly higher in patients who had angina as their predominant complaint (3.67 mg/dl vs. 1.67 mg/dl: p < 0.01), while levels of NT-pro-BNP was higher in those patients who had any element of heart failure at presentation (2616.39 pg/ml vs. 1068.3 pg/ml; p < 0.01). Troponin-T was highest in patients who had an element of both heart failure and angina at presentation (p < 0.01). The TIMI risk score expectedly had a positive and strong correlation with elevated troponin-T, but had no correlation with elevation of hs-CRP and NT-pro-BNP in isolation. However, when any two biomarkers were elevated, the patients were in the intermediate risk group as per TIMI risk score irrespective of troponin-T-elevation. When all the three biomarkers were elevated, the risk equaled the high-risk category of TIMI risk score. Elevated hs-CRP (3.40 mg/dl vs. 1.38 mg/dl; p < 0.001) and troponin-T (2.37 ng/ml vs. 1.23 ng/ml; p < 0.001) at baseline correlated independently with the occurrence of re-ischemia, while elevated NT-pro-BNP alone correlated significantly with the development of heart failure within 30 days of follow-up (4247.76 pg/ml vs. 1210.86 pg/ml; p < 0.01). The highest risk of death from any cardiovascular cause within 30 days of follow-up was significantly higher when all the three biomarkers were elevated. CONCLUSION: The use of NT-pro-BNP, hs-CRP, and troponin-T in combination appears to add critical prognostic insight to the assessment of patients with ACS.

Progression of chronic pulmonary tuberculosis in mice intravenously infected with ethambutol resistant Mycobacterium tuberculosis.

Purpose: Ethambutol (EMB) is an important first line drug, however little information on its molecular mechanism of resistance and pathogenicity of resistant isolates is available. Present work was designed to study virulence of the EMB resistant M. tuberculosis strains and the host responses in-vivo on infection of EMB resistant M. tuberculosis using Balb/c mouse model of infection. Methods: Three groups of Balb/c mice (female, age 4-6 wk; 21 mice in each group) were infected intravenously with 106 CFU of M. tuberculosis H37Rv and two EMB resistant clinical isolates. Age and sex matched control animals were mock inoculated with Middlebrook 7H9 broth alone. At 10, 20, 30, 40, 50, 60, and 70 days post-infection three animals from each group were sacrificed by cervical dislocation and lung tissue was collected for further analysis. Results: Infection with EMB resistant M. tuberculosis led to progressive and chronic disease with significantly high bacillary load (p=0.02). Massive infiltration and exacerbated lung pathology with increased expression of IFN-gamma and TNF-alpha was observed in lungs of mice infected with EMB resistant strains. The present study suggests that infection with EMB resistant M. tuberculosis leads to chronic infection with subsequent loss of lung function, bacterial persistence with elevated expression of TNF-alpha resulting in increased lung pathology. Conclusion: These findings highlight that EMB resistant M. tuberculosis regulates host immune response differentially and its pathogenicity is different from drug sensitive strains of M. tuberculosis.

"Poor man's risk factor": correlation between high sensitivity C-reactive protein and socio-economic class in patients of acute coronary syndrome.

