Ashok Krishnaswami

Cyclic Flow variations after coronary angioplasty in humans: Clinical and angiographic characteristics and elimination with 7E3 monoclonal antiplatelet antibody☆

OBJECTIVES We tested the hypothesis that cyclic alterations in coronary artery blood flow that occurred after coronary angioplasty could be attenuated or abolished by a monoclonal antibody to the platelet surface membrane GP IIb/IIIa receptor. BACKGROUND Coronary artery cyclic flow variations may occur after coronary angioplasty in experimental animal models and humans. In animal models of coronary thrombosis, cyclic alterations in flow often have preceded thrombotic occlusion or reocclusion. Several agents that inhibit platelet function have been shown to attenuate or eliminate cyclic flow variations in these models. METHODS We monitored coronary artery flow in 27 patients for 30 min after coronary angioplasty, using 0.018-in. (0.046 cm) coronary guide wires with pulsed wave Doppler ultrasound transducers on the distal tips. Clinical data were collected and quantitative analyses performed on coronary arteriograms made before and after the angioplasty procedures. We compared findings in patients with and without cyclic flow variations detected. RESULTS There were 20 men and 7 women. Mean age was 58 years, and 63% had unstable angina. They received standard doses of nitrates, aspirin, heparin, calcium channel antagonists and other medications clinically indicated. Nevertheless, we detected cyclic flow variations in five patients (19%). Four of these patients had stable flow restored with intravenous injection of 0.25 mg/kg normal body weight of monoclonal antibody c7E3 Fab to the platelet GP IIb/IIIa receptor. In one patient, stable flow was restored by repeat dilation when an immediate angiogram revealed renarrowing. Patients developing cyclic alterations in flow had longer lesions (18.7 +/- 7.5 mm vs. 13.1 +/- 5.7 mm, p < 0.05) that had responded less well to angioplasty (stenosis postangioplasty 47 +/- 13% vs. 33 +/- 15%, p < 0.05). CONCLUSIONS Cyclic alterations in coronary artery blood flow may occur in some patients after coronary angioplasty, despite the use of standard antiplatelet, antithrombotic and antivasospastic medications. We found that they could be eliminated by this monoclonal antibody that blocks the final common event of platelet aggregation.

Thiazolidinediones: a 2010 perspective.

A large number of cardiology clinical trials have mortality as an endpoint unless adequate surrogate endpoints are available. Although there are nine classes of agents used in the treatment of diabetes mellitus, none have shown a mortality benefit in clinical trials. The United Kingdom Prospective Diabetic Study was the first to suggest that metformin given for diabetes mellitus had a trend toward lowering mortality. The accidental discovery of peroxisome proliferator-activated receptors (PPARs) led to the introduction of the thiazolidinediones (TZD), a PPAR agent with a suggestion of a promise for the future. As the incidence of cardiovascular complications related to diabetes mellitus increases, there is a sense of urgency to produce antidiabetic medications that achieve not only nontoxic glycemic control but also improved cardiovascular outcomes. The goal of this review is to aid the clinician to appropriately assess the benefits and risks of TZD use when prescribing for patients.

Prognostic Impact of the Presence and Absence of Angina on Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Stable Coronary Artery Disease: Results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) Trial

