Alexander C. Fanaroff

Does This Patient With Chest Pain Have Acute Coronary Syndrome?: The Rational Clinical Examination Systematic Review

IMPORTANCE About 10% of patients with acute chest pain are ultimately diagnosed with acute coronary syndrome (ACS). Early, accurate estimation of the probability of ACS in these patients using the clinical examination could prevent many hospital admissions among low-risk patients and ensure that high-risk patients are promptly treated. OBJECTIVE To review systematically the accuracy of the initial history, physical examination, electrocardiogram, and risk scores incorporating these elements with the first cardiac-specific troponin. STUDY SELECTION MEDLINE and EMBASE were searched (January 1, 1995-July 31, 2015), along with reference lists from retrieved articles, to identify prospective studies of diagnostic test accuracy among patients admitted to the emergency department with symptoms suggesting ACS. DATA EXTRACTION AND SYNTHESIS We identified 2992 unique articles; 58 met inclusion criteria. MAIN OUTCOMES AND MEASURES Sensitivity, specificity, and likelihood ratio (LR) of findings for the diagnosis of ACS. The reference standard for ACS was either a final hospital diagnosis of ACS or occurrence of a cardiovascular event within 6 weeks. RESULTS The clinical findings and risk factors most suggestive of ACS were prior abnormal stress test (specificity, 96%; LR, 3.1 [95% CI, 2.0-4.7]), peripheral arterial disease (specificity, 97%; LR, 2.7 [95% CI, 1.5-4.8]), and pain radiation to both arms (specificity, 96%; LR, 2.6 [95% CI, 1.8-3.7]). The most useful electrocardiogram findings were ST-segment depression (specificity, 95%; LR, 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia (specificity, 91%; LR, 3.6 [95% CI,1.6-5.7]). Both the History, Electrocardiogram, Age, Risk Factors, Troponin (HEART) and Thrombolysis in Myocardial Infarction (TIMI) risk scores performed well in diagnosing ACS: LR, 13 (95% CI, 7.0-24) for the high-risk range of the HEART score (7-10) and LR, 6.8 (95% CI, 5.2-8.9) for the high-risk range of the TIMI score (5-7). The most useful for identifying patients less likely to have ACS were the low-risk range HEART score (0-3) (LR, 0.20 [95% CI, 0.13-0.30]), low-risk range TIMI score (0-1) (LR, 0.31 [95% CI, 0.23-0.43]), or low to intermediate risk designation by the Heart Foundation of Australia and Cardiac Society of Australia and New Zealand risk algorithm (LR, 0.24 [95% CI, 0.19-0.31]). CONCLUSIONS AND RELEVANCE Among patients with suspected ACS presenting to emergency departments, the initial history, physical examination, and electrocardiogram alone did not confirm or exclude the diagnosis of ACS. Instead, the HEART or TIMI risk scores, which incorporate the first cardiac troponin, provided more diagnostic information.

G Protein–Coupled Receptor Kinase-5 Attenuates Atherosclerosis by Regulating Receptor Tyrosine Kinases and 7-Transmembrane Receptors

Objective—G protein–coupled receptor kinase-5 (GRK5) is a widely expressed Ser/Thr kinase that regulates several atherogenic receptors and may activate or inhibit nuclear factor-&kgr;B (NF-&kgr;B). This study sought to determine whether and by what mechanisms GRK5 affects atherosclerosis. Methods and Results—Grk5−/−/Apoe−/− mice developed 50% greater aortic atherosclerosis than Apoe−/− mice and demonstrated greater proliferation of macrophages and smooth muscle cells (SMCs) in atherosclerotic lesions. In Apoe−/− mice, carotid interposition grafts from Grk5−/− mice demonstrated greater upregulation of cell adhesion molecules than grafts from wild-type mice and, subsequently, more atherosclerosis. By comparing Grk5−/− with wild-type cells, we found that GRK5 desensitized 2 key atherogenic receptor tyrosine kinases: the platelet-derived growth factor receptor-&bgr; in SMCs, by augmenting ubiquitination/degradation; and the colony-stimulating factor-1 receptor (CSF-1R) in macrophages, by reducing CSF-1-induced tyrosyl phosphorylation. GRK5 activity in monocytes also reduced migration promoted by the 7-transmembrane receptor for monocyte chemoattractant protein-1 CC chemokine receptor-2. Whereas GRK5 diminished NF-&kgr;B-dependent gene expression in SMCs and endothelial cells, it had no effect on NF-&kgr;B activity in macrophages. Conclusion—GRK5 attenuates atherosclerosis through multiple cell type-specific mechanisms, including reduction of SMC and endothelial cell NF-&kgr;B activity and desensitization of receptor-specific signaling through the monocyte CC chemokine receptor-2, macrophage CSF-1R, and the SMC platelet-derived growth factor receptor-&bgr;.