OBJECTIVE: Inflammation has been proposed as one of the factors responsible for the development of coronary artery disease (CAD) and high sensitivity C-reactive protein (hs CRP) at present is the strongest marker of inflammation. We did a study to assess the correlation of hs-CRP with socio-economic status (SES) in patients of CAD presenting as acute coronary syndrome (ACS). METHODS: Baseline hs-CRP of 490 patients of ACS was estimated by turbidimetric immunoassay. Patients were stratified by levels of hs-CRP into low (<1 mg/L); intermediate (1-3 mg/L) or high (>3 mg/L) groups and in tertiles of 0-0.39 mg/L, 0.4-1.1 mg/L and >1.1 mg/L, respectively. Classification of patient into upper (21.4%), middle (45.37 percent) and lower (33.3%) SES was based on Kuppuswami Index which includes education, income and profession. Presence or absence of traditional risk factors for CAD diabetes, hypertension, dyslipidemia and smoking was recorded in each patient. RESULTS: Mean levels of hs-CRP in lower, middle and upper SES were 2.3 +/- 2.1 mg/L, 0.8 +/- 1.7 mg/L and 1.2 +/- 1.5 mg/L, respectively. hs-CRP levels were significantly higher in low SES compared with both upper SES (p = 0.033) and middle SES (p = 0.001). Prevalence of more than one traditional CAD risk factors was seen in 13.5%, 37.5% and 67.67 percent; in patient of lower, middle and upper SES. It was observed that multiple risk factors had a linear correlation with increasing SES. Of the four traditional risk factors of CAD, smoking was the only factor which was significantly higher in lower SES (73%) as compared to middle (51.67 percent;) and upper (39.4%) SES. We found that 62.3%, 20.8% and 26.5% patients of low, middle and upper SES had hs-CRP values in the highest tertile. Median value of the Framingham risk score in low, middle and upper SES as 11, 14 and 18, respectively. We observed that at each category of Framingham risk, low SES had higher hs-CRP. CONCLUSION: We conclude from our study that patient of lower SES have significantly higher levels of hs-CRP despite the fact that they have lesser traditional risk factors and lower Framingham risk. These findings add credit to our belief that inflammation may be an important link in the pathophysiology of atherosclerosis and its complications especially in patients of low SES who do not have traditional risk factors.

Ruptured left sinus of valsalva aneurysm to right atrium.

A 6-year-old child presented with left sinus of Valsalva aneurysm opening in right atrium. Origin of sinus of Valsalva from left aortic sinus and its opening into right atrium is extremely rare. The anomaly was corrected surgically by patch closure at the aortic end. Follow-up echocardiography did not reveal any residual shunt in right atrium.

Short-term (48 hours) versus long-term (7 days) antibiotic prophylaxis for permanent pacemaker implantation.

BACKGROUND: Infection following permanent pacemaker implantation is a dreaded complication. Antibiotic prophylaxis for 1-10 days at the time of implant has been used in the past but there is no consensus regarding its duration. We carried out a prospective, randomized study of two durations of antibiotic prophylaxis to determine which one was more effective. METHODS AND RESULTS: One hundred and seventy-eight patients undergoing permanent pacemaker implantation for the first time were randomized to receive short duration (group A, n = 8 8) or longer duration (group B, n = 90) antibiotic prophylaxis for 2 days and 7 days, respectively. Patients in both groups received cloxacillin 2 g 2 hours prior to the procedure followed by ampicillin and cloxacillin (50 mg/kg/day in 4 divided doses) and gentamicin (3 mg/kg/day in 2 divided doses) for the respective duration. Patients were followed up for 1-17.3 months (9.3 +/- 1.8 months) in group A and 1-16.5 months (8.9 +/- 2 months) in group B. One patient in group B had an infection at the pacemaker site and two patients in each group had to undergo reimplantation due to pus in the pocket. There was no significant difference in the primary end-point in both groups. CONCLUSIONS: A short course (48 hours) of antibiotic prophylaxis following permanent pacemaker implantation is as effective as a longer course (7 days).

Lipoprotein (a) and lipid levels in young patients with myocardial infarction and their first-degree relatives.