OBJECTIVES The purpose of this analysis was to assess in patients with type 2 diabetes and stable coronary artery disease (CAD) whether the risk of all-cause mortality and cardiovascular events varied according to the presence or absence of angina and angina equivalent symptoms. BACKGROUND Data on the prognostic value of symptoms in these patients are limited. METHODS Post-hoc analysis was performed in 2,364 patients with type 2 diabetes and documented CAD enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of death and composite of death, myocardial infarction, and stroke during a 5-year follow-up according to cardiac symptoms at baseline. RESULTS There were 1,434 patients with angina (A), 506 with angina equivalents (E), and 424 with neither of these (N). The cumulative death rates (total 316) were 12% in A, 14% in E, and 10% in N (p = 0.3), and cardiovascular composite rates (total 548) were 24% in A, 24% in E, and 21% in N (p = 0.5). Compared with N, the hazard ratios adjusted for confounders were not different for death in A (1.11; 99% CI: 0.81 to 1.53) and E (1.17; 99% CI: 0.81 to 1.68) or for cardiovascular events in A (1.17; 99% CI: 0.92 to 1.50) and E (1.11; 99% CI: 0.84 to 1.48). CONCLUSIONS Whatever their symptom status, patients with type 2 diabetes and stable CAD were at similar risk of cardiovascular events and death. These findings suggest that these patients may be similarly managed in terms of risk stratification and preventive therapies. (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305).

Asymmetric dimethylarginine and coronary artery calcium scores are increased in patients infected with human immunodeficiency virus.

OBJECTIVE Patients infected with human immunodeficiency virus (HIV) have an increased risk for cardiovascular events and mortality. Elevated concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are associated with increased subclinical atherosclerosis and cardiovascular events. The objective of this study was to determine whether plasma ADMA levels are increased in patients infected with HIV and whether this is associated with cardiovascular risk factors, inflammatory/thrombotic biomarkers, and elevated coronary artery calcium scores (CACS). METHODS HIV-infected patients and control patients were recruited in a case-control study. Medical history and laboratory measurements including plasma ADMA and biomarkers for inflammation and thrombosis such as C-reactive protein (CRP), fibrinogen, and homocysteine were obtained in both cohorts. Using multidetector computed tomography, CACS were measured in Agatston Units (AU). Bivariate differences between HIV-infected and control patients were analyzed. RESULTS HIV-infected patients (n=37, male=27, age=45 years) had significantly higher concentrations of ADMA (0.40±0.10 μmol/l) compared to a similarly matched cohort of non-HIV-infected patients (n=43, male=27, age=45 years), (0.35±0.07 μmol/l, p=0.03). There were no significant differences in CRP, homocysteine, and fibrinogen between the two cohorts. However, HIV-infected patients had a higher CACS distribution compared to control patients [0.0 (8.5) vs. 0.0 (0.0) AU, p=0.01]. In a multivariable regression analysis HIV-infected patients with a relative CACS of 75-90% for age and gender had the highest ADMA concentrations (0.48±0.09 μmol/l, p=0.04) among all CACS subgroups. CONCLUSION HIV-infected patients have significantly higher ADMA concentrations compared to control patients. In addition, increased CACS was associated with elevated ADMA concentrations. Thus, increased ADMA levels appear to be associated with the presence of subclinical atherosclerosis in HIV-infected patients.

Coronary artery bypass grafting and percutaneous coronary intervention in patients with end-stage renal disease

OBJECTIVES To determine the relative risks of long-term mortality between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) among patients with end-stage renal disease (ESRD). METHODS We identified 1015 patients with ESRD who underwent coronary revascularization between 1996 and 2008 within Kaiser Permanente Northern California. We obtained clinical variables from health plan databases, state death certificates and social security administration files. Our primary and secondary outcomes, respectively, were all-cause mortality and repeat revascularization. Our primary predictor was CABG compared with PCI. We used a Cox proportional hazards model for multivariable analyses. RESULTS The mean age of CABG and PCI patients was similar (64.7 ± 10.6 and 63.4 ± 9.3, respectively, P = 0.06). The CABG group had a higher proportion of diabetics (P = 0.045), and higher nitrate use (P = 0.01). Adjusted for age, gender, race, year of index revascularization, number of vessels intervened, duration of dialysis and baseline comorbidities, patients referred for CABG during the first year had a hazard ratio (HR) of 1.16 [95% confidence interval (CI), 0.80-1.67] for mortality compared with PCI. During Years 1-5, the HR was 0.91 (95% CI, 0.63-1.33) with an overall HR of 0.73 (95% CI, 0.43-1.22). The sub-HR as calculated by the Fine-Gray competing risk model was 0.51 (95% CI, 0.31-0.85). CONCLUSIONS As there are no randomized clinical trials in this area, our observational study adds to the growing body of literature that suggests a significant decrease in repeat revascularization with CABG and at least equivalency in long-term mortality with CABG when compared with PCI in ESRD patients.