Kalirin Promotes Neointimal Hyperplasia by Activating Rac in Smooth Muscle Cells

Objective—Kalirin is a multifunctional protein that contains 2 guanine nucleotide exchange factor domains for the GTPases Rac1 and RhoA. Variants of KALRN have been associated with atherosclerosis in humans, but Kalirin’s activity has been characterized almost exclusively in the central nervous system. We therefore tested the hypothesis that Kalirin functions as a Rho-guanine nucleotide exchange factor in arterial smooth muscle cells (SMCs). Approach and Results—Kalirin-9 protein is expressed abundantly in aorta and bone marrow, as well as in cultured SMCs, endothelial cells, and macrophages. Moreover, arterial Kalirin was upregulated during early atherogenesis in apolipoprotein E-deficient mice. In cultured SMCs, signaling was affected similarly in 3 models of Kalirin loss-of-function: heterozygous Kalrn deletion, Kalirin RNAi, and treatment with the Kalirin Rho-guanine nucleotide exchange factor -1 inhibitor 1-(3-nitrophenyl)-1H-pyrrole-2,5-dione. With reduced Kalirin function, SMCs showed normal RhoA activation but diminished Rac1 activation, assessed as reduced Rac-GTP levels, p21-activated kinase autophosphorylation, and SMC migration. Kalrn–/+ SMCs proliferated 30% less rapidly than wild-type SMCs. Neointimal hyperplasia engendered by carotid endothelial denudation was ≈60% less in Kalrn–/+ and SMC-specific Kalrn–/+ mice than in control mice. Conclusion—Kalirin functions as a guanine nucleotide exchange factor for Rac1 in SMCs, and promotes SMC migration and proliferation both in vitro and in vivo.

Antithrombotic agents for secondary prevention after acute coronary syndromes: A systematic review and network meta-analysis

BACKGROUND Nine oral antithrombotic medications currently available in the United States and Europe have been studied in clinical trials for secondary prevention of cardiac events following acute coronary syndrome (ACS). Few combinations of these medications have been directly compared, and studies have used multiple different comparator regimens. METHODS We performed a systematic review and network meta-analysis of randomized controlled trials evaluating one or more available oral antithrombotic therapies in patients with ACS or prior myocardial infarction (MI). Co-primary outcomes were all-cause and cardiovascular mortality compared with imputed placebo and aspirin monotherapy. RESULTS Forty-seven studies (196,057 subjects) met inclusion criteria and were included in the systematic review. Almost all studies tested either aspirin monotherapy compared with placebo or a combination of antithrombotic agents that included aspirin. Nearly all regimens reduced all-cause and cardiovascular mortality compared with imputed placebo. However, compared with imputed aspirin monotherapy, only combination therapy with aspirin plus ticagrelor was associated with lower cardiovascular mortality (OR 0.80, 95% CI 0.68-0.93), and triple therapy with aspirin, clopidogrel, and very low dose rivaroxaban was associated with lower all-cause mortality (OR 0.67, 95% CI 0.49-0.90). Major bleeding was increased 45-95% with dual antithrombotic therapy, and 2-6-fold with triple therapy. CONCLUSION Few combinations of antithrombotic therapy were associated with a reduction in mortality compared with aspirin monotherapy, highlighting the difficulty in clinical interpretation of composite ischemic endpoints. Future studies may need to focus on limiting the number of antithrombotic therapies tested in combination to best balance ischemic event reduction and bleeding.

Patient Selection for Advanced Heart Failure Therapy Referral

Despite advances in medical therapy for chronic heart failure (HF), advanced HF carries a dismal prognosis. Options such as transplantation and durable mechanical circulatory support have greatly improved outcomes for these patients, but their introduction has introduced significant complexity to patient management. Although much of this management occurs at specialized heart transplant centers, it is the responsibility of the primary cardiologist of the patient with advanced HF to refer patients at the appropriate time and to help them navigate the difficult decisions related to the pursuit of advanced therapies. We present a unique pathway that incorporates guidelines, recent data, and expert opinion to help general cardiologists determine which patients should be referred for transplantation or durable mechanical circulatory support, and when they should be referred. Decision making on referral to the heart transplant center is also summarized.

