Ticagrelor as an alternative in clopidogrel-associated neutropenia.

Aspirin in combination with platelet P2Y12 receptor blocker has become the mainstay antiplatelet treatment strategy for the prevention of stent thrombosis. Ticlopidine was the first widely used P2Y12 receptor blockers, but clopidogrel has mostly replaced the use of ticlopidine due to its more favorable adverse event profile on bone marrow. However, when clopidogrel induced bone marrow toxicity occurs, little is known about the efficacy and safety of alternative treatments, and thus, in these cases, medical decisions may be very difficult. We report a case of clopidogrel-induced severe neutropenia in a patient treated with coronary stent and safety of alternative treatment with ticagrelor.

Lesson of the month 1: broken heart in the intensive care unit.

Takotsubo cardiomyopathy (TCM) is an unusual form of acute cardiomyopathy showing left ventricular apical ballooning. TCM can masquerade as ST elevation myocardial infarction (STEMI). TCM usually occurs following a variety of emotional stressors, but physical stressors can also trigger the condition, as highlighted by the present case. TCM can occur after an acute medical illness; therefore, physicians should be aware of this condition as a potential cause of inotrope-resistant hypotension. In patients with hypotension and moderate-to-severe left ventricular outflow tract (LVOT) obstruction, inotropic agents should be avoided, because they can worsen the degree of obstruction. Instead, beta-blockers are preferred, because they are capable of resolving the obstruction and consequently improve the haemodynamics.

Mineralocorticoid receptor antagonism confers cardioprotection in heart failure.

The symptoms and signs constituting the congestive heart failure (CHF) syndrome have their pathophysiologic origins rooted in a salt-avid renal state mediated by effector hormones of the renin-angiotensin-aldosterone and adrenergic nervous systems. Controlled clinical trials, conducted over the past decade in patients having minimally to markedly severe symptomatic heart failure, have demonstrated the efficacy of a pharmacologic regimen that interferes with these hormones, including aldosterone receptor binding with either spironolactone or eplerenone. Potential pathophysiologic mechanisms, which have not hitherto been considered involved for the salutary responses and cardioprotection provided by these mineralocorticoid receptor antagonists, are reviewed herein. In particular, we focus on the less well-recognized impact of catecholamines and aldosterone on monovalent and divalent cation dyshomeostasis, which leads to hypokalemia, hypomagnesemia, ionized hypocalcemia with secondary hyperparathyroidism and hypozincemia. Attendant adverse cardiac consequences include a delay in myocardial repolarization with increased propensity for supraventricular and ventricular arrhythmias, and compromised antioxidant defenses with increased susceptibility to nonischemic cardiomyocyte necrosis.

Stressor states and the cation crossroads.

Neurohormonal activation involving the hypothalamic-pituitary-adrenal axis and adrenergic nervous and renin-angiotensin-aldosterone systems is integral to stressor state-mediated homeostatic responses. The levels of effector hormones, depending upon the degree of stress, orchestrate the concordant appearance of hypokalemia, ionized hypocalcemia and hypomagnesemia, hypozincemia, and hyposelenemia. Seemingly contradictory to homeostatic responses wherein the constancy of extracellular fluid would be preserved, upregulation of cognate-binding proteins promotes coordinated translocation of cations to injured tissues, where they participate in wound healing. Associated catecholamine-mediated intracellular cation shifts regulate the equilibrium between pro-oxidants and antioxidant defenses, a critical determinant of cell survival. These acute and chronic stressor-induced iterations in extracellular and intracellular cations are collectively referred to as the cation crossroads. Intracellular cation shifts, particularly excessive accumulation of Ca2+, converge on mitochondria to induce oxidative stress and raise the opening potential of their inner membrane permeability transition pores (mPTPs). The ensuing loss of cationic homeostasis and adenosine triphosphate (ATP) production, together with osmotic swelling, leads to organellar degeneration and cellular necrosis. The overall impact of iterations in extracellular and intracellular cations and their influence on cardiac redox state, cardiomyocyte survival, and myocardial structure and function are addressed herein.

Can we cause regression of coronary atherosclerosis?