The Role of B-Type and Other Natriuretic Peptides in Health and Disease

Natriuretic peptide (NP) physiology is a complex field. NPs also are known to be highly phylogenetically preserved. NPs can be thought of as counterregulatory hormones antagonizing the effects of the renin-angiotensin-aldosterone and sympathetic systems. These peptides are primarily responsible for maintaining salt and water homeostasis, but they also have vasodilatory properties. It was originally thought that B-type NP (BNP) and N-terminal-pro-BNP are secreted in a 1:1 ratio. However, recent data has shed further light into this area. Commercial assays for NPs will need to keep up with these changes. Currently, BNP levels within Kaiser Permanente are obtained by multiple providers in a variety of clinical scenarios in order to help them manage their patients. Therefore, a basic understanding of the physiology of NPs and the methodology of assays are needed to appropriately interpret an NP test result within the corresponding clinical scenario.

Temporal Trends in Mortality after Coronary Artery Revascularization in Patients with End-Stage Renal Disease

BACKGROUND Recent studies that have assessed the comparative effectiveness between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with end-stage renal disease (ESRD) that have included analyses of temporal trends in mortality have noted mixed results. METHODS We conducted an observational longitudinal cohort study of all adults with ESRD undergoing CABG or PCI within Kaiser Permanente Northern California. The primary predictor, index period of revascularization, was categorized into 3 periods: 1996-1999 (reference), 2000-2003, and 2004-2008, with the primary outcome being 3-year all-cause mortality. A multivariable Cox regression model with the assumption of independent censoring was used to determine the adjusted relative risk of the primary predictor. RESULTS Among 1015 ESRD patients, 3-year mortality showed no significant change in the 2000-2003 period but was lower during the 2004-2008 period with an adjusted hazard ratio of 0.66 (95% confidence interval: 0.49-0.88; trend test p = 0.01). No change in 30-day mortality was noted. Further adjustment for receipt of medications at baseline and after revascularization did not materially affect risk estimates. No significant interactions were observed between the type of revascularization (CABG or PCI) and the period of the index revascularization. CONCLUSIONS Among a high-risk cohort of patients with ESRD and coronary artery disease within Kaiser Permanente Northern California who were referred for coronary revascularization by either CABG or PCI, the relative risk of mortality in the 2004-2008 period decreased by 34% compared with the 1996-1999 period, with the benefit primarily in the decrease in late mortality.

Presentation in Patients With Angiographically Documented Coronary Artery Disease and Type II Diabetes Mellitus (from the BARI 2D Clinical Trial)

Clinically stable patients with type 2 diabetes mellitus and coronary artery disease are not often thought to present with the symptom of typical angina. The aims of this study were to enumerate the proportion of patients presenting with typical angina or other cardiac symptoms and to elucidate what important clinical variables are associated with the presence of typical angina in patients with type 2 diabetes mellitus and angiographically documented coronary artery disease. Symptoms of angina, anginal equivalents, or an absence of symptoms were obtained using baseline data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial (n = 2,319). A bivariate analysis stratified by the presence or absence of previous revascularization and logistic regression modeling with a stepwise covariate selection was used. Eighty-two percent of patients had symptoms, while 18% presented asymptomatically. This was further divided approximately into typical angina (1/5), anginal equivalents (1/5), combination (2/5), and asymptomatic (1/5). A history of previous revascularization was a determinant of the type of symptom presentation with regard to the variables gender, age, current insulin use, myocardial jeopardy index score, and use of β blockers. In the multivariate logistic regression analysis, of the available candidate variables, only a history of β-blocker use (odds ratio 1.53, 95% confidence interval 1.24 to 1.94, p <0.0001) and previous percutaneous coronary intervention (odds ratio 1.55, 95% confidence interval 1.24 to 1.94, p <0.0001) had higher odds of an association with typical angina. In conclusion, a large proportion of patients with type 2 diabetes mellitus and coronary artery disease indeed have symptoms. Future studies of long-term outcomes associated with these symptoms are needed.