BACKGROUND: Studies among emigrant Indians have stressed the role of a powerful genetic factor, lipoprotein (a), in the causation of premature coronary artery disease. This study was carried out to assess lipoprotein (a) and lipid levels in 50 consecutive young north Indian patients (age less than 45 years, mean age 39+/-3.7 years) with myocardial infarction, their first-degree relatives (n=125, mean age 36+/-16 years), and age- and sex-matched controls (n=50, mean age 34+/-6.9 years). METHODS AND RESULTS: Blood samples for lipid estimation were taken within 24 hours of myocardial infarction and after overnight fasting for twelve hours. Lipoprotein (a) levels were estimated by the ELISA technique using preformed antibodies while lipid levels were estimated by kits using the colorimetric method. All were male patients. The mean lipoprotein (a) level was 22.28+5.4 mg/dl in patients, 13.88+5.19 mg/dl in their first-degree relatives and 9.28+22.59 mg/dl in controls. In addition, it was significantly higher in young patients with myocardial infarction and their relatives as compared to controls (p<0.001 for patients v. controls and p<0.05 for relatives v. controls). There was no significant difference in the levels of total cholesterol and low-density lipoprotein cholesterol among the three groups. High-density lipoprotein cholesterol was significantly lower in young patients with myocardial infarction (30.16+/-9.45 mg/dl) and their first-degree relatives (33.28+/-8.45 mg/dl) as compared to controls (46.8+/-8.04 mg/dl) (p<0.001 for patients v. controls and p<0.01 for relatives v. controls). Triglyceride levels were significantly higher in patients as compared to controls (202+/-76 mg/dl v. 149 + 82.99 mg/dl, p<0.05). Smoking was more prevalent in young patients with myocardial infarction as compared to controls (44% v. 36%, p<0.05). CONCLUSIONS: Smoking, high lipoprotein (a) and triglyceride levels and low high-density lipoprotein levels may be important risk factors for coronary artery disease in the younger population; also, there is familial clustering of high lipoprotein (a) levels in first-degree relatives of young patients with myocardial infarction.

Left ventricular pacing through coronary sinus tributaries: initial experience.

BACKGROUND: Left ventricular pacing is increasingly being used as a part of biventricular pacing in congestive heart failure but data on safety, feasibility, reliability and lead maturation are sparse. METHODS AND RESULTS: Seventeen patients (13 males and 4 females) with persistent symptomatic degenerative complete heart block underwent temporary left ventricular pacing by a left subclavian puncture through the coronary sinus to its tributaries using a unipolar permanent pacing lead connected to an external pulse generator. The left ventricular pacing was done for two weeks. Permanent right ventricular apical pacing was also done at the same time through a right cephalic vein cut-down or subclavian puncture and the pacing rate was kept below that of the initial left ventricular pacing rate. Pacing parameters of the left and right ventricles were assessed at the time of implantation and at two weeks. Out of 17 patients, left ventricular pacing was successful in 11 (67.7%) patients. The time taken for the total procedure was 56+/-18.1 min. Lead displacement was noted in one patient without loss of pacing. At the time of implant and after two weeks, left ventricular pacing threshold, impedance, R wave height and slew rate were not different as compared to right ventricular pacing. Holter recording for 24 hours revealed regular left ventricular pacing at the end of two weeks in all patients. CONCLUSIONS: The present study shows that left ventricular pacing through coronary sinus tributaries is feasible and reliable. Acute and subacute maturation of left ventricular pacing are similar to right ventricular apical pacing.

Megadose heparin and streptokinase produce similar TIMI 3 flow at discharge in patients of acute myocardial infarction presenting between 7-12 hours.

The present study was undertaken to assess the impact of megadose heparin bolus on angiographic patency of infarct-related artery in patients of acute myocardial infarction presenting between 7-12 hours and to compare it with streptokinase. Forty-seven patients (27 males, mean age 58.1 +/- 9.6 years) of acute myocardial infarction between 7-12 hours of onset of chest pain were randomised to receive either megadose heparin bolus (300 IU/kg body weight, group 1, n = 24; or streptokinase 1.5 million units over one hour, group 2, n = 23). Parameters noted were: relief of pain at 90 minutes, 50 percent or more resolution of ST segment at 90 minutes, TIMI grade flow and left ventricular ejection fraction at discharge. Mean age (59.0 +/- 12.9 years in group 1; 57.2 +/- 8.1 years in group 2), mean time to drug (7.5 +/- 1.3 hours in group 1; 7.8 +/- 1.6 hours in group 2), site of anterior wall infarction (12 in group 1, 10 in group 2), relief of pain at 90 minutes (15 in group 1, 14 in group 2) and more than 50 percent resolution of ST segment elevation at 90 minutes (12 patients in each group) were similar. On coronary angiography performed in 42 patients (21 in each group) at a mean interval of 7.2 +/- 1.3 days after acute myocardial infarction, TIMI grade 3 flow was seen in 7 (33.3%) patients in each group and TIMI grade 2/3 flow was also similar in both the groups (p = NS). No major bleed occurred in either group. We conclude that heparin given as a megadose bolus produces similar TIMI 3 flow in infarct-related artery as compared to streptokinase in acute myocardial infarction patients presenting between 7-12 hours.