With the advent of effective antiatherosclerotic therapies, especially lipid lowering agents, cardiovascular morbidity and mortality rates associated with coronary atherosclerosis can be reduced. A growing body of evidence suggests such therapies can retard the progression of coronary atherosclerosis and with aggressive treatment regimens can cause regression. Antiatherosclerotic, and especially lipid lowering therapies, have the potential to become an alternative to invasive interventions. This report examines clinical studies that have addressed the regression of human coronary atherosclerosis by medical therapy.

Macro- and micronutrients in patients with congestive heart failure, particularly African-Americans.

Not all patients with heart failure, defined as a reduced ejection fraction, will have an activation of the RAAS, salt and water retention, or the congestive heart failure (CHF) syndrome. Beyond this cardiorenal perspective, CHF is accompanied by a systemic illness that includes oxidative stress, a proinflammatory phenotype, and a wasting of soft tissues and bone. A dyshomeostasis of calcium, magnesium, zinc, selenium, and vitamin D contribute to the appearance of oxidative stress and to compromised endogenous defenses that combat it. A propensity for hypovitaminosis D, given that melanin is a natural sunscreen, and for secondary hyperparathyroidism in African-Americans make them more susceptible to these systemic manifestations of CHF-a situation which is further threatened by the calcium and magnesium wasting that accompanies the secondary aldosteronism of CHF and the use of loop diuretics.

Meta-Analysis Comparing Complete Revascularization Versus Infarct-Related Only Strategies for Patients With ST-Segment Elevation Myocardial Infarction and Multivessel Coronary Artery Disease.

Several recent randomized controlled trials (RCTs) demonstrated better outcomes with multivessel complete revascularization (CR) than with infarct-related artery-only revascularization (IRA-OR) in patients with ST-segment elevation myocardial infarction. It is unclear whether CR should be performed during the index procedure (IP) at the time of primary percutaneous coronary intervention (PCI) or as a staged procedure (SP). Therefore, we performed a pairwise meta-analysis using a random-effects model and network meta-analysis using mixed-treatment comparison models to compare the efficacies of 3 revascularization strategies (IRA-OR, CR-IP, and CR-SP). Scientific databases and websites were searched to find RCTs. Data from 9 RCTs involving 2,176 patients were included. In mixed-comparison models, CR-IP decreased the risk of major adverse cardiac events (MACEs; odds ratio [OR] 0.36, 95% CI 0.25 to 0.54), recurrent myocardial infarction (MI; OR 0.50, 95% CI 0.24 to 0.91), revascularization (OR 0.24, 95% CI 0.15 to 0.38), and cardiovascular (CV) mortality (OR 0.44, 95% CI 0.20 to 0.87). However, only the rates of MACEs, MI, and CV mortality were lower with CR-SP than with IRA-OR. Similarly, in direct-comparison meta-analysis, the risk of MI was 66% lower with CR-IP than with IRA-OR, but this advantage was not seen with CR-SP. There were no differences in all-cause mortality between the 3 revascularization strategies. In conclusion, this meta-analysis shows that in patients with ST-segment elevation myocardial infarction and multivessel coronary artery disease, CR either during primary PCI or as an SP results in lower occurrences of MACE, revascularization, and CV mortality than IRA-OR. CR performed during primary PCI also results in lower rates of recurrent MI and seems the most efficacious revascularization strategy of the 3.

Functional valvular incompetence in decompensated heart failure: noninvasive monitoring and response to medical management.