Association of Age to Mortality and Repeat Revascularization in End-Stage Renal Disease Patients: Implications for Clinicians and Future Health Policies

BACKGROUND The clinical effects of age occur over an age continuum, yet age as a primary predictor is often analyzed using arbitrary age cut-points. OBJECTIVE To assess whether transformation of a continuous variable such as age using a spline function can uncover nonlinear associations between age and cardiovascular outcomes. DESIGN Observational retrospective cohort study in 1015 Kaiser Permanente Northern California patients with end-stage renal disease after index coronary revascularization. Age, the primary predictor, was modeled by 5 different techniques: 1) dichotomized at 65 years or older; 2) at 80 years or older (as a sensitivity analysis); 3) categorized as younger than 55 years (reference), 55 to 64, 65 to 74, and 75 years or older; 4) linear (every 5 years) variable; and 5) nonlinear by transformation into a cubic spline. Age categories were changed in a sensitivity analysis. MAIN OUTCOME MEASURES Primary and secondary outcomes were all-cause mortality and repeat revascularization, respectively. RESULTS Graphical assessment demonstrated that age dichotomized at either 65 years and older or 80 years and older led to loss of information. Categorized age underestimated or overestimated risk at the extremes of age. A sensitivity analysis demonstrated that an arbitrary change in the age category led to a different conclusion. Age modeled linearly adequately represented mortality risk but was suboptimal with repeat revascularization. Only the cubic spline demonstrated the nonlinear association between age and repeat revascularization. CONCLUSION Employing the continuous variable age as a case study, we have demonstrated that the use of flexible transformations, such as spline functions, can unearth clinically meaningful associations that would not have been possible otherwise. Future research should determine whether incorporation of these methods can improve decision making at a population level.

Multimorbidity is strongly associated with long-term but not short-term mortality after cardiac valve replacement

BACKGROUND The presence of multimorbidity is known to be related to adverse clinical outcomes. However, its association with mortality in patients undergoing cardiac valve replacement is not known. METHODS Multimorbidity (as a continuous variable) was characterized in adults receiving cardiac valve replacement surgery between 2008 and 2012 within Kaiser Permanente Northern California based on information from health plan electronic health records. Our primary outcome was 3-year all-cause mortality after surgery. We used Cox proportional hazards regression to evaluate the independent association of each additional comorbidity with mortality. RESULTS Among 3686 eligible patients, mean age was 67.9±13.5years and median comorbidity burden was 3 (IQR: 2). The presence of most individual comorbidities except hypertension and hyperlipidemia did not occur in isolation. The unadjusted annual incidence (per 100 person-years) of death increased with higher comorbidity burden: ≤1: 4.61 (95% CI: 3.29-6.45), 2-3: 13.7 (95% CI: 11.9-15.8), 4-5: 23.6 (95% CI: 20.6-26.9), and ≥6: 43.4(95% CI: 34.6-54.4). Advancing age, diabetes mellitus, cerebrovascular accident, heart failure, lung disease, urgent status and use of aldosterone-receptor antagonists were independently associated with an increased risk of mortality. In multivariable analyses, each additional comorbidity was significantly associated with an increased risk of long-term (adjusted hazard ratio (HR) 1.30, 95% CI: 1.22-1.39) but not short-term mortality (HR 0.92, 95% CI: 0.80-1.07). CONCLUSIONS Our study demonstrated that multimorbidity in patients undergoing cardiac valve replacement is significantly associated with long-term but not short-term mortality.