Intensive Care Unit Utilization and Mortality Among Medicare Patients Hospitalized With Non–ST-Segment Elevation Myocardial Infarction

Importance Intensive care unit (ICU) utilization may have important implications for the care and outcomes of patients with non–ST-segment elevation myocardial infarction (NSTEMI). Objectives To examine interhospital variation in ICU utilization in the United States for older adults with hemodynamically stable NSTEMI and outcomes associated with ICU utilization among patients with low, moderate, or high mortality risk. Design, Setting, and Participants This study was a retrospective analysis of 28 018 Medicare patients 65 years or older admitted with NSTEMI to 346 hospitals participating in the Acute Coronary Treatment and Intervention Outcomes Network (ACTION)–Get With the Guidelines from April 1, 2011, through December 31, 2012. Patients with cardiogenic shock or cardiac arrest on presentation were excluded. Data analysis was performed from May 7 through October 8, 2015. Exposures Hospitals with high (>70% of patients with NSTEMI treated in an ICU during the index hospitalization), intermediate (30%-70%), or low (<30%) ICU utilization. Main Outcomes and Measures Thirty-day mortality. Results Of 28 018 patients with NSTEMI 65 years or older (median age, 77 years [interquartile range, 71-84 years]; female, 13 055 [46.6%]; nonwhite race, 3931 [14.0%]), 11 934 (42.6%) had an ICU stay. The proportion of patients with NSTEMI treated in the ICU varied across hospitals (median, 38%; interquartile range, 26%-54%), but no significant differences were found in hospital or patient characteristics among high, intermediate, or low ICU utilization hospitals. Compared with high ICU utilization hospitals, low or intermediate ICU utilization hospitals were only marginally more selective of higher-risk patients, as determined by ACTION in-hospital mortality risk score or initial troponin level. The median ACTION risk score for patients treated in the ICU at low and intermediate ICU utilization hospitals was 34 compared with 33 for patients not treated in the ICU; at high ICU utilization hospitals, the median ACTION mortality risk score was 33 for patients treated in the ICU and 34 for patients not treated in the ICU. Thirty-day mortality rates did not significantly differ based on hospital ICU utilization (high vs low: 8.7% vs 8.7%; adjusted odds ratio, 0.91; 95% CI, 0.76-1.08; intermediate vs low: 9.6% vs 8.7%; adjusted odds ratio, 1.06; 95% CI, 0.94-1.20). The association between hospital ICU utilization and mortality did not change when considered among patients with ACTION risk scores greater than 40, 30 to 40, and less than 30 (adjusted interaction P = .86). Conclusions and Relevance Utilization of the ICU for older patients with NSTEMI varied significantly among hospitals. This variability was not explained by hospital characteristics or driven by patient risk. Mortality after myocardial infarction did not significantly differ among high, intermediate, or low ICU utilization hospitals.

Peripheral Artery Disease and Transcatheter Aortic Valve Replacement Outcomes: A Report From the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Therapy Registry

Background— Peripheral artery disease (PAD) is associated with increased cardiovascular mortality, and PAD risk factors overlap with those for aortic stenosis. The prevalence and outcomes associated with PAD in a population undergoing transcatheter aortic valve replacement (TAVR) are unknown. Methods and Results— Using the Society of Thoracic Surgeons/Transcatheter Valve Therapy Registry linked to Medicare claims data, we identified patients ≥65 years old undergoing TAVR from 2011 to 2015. We calculated hazard ratios for 1-year adverse outcomes, including mortality, readmission, and bleeding, for patients with PAD compared with those without, adjusting for baseline characteristics and postprocedure medications. Analyses were performed separately by access site (transfemoral and nontransfemoral). Of 19 660 patients undergoing transfemoral TAVR, 4810 (24.5%) had PAD; 3730 (47.9%) of 7780 patients undergoing nontransfemoral TAVR had PAD. In both groups, patients with PAD were significantly more likely to have coronary and carotid artery diseases. At 1-year follow-up, patients with PAD undergoing TAVR via transfemoral access had a higher incidence of death (16.8% versus 14.4%; adjusted hazard ratio, 1.14; P=0.01), readmission (45.5% versus 42.1%; hazard ratio, 1.11; P<0.001), and bleeding (23.1% versus 19.7%; hazard ratio, 1.18; P<0.001) compared with patients without PAD. Patients with PAD undergoing TAVR via nontransfemoral access did not have significantly higher rates of 1-year mortality or readmission compared with patients without PAD. Conclusions— PAD is common among patients undergoing commercial TAVR via transfemoral and nontransfemoral access. Among patients undergoing transfemoral TAVR, PAD is associated with a higher incidence of 1-year adverse outcomes compared with absence of PAD. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01737528.Background Peripheral artery disease (PAD) is associated with increased cardiovascular mortality, and PAD risk factors overlap with those for aortic stenosis (AS). The prevalence of and outcomes associated with PAD in a population undergoing transcatheter aortic valve replacement (TAVR) is unknown.