OBJECTIVE: We hypothesized that functional mitral and tricuspid valvular incompetence (MR and TR, respectively) are reversible causes of reduced cardiac output in decompensated heart failure (DF) that accompanies systolic dysfunction in ischemic or nonischemic cardiomyopathy. BACKGROUND: DF, defined as signs and symptoms of heart failure at rest, is rooted in a salt-avid state transduced by neurohormonal activation secondary to impaired renal perfusion. Functional MR and TR are reversible causes of reduced systemic blood flow. Their impact on cardiac output, thoracic fluid content, cardiac chamber dimensions, and valvular apparatus function can be monitored noninvasively, before and after optimized medical management. METHODS: Fourteen male subjects (66 +/- 8 years old) with reduced ejection fraction (24 +/- 5%) secondary to ischemic (71%) or nonischemic (29%) cardiomyopathy, who developed DF with clinical evidence of mitral (MR) and tricuspid (TR) valvular incompetence, were each assessed by bioimpedance and echocardiography before and 1 week after optimized medical management restored compensated failure. RESULTS: Pharmacologic elimination of DF was accompanied by a reduction in body weight (P < 0.01). Hemodynamic improvements included a rise in cardiac index (2.1 to 2.6 L/min/m2; P < 0.01) and a reduction in predicted pulmonary artery systolic pressure (58 to 35 mm Hg; P < 0.001), thoracic fluid content (39 to 32 kOhm; P < 0.001), and systemic vascular resistance (1633 to 1209 dynes/sec/cm5; P < 0.001). Improvements in functional MR and TR included reductions in left and right atrial areas (27 to 24 cm and 26 to 23 cm2, respectively; P < 0.001), color-flow grading of MR and TR severity (P < 0.01), mitral regurgitant volume (105 to 65 mL; P < 0.001), and effective MR orifice size (0.8 to 0.6 cm2; P < 0.01). CONCLUSIONS: In DF, functional MR and TR contribute to reduced cardiac output, increased thoracic fluid content, and systemic vascular resistance, together with enlarged atria and valvular orifice size, which can be improved by medical management. Bioimpedance and echocardiography provide for serial noninvasive assessments of hemodynamic status and valvular function in such cases.

An 81-year-old man with an abnormal right-sided heart shadow on chest radiograph.

An 81-year-old man presented with a 1-week history of dry cough. He also complained of mild dyspnea, wheezing, and low-grade fever. He denied hemoptysis, fever, rashes, or chest pain. The patient's medical history included coronary artery bypass surgery, hypertension, gastroesophageal reflux disease, and COPD. The patient was a retired welder and an ex-smoker.

Comprehensive Cardiovascular Risk Factor Control Improves Survival: The BARI 2D Trial.

BACKGROUND: It is unclear whether achieving multiple risk factor (RF) goals through protocol-guided intensive medical therapy is feasible or improves outcomes in type 2 diabetes mellitus. OBJECTIVES: This study sought to quantify the relationship between achieved RF goals in the BARI 2D (Bypass Angioplasty Investigation Revascularization 2 Diabetes) trial and cardiovascular events/survival. METHODS: We performed a nonrandomized analysis of survival/cardiovascular events and control of 6 RFs (no smoking, non-high-density lipoprotein cholesterol <130 mg/dl, triglycerides <150 mg/dl, blood pressure [systolic <130 mm Hg; diastolic <80 mm Hg], glycosylated hemoglobin <7%) in BARI 2D. Cox models with time-varying number of RFs in control were adjusted for baseline number of RFs in control, clinical characteristics, and trial randomization assignments. RESULTS: In 2,265 patients (mean age 62 years, 29% women) followed up for 5 years, the mean ± SD number of RFs in control improved from 3.5 ± 1.4 at baseline to 4.2 ± 1.3 at 5 years (p < 0.0001). The number of RFs in control during the trial was strongly related to death (global p = 0.0010) and the composite of death, myocardial infarction, and stroke (global p = 0.0035) in fully adjusted models. Participants with 0 to 2 RFs in control during follow-up had a 2-fold higher risk of death (hazard ratio: 2.0; 95% confidence interval: 1.3 to 3.3; p = 0.0031) and a 1.7-fold higher risk of the composite endpoint (hazard ratio: 1.7; 95% confidence interval: 1.2 to 2.5; p = 0.0043), compared with those with 6 RFs in control. CONCLUSIONS: Simultaneous control of multiple RFs through protocol-guided intensive medical therapy is feasible and relates to cardiovascular morbidity and mortality in patients with coronary disease and type 2 diabetes mellitus. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305).

Outcome of percutaneous coronary intervention versus coronary bypass grafting for patients with low left ventricular ejection fractions, unstable angina pectoris, and risk factors for adverse outcomes with bypass (the AWESOME Randomized Trial and Registry).