Accelerated infusion of streptokinase in acute myocardial infarction results in better TIMI flow grade in infarct-related artery.

Bolus followed by rapid infusion of tissue plasminogen activator results in higher grade of TIMI flow in infarct-related artery as compared to slow infusion. In the present study, an accelerated regimen of streptokinase given over 15 minutes was compared with conventional infusion over one hour in 47 patients presenting within 12 hours of acute myocardial infarction. Forty-seven patients (44 males, 3 females; mean age 54.0 +/- 1.1 years) were randomly allocated to receive 1.5 million units of streptokinase either over 15 minutes (group 1, n = 24) or over one hour (group 2, n = 23) at a mean interval of 5.4 +/- 3.6 hours after onset of symptoms. All the patients received aspirin and intravenous heparin (1000 U/hr) for 96 hours after thrombolysis. Coronary angiography was performed in 43 patients (22 in group 1, 21 in group 2) prior to discharge from the hospital (mean 7 +/- 2.1 days after acute myocardial infarction) and patency of the infarct-related artery and grade of TIMI flow were determined. Infarct-related artery was patent (TIMI 2/3 flow) in 19 (86.4%) patients in group 1 as compared to 12 (57.1%) in group 2 (p < 0.05). TIMI grade 3 flow in the infarct-related artery was present in 13 (59.1%) in group 1 as compared to 7 (33.3%) in group 2 (p = 0.1). There was no significant difference between group 1 and 2 in time of presentation (mean 5.3 +/- 3.9 hrs vs 5.5 +/- 3.2 hrs), time to needle in hospital (25.6 +/- 11.2 min vs 26.3 +/- 6.2 min), site of infarct (anterior myocardial infarction 12 in group 1 vs 11 in group 2), relief of pain at 90 min (13 vs 12), more than 50 percent reduction of ST elevation at 90 minutes (17 vs 12) and left ventricular ejection fraction (48.8 +/- 9.1% vs 49.8 +/- 16.0%), respectively. Streptokinase was well tolerated in both the groups, although hypotension was more common with the accelerated regimen (5 in group 1 vs 3 in group 2; p = NS). Thus, 'accelerated' streptokinase given over 15 minutes in patients presenting within 12 hours of acute myocardial infarction is well tolerated and results in higher grades of TIMI flow in the infarct-related artery as compared to the "conventional" one-hour infusion regimen.

Antitubercular treatment does not prevent constriction in chronic pericardial effusion of undetermined etiology: a randomized trial.

Patients of chronic exudative pericardial effusion are frequently treated with antitubercular treatment on presumptive grounds in developing countries, in a hope to prevent constrictive pericarditis. To assess the impact of antitubercular treatment on development of constrictive pericarditis in chronic large exudative pericarditis effusion of undetermined etiology, 25 patients above 12 years of age, with large pericarditis effusion beyond 12 weeks duration, were randomized in a prospective 2:1 fashion, to receive either 3-drug antitubercular treatment (group A) or placebo (group B) for six months. End points studied were, development of pericardial thickness as diagnosed by CT scan and constrictive pericarditis as diagnosed by cardiac catheterization. Twenty-one patients (14 in group A and 7 in group B) completed the study protocol. In all, five (23.8%) patients developed constrictive pericarditis/pericardial thickening. Histopathological examination of pericardiectomy specimens in over five patients were negative for tubercular pathology. Pericardial effusion resolved completely in another 10 (47.8%) patients. There was no significant difference in both the groups in development of constrictive pericarditis/pericardial thickening (group A: n = 3, 21.4% and group B: n = 2, 29.6%, p = NS). On multivariate analysis, development of constrictive pericarditis/pericardial thickening was associated with recurrent tamponade (p = 0.01), presence of tamponade at admission (p = 0.07) and haemorrhagic pericardial effusion (p = 0.08). Thus, antitubercular treatment does not prevent the development of constrictive pericarditis in patients of large chronic pericardial effusion of undetermined etiology.