The impact of a measurement and feedback intervention on blood pressure control in ambulatory cardiology practice

BACKGROUND Although hypertension is a modifiable cardiovascular risk factor, up to one-third of ambulatory patients have uncontrolled blood pressure (BP). We evaluated the impact of a targeted provider feedback intervention on rates of BP control. METHODS Clinic BP readings were aggregated among approximately 3,000 hypertensive patients followed up in 42 outpatient cardiology clinic practices at a large quaternary care academic medical center. Physician practices received quarterly reports on BP control rates. Provider-specific reports were benchmarked vs overall peer performance and distributed quarterly between September 2011 and September 2012. Rates of BP control were evaluated before and after the intervention. Medical record reviews were performed for a subset of patients with uncontrolled BP before (n = 300) and after (n = 300) the intervention to evaluate provider responses and interventions. RESULTS At baseline, 27.9% of clinic patients had uncontrolled BP. After one 1 of reports, the rate of uncontrolled BP remained unchanged (27.7%, P = .86). Analysis of provider performance revealed a subset of providers who consistently outperform their peers. In the sample of patients selected for medical record reviews, at baseline (n = 300) and follow-up (n = 300), cardiologists discussed BP in 80% of clinic notes for patients with uncontrolled BP. Cardiologists more frequently documented repeat measurements after the intervention (28.0% vs 35.7%, P = .04). No other changes were found in documentation of provider responses to BP. CONCLUSIONS Clinician-specific audit and feedback reports as a stand-alone intervention did not affect overall BP control rates in cardiology clinics. Future BP control interventions should consider real-time patient-specific reminders, provider incentive programs, and patient engagement interventions.

Acute Coronary Syndrome

ACS includes both unstable angina (increasing chest pain, or chest pain at rest) and myocardial infarction (heart attack). Most cases are caused by a blocked blood vessel in the heart. Because of the blockage, the heart muscle does not get enough blood or oxygen. A Rational Clinical Examination in the November 10, 2015, issue of JAMA provides more information on ACS. Patients who already have blocked blood vessels in the heart have especially high risk for ACS. Other risk factors include • High blood pressure • High cholesterol • Cigarette smoking • Diabetes • Increasing age

Risk Score to Predict Need for Intensive Care in Initially Hemodynamically Stable Adults With Non–ST‐Segment–Elevation Myocardial Infarction

Background Intensive care unit (ICU) use for initially stable patients presenting with non–ST‐segment–elevation myocardial infarction (NSTEMI) varies widely across hospitals and minimally correlates with severity of illness. We aimed to develop a bedside risk score to assist in identifying high‐risk patients with NSTEMI for ICU admission. Methods and Results Using the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry linked to Medicare data, we identified patients with NSTEMI aged ≥65 years without cardiogenic shock or cardiac arrest on presentation. Complications requiring ICU care were defined as subsequent development of cardiac arrest, shock, high‐grade atrioventricular block, respiratory failure, stroke, or death during the index hospitalization. We developed and validated a model and integer risk score (Acute Coronary Treatment and Intervention Outcomes Network (ACTION) ICU risk score) that uses variables present at hospital admission to predict requirement for ICU care. Of 29 973 patients with NSTEMI, 4282 (14%) developed a complication requiring ICU‐level care, yet 12 879 (43%) received care in an ICU. Signs or symptoms of heart failure, initial heart rate, initial systolic blood pressure, initial troponin, initial serum creatinine, prior revascularization, chronic lung disease, ST‐segment depression, and age had statistically significant associations with requirement for ICU care after adjusting for other risk factors. The ACTION ICU risk score had a C‐statistic of 0.72. It identified 11% of patients as having very high risk (>30%) of developing complications requiring ICU care and 49% as having low likelihood (<10%) of requiring an ICU. Conclusions The ACTION ICU risk score quantifies the risk of initially stable patients with NSTEMI developing a complication requiring ICU care, and could be used to more effectively allocate limited ICU resources.