The recently concluded Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) was a randomized clinical trial of percutaneous coronary intervention versus coronary bypass graft surgery among patients with medically refractory ischemia who were at high risk for coronary bypass graft surgery because of > or =1 risk factors that included severely reduced left ventricular (LV) function, defined as LV ejection fraction <35%. This study reports the outcome of patients with LV ejection fraction <35% in the randomized clinical trial and the physician-directed and patient choice registries of the AWESOME study.

Comparative pharmacodynamic evaluation of eptifibatide and tirofiban HCl in patients undergoing percutaneous coronary intervention (the TAM1 Study).

We performed a comparative analysis of platelet aggregation inhibition achieved with the glycoprotein IIb/IIIa inhibitors eptifibatide and tirofiban HCl in patients who underwent percutaneous coronary intervention and used light transmission aggregometric assays with D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone as an anticoagulant and 20 micromol of adenosine diphosphate as an agonist. Taking into account the differences in clinical efficacy of these 2 drugs in large trials investigating percutaneous coronary intervention, we hypothesized that the variable clinical effects might be related to variability in the magnitude and consistency of platelet aggregation inhibition achieved with dosing regimens of these glycoprotein IIb/IIIa inhibitors.

Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis.

INTRODUCTION: There is conflicting evidence about the impact of gender on outcomes after coronary artery bypass grafting (CABG). METHODS: We performed a multivariate logistic regression and propensity score matched analyses in 13,115 patients (75% men) who underwent CABG between January 1, 1995 and December 31, 2009. The primary outcome was in-hospital mortality. Secondary outcomes included post-operative respiratory failure, stroke, myocardial infarction, sternal and leg wound infections, atrial fibrillation (AF), renal failure, need for postoperative intra-aortic balloon pump (IABP) support, and length of hospital stay. RESULTS: A higher proportion of women (184; 5.6%) suffered in-hospital death compared to men (264; 2.7%), p<0.0001. After propensity score matching (n=3600 total, 1800 in each group), female gender was an independent predictor of mortality after isolated CABG (odds ratio [OR]=1.84; 95% confidence interval [CI] 1.22-2.78). Women also experienced a higher incidence of postoperative complications including stroke (3.8% vs. 2.3%, OR 1.37; 95% CI 1.08-1.73) and leg wound infection (3.4% vs. 1.7%, OR 1.75; 95% CI 1.36-2.54) on multivariate regression analyses. However, these differences were not significant after propensity score matching. We also observed a lower risk of post-operative AF (21.2% vs. 22.1%, OR 0.78; 95% CI 0.70-0.86) in women that remained significant after propensity matching (O.R. 0.76; 95% C.I. 0.65-0.90). Length of hospital stay was longer in women compared with men (11.9 ± 9.0 vs. 10.4 ± 9.2 days, p<0.0001). CONCLUSIONS: Female gender is an independent predictor of increased mortality and a lower incidence of post-operative AF after isolated CABG.

Clinical outcomes of percutaneous interventions in saphenous vein grafts using drug-eluting stents compared to bare-metal stents: a comprehensive meta-analysisof all randomized clinical trials.

BACKGROUND: Clinical outcomes of percutaneous coronary intervention (PCI) in patients with saphenous vein grafts (SVGs) remain poor despite the use of drug-eluting stents (DES). There is a disparity in clinical outcomes in SVG PCI based on various registries, and randomized clinical data remain scant. We conducted a meta-analysis of all existing randomized controlled trials (RCTS) comparing bare-metal stents (BMS) and DES in SVGPCIs. HYPOTHESIS: PCI in patients with SVG disease using DES may reduce need for repeat revascularization without an excess mortality when compared to BMS. METHODS: An aggregate data meta-analysis of clinical outcomes in RCTs comparing PCI with DES vs BMS for SVGs reporting at least 12 months of follow-up was performed. A literature search between Janurary 1, 2003 and September 30, 2011 identified 4 RCTs (812 patients; DES = 416, BMS = 396). Summary odds ratio (OR) and 95% confidence interval (CI) were calculated using the random-effects model. The primary endpoint was all-cause mortality. Secondary outcomes included nonfatal myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE). These outcomes were assessed in a cumulative fashion at 30 days, 18 months, and 36 months. RESULTS: There were no intergroup differences in baseline clinical and sociodemographic characteristics. At a median follow-up of 25 months, patients in the DES and BMS group had similar rates of death (OR: 1.63, 95% CI: 0.45-5.92), MI (OR; 0.83, 95% CI: 0.27-2.60), and MACE (OR: 0.58, 95% CI: 0.25-1.32). Patients treated with DES had lower rates of repeat revascularization (OR: 0.40, 95% CI: 0.22-0.75). CONCLUSIONS: In this comprehensive meta-analysis of all RCTs comparing clinical outcomes of PCI using DES vs BMS in patients with SVG disease, use of DES was associated with a reduction in rate of repeat revascularization and no difference in rates of all-cause death and MI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21984 Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service (HSR&D) Career Development Award (CDA-09-028), and has research support from Merck and National Football League Charities (all grants to the institution and not individual). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Oxidative stress and cardiomyocyte necrosis with elevated serum troponins: pathophysiologic mechanisms.