Improvement in contractility of infarct zone after dobutamine infusion predicts good (TIMI II or III) flow in infarct related artery.

Eighteen patients of 'Q' wave acute myocardial infarction (AMI) (age 50 +/- 6.2 years), underwent dobutamine stress echocardiography (DSE) before hospital discharge (7.2 +/- 1.3 days after AMI) to find out the correlation between response of infarct zone to dobutamine infusion and TIMI grade flow in infarct related artery (IRA). The aim of study was to test the hypothesis that infarct zone which shows improvement in contractility after dobutamine infusion has viable myocardial tissue and would have good flow (TIMI II or III) in IRA. Echocardiographically, improvement in contractility in the centre of infarct zone by at least 1 grade (on a scale of 4) was termed as positive response on DSE. The mean dose of dobutamine was 19.4 micrograms/kg/min. Ten patients had positive response on DSE; 8 of them had good antegrade flow in IRA. Eight patients had no improvement in contractility of infarct zone on DSE; 6 of them had poor flow in IRA. Clinical markers of reperfusion (relief of chest pain, early ST settlement, peak CPK-MB levels), age of patient, site of AMI, time to thrombolysis, resting left ventricular ejection fraction, wall motion score of the infarct zone and presence of collaterals were not significantly different in patients with good or poor flow in IRA. Thus, improvement in contractility of infarct zone after dobutamine infusion can predict good flow (TIMI II or III) in IRA with 80 percent sensitivity, 75 percent specificity, 80 percent diagnostic accuracy, 80 percent positive predictive value and 75 percent negative predictive value.

In vitro and in vivo therapeutic activity of Parthenium hysterophorus against Trypanosoma evansi.

Crude 50% ethanolic extract of P. hysterophorus flowers exhibited trypanocidal activity in vitro at all the four concentrations tested i.e. 5, 50, 500 and 1000 micrograms/ml. In vivo trial revealed that the extract exerted antitrypanosomal effect at doses of 100 and 300 mg/kg body wt, i.p. as evidenced by significantly reduced (P < 0.01) mean parasitaemia on days 3, 4, 5 and 6 when compared with untreated control group. Further at 100 and 300 mg/kg, body wt doses, the survival period was significantly (P < 0.05) prolonged as compared to control group. The extract was, however, found toxic to the animals at 1000 mg/kg dose.

Predischarge dobutamine induced distant wall motion abnormalities after acute myocardial infarction predict multivessel disease.

Presence of multivessel coronary artery disease (MVD) identifies a high risk subgroup after acute myocardial infarction (AMI). Dobutamine stress echocardiography (DSE) has recently emerged as a promising non invasive test to detect the presence and extent of coronary artery disease. Forty six consecutive patients (38 males, 8 females; mean age 48.6 +/- 10.4 years) of Q-wave acute myocardial infarction were subjected to submaximal treadmill test (TMT) and dobutamine stress echocardiography to see their ability to predict multivessel coronary artery disease as detected by coronary angiography before hospital discharge. Dobutamine infusion was started at 5 micrograms/kg/min to a maximum of 40 micrograms/kg/min, to achieve 70 percent of the age predicted heart rate. Appearance of new regional wall motion abnormality was interpreted as positive DSE for MVD. Mean peak infusion dose of dobutamine used in the study was 28.56 +/- 5.67 micrograms/kg/min. In none of the patients, the test had to be terminated due to side effects. The sensitivity and specificity of DSE to predict MVD was 80 percent and 93.7 percent, respectively as compared to 45 percent and 86 percent for submaximal TMT. Thus, DSE in patients of AMI before hospital discharge is a safe procedure with fairly accurate prediction of multivessel coronary artery disease.

Beneficial effects of long-term metoprolol therapy on cardiac haemodynamics in patients with mitral stenosis in sinus rhythm--a randomised clinical trial.

We conducted a placebo controlled randomised clinical trial to evaluate the effects of 6 months therapy with metoprolol on resting and exercise haemodynamics in 31 patients with isolated mitral stenosis in sinus rhythm. Twenty six of them (placebo n = 13, metoprolol n = 13) completed the study protocol. Their mean age was 23.1 +/- 7.9 years and the mean mitral valve area was 0.93 +/- 0.25 cm2. The dose of metoprolol ranged between 50-100 mg per day. The primary outcome variables for the study were the resting and exercise mean pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) and the secondary outcome variables consisted of resting and exercise heart rate, mean pulmonary artery pressure (PAP), mean pulmonary vascular resistance (PVR) and clinical improvement on visual analog scale. These outcome variables were assessed blindly. The resting and exercise mean PCWP (mmHg) increased by 9.1 +/- 3.1 and 16.4 +/- 6.4 on placebo and 2.5 +/- 2.1 and -4.6 +/- 2.3 on metoprolol after 6 months therapy. These differences were statistically significant (p < 0.01). The resting and exercise CI (liters/min/m2) decreased by 0.2 +/- 0.1 and 0.1 +/- 0.1 on placebo and 0.3 +/- 0.5 and 0.3 +/- 1.0 on metoprolol. These haemodynamic effects were accompanied with much better symptomatic improvement in patients treated with metoprolol. The differences in change in mean PAP and PVR in two groups were statistically not significant. Our results suggest that the symptomatic patients with MS, waiting for definitive intervention for 6 months or less, would benefit if given beta blockers during this period.

Etiology of isolated mitral regurgitation: a clinico-echocardiographic study.

One hundred and ninety two consecutive patients with isolated mitral regurgitation (MR) with an audible murmur were studied for determination of etiology. There were 95 males & 97 females (mean age 24.5 +/- 10.8 years; range 13 to 58 years) with 102 patients in NYHA classes I and II, 81 in class III and 9 in NYHA class IV. The etiological grouping was: rheumatic 74 (38.5%), probable rheumatic 28 (15%), mitral valve prolapse 26 (13.5%), dilated cardiomyopathy 15 (8%), infective endocarditis 12 (6%), isochaemic heart disease 10 (5%), miscellaneous group (including rupture chordae tendinae, aortoarteritis etc) 9 (4.5%) and patients with indeterminate etiology 18 (9.5%). Etiology could be determined in 174 out of 192 cases. The clinical methods combined with echocardiography were helpful in 79 cases while echocardiography alone could diagnose etiology in 89 cases. Clinical features alone gave the diagnosis in 6 patients. The findings of gross morphology of the surgically removed mitral valves in 30 patients of this study were similar to their pre-operative etiologic diagnosis based on clinical and echocardiographic features. These findings may be of value in planning treatment and prophylactic strategies in cases of isolated MR.

The efflux of nor-epinephrine from platelets in genetic hypertension.

Platelets have been used as a model of sympathetic neurons to study the storage of nor-adrenaline in normotensive individuals belonging to families with essential hypertension for at least two generations. The efflux and initial efflux rate (K) of noradrenaline was determined in 36 young relatives (mean age 29.2 years) and in 20 young controls with no family history of hypertension (mean age 26.5 years). From the groups of relatives all those with definite hypertension had been excluded. Efflux and efflux rate K was significantly higher in young relatives (50.82 +/- 3.84 and 28.2 +/- 6.3) than in the controls (39.2 +/- 0.71 and 15.2 +/- 4.8). Of the relatives 25.2% had higher K values than any of the controls.

Modified cephalic vein guide wire technique for permanent pacemaker implantation.

This report describes a modified cephalic vein guide wire technique used for implantation of 18 consecutive pacemakers using bipolar leads. The modified technique appears to be a safe and simple procedure for single chamber permanent pacing. Its use may also be extended in implanting dual chamber pacemakers.