The progressive nature of heart failure is linked to multiple factors, including an ongoing loss of cardiomyocytes and necrosis. Necrotic cardiomyocytes leave behind several footprints: the spillage of their contents leading to elevations in serum troponins; and morphologic evidence of tissue repair with scarring. The pathophysiologic origins of cardiomyocyte necrosis relates to neurohormonal activation, including the adrenergic nervous system. Catecholamine-initiated excessive intracellular Ca accumulation and mitochondria Ca overloading in particular initiate a mitochondriocentric signal-transducer-effector pathway to necrosis and which includes the induction of oxidative stress and opening of their inner membrane permeability transition pore. Hypokalemia, ionized hypocalcemia and hypomagnesemia, where consequent elevations in parathyroid hormone further account for excessive intracellular Ca accumulation, hypozincemia and hyposelenemia each compromise metalloenzyme-based antioxidant defenses. The necrotic loss of cardiomyocytes and adverse structural remodeling of myocardium is related to the central role played by a mitochondriocentric pathway initiated by neurohormonal activation.

Percutaneous intervention versus coronary bypass surgery for patients older than 70 years of age with high-risk unstable angina.

BACKGROUND: The Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) study was a multicenter Veterans Affairs randomized trial and registry that compared long-term survival of percutaneous coronary intervention with coronary artery bypass graft surgery for the treatment of patients with medically refractory myocardial ischemia and at least one additional risk factor for an adverse outcome with bypass. Both the randomized trial and the registry demonstrated comparable 3-year survival. The purpose of this study was to compare bypass and percutaneous intervention survival of AWESOME patients who were older than 70 years of age. METHODS: Over a 5-year period (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of the following five risk factors (prior heart surgery, myocardial infarction within 7 days, left ventricular ejection fraction less than 35%, age > 70 years, intraaortic balloon pump requirement to stabilize) were identified. Of these patients, 1,278 were older than 70 years of age. Eight hundred, seventy-one patients were turned down by at least one physician, 407 were acceptable to both physician and surgeon for randomization, and 236 (60%) consented to randomization. Of the 1,042 eligible patients who were not randomized, 871 had their revascularization directed by a physician who was not involved in the study. One hundred, seventy-one patients who were acceptable for randomization by both the interventional cardiologist and the cardiac surgeon refused consent. RESULTS: Bypass and percutaneous intervention survival were compared using Kaplan-Meier curves and log rank tests. Bypass and percutaneous intervention 36-month survival rates for patients older than 70 years of age were 76% and 75%, respectively, among the eligible patients. Survival was 71% and 78% among those patients who were randomized and 76% and 67% in the physician-directed subgroup. Of those patients who chose their revascularization techniques, the survivals were 79% and 85%, respectively. The survival differences are not large, and none of the global log rank tests of bypass compared with percutaneous intervention survival showed a statistically significant difference over 5 years. CONCLUSIONS: Both the randomized and registry subgroups of patients who were older than 70 years of age support the trial conclusions that either bypass or percutaneous intervention effectively relieves medically refractory ischemia among high-risk unstable angina patients whose age was greater than 70 years.