Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

BACKGROUND: The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published. METHODS: We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1,000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes. CONCLUSIONS: In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors.

The cardiovascular in-training examination: development, implementation, results, and future directions.

BACKGROUND: The American College of Cardiology (ACC), in collaboration with the National Board of Medical Examiners (NBME), developed the first standardized in-training examination (ITE) for cardiovascular disease fellows-in-training (FITs). In addition to testing knowledge, this examination uses the newly developed ACC Curricular Milestones to provide specific, competency-based feedback to program directors and FITs. The ACC ITE has been administered more than 5,000 times since 2011. OBJECTIVES: This analysis sought to report the initial experience with the ITE, including feasibility and reliability of test development and implementation, as well as the ability of this process to provide useful feedback in key content areas. METHODS: The annual ACC ITE has been available to cardiovascular disease fellowship programs in the United States since 2011. Questions for this Web-based, secure, multiple-choice examination were developed by a group of cardiovascular disease specialists and each question was analyzed by the NBME to ensure quality. Scores were equated and standardized to allow for comparability. Trainees and program directors were provided detailed feedback, including a list of the curricular competencies tested by those questions answered incorrectly. RESULTS: The ITE was administered 5,118 times. In 2013, the examination was taken by 1,969 fellows, representing 194 training programs. Among the 3 training years, there was consistency in the examination scores. Total test scores and scores within each of the content areas increased with each FIT year (there was a statistically significant difference in each cohort's average scale score across administration years). There was also significant improvement in examination scores across the fellowship years. CONCLUSIONS: The ACC ITE is a powerful tool available to all training programs to assess medical knowledge. This examination also delivers robust and timely feedback addressing individual knowledge gaps, and thus, may serve as a basis for improving training curricula.

Training present and future cardiologists.

The future of cardiology rests in the hands and minds of cardiovascular trainees and fellowship programs. Education and training is rapidly changing, and the paradigm of "see one, do one, teach one" has now been replaced by formal assessments of competency, the incorporation of practice improvement and systems-based practice, and a focus on duty hours. To keep up with the expanding knowledge and science in cardiovascular medicine, the cardiology community needs to understand new educational initiatives and formulate pathways to teach, mentor, and educate trainees to become competent cardiovascular specialists. The author highlights some of the present and future issues facing cardiovascular training.

Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.

AIMS: There is growing need for the identification of novel non-invasive methodologies for the identification of individuals at risk for adverse cardiovascular (CV) events. We examined whether endothelial dysfunction, as detected by non-invasive peripheral arterial tonometry (EndoPAT), can predict late CV events. METHODS AND RESULTS: Reactive hyperaemia (RH) was induced following upper arm occlusion of systolic blood pressure in 270 outpatients (54 +/- 12 years, 48% female). The natural logarithmic scaled RH index (L_RHI) was calculated from the ratio between the digital pulse volume during RH and at baseline. The patients were followed for CV adverse events (AE: cardiac death, myocardial infarction, revascularization or cardiac hospitalization) during a 7-year follow-up (inter-quartile range = 4.4-8). Cox models were used to estimate the association of EndoPAT results with AE adjusted for age. During the follow-up, AE occurred in 86 patients (31%). Seven-year AE rate was 48% in patients with L_RHI < 0.4 vs. 28% in those with L_RHI >or= 0.4 (P = 0.03). Additional univariate predictors of AE were advancing age (P = 0.02) and prior coronary bypass surgery (P = 0.01). The traditional Framingham risk score was not higher in patients with AE. Multivariate analysis identified L_RHI < 0.4 as an independent predictor of AE (P = 0.03). CONCLUSION: A low RH signal detected by EndoPAT, consistent with endothelial dysfunction, was associated with higher AE rate during follow-up. L_RHI was an independent predictor of AE. Non-invasive assessment of peripheral vascular function may be useful for the identification of patients at risk for cardiac AEs.

Assessment of vascular endothelial function with peripheral arterial tonometry: information at your fingertips?

Endothelial dysfunction is an important component in the pathogenesis of atherosclerosis. The ability to assess the endothelium in a meaningful manner has been the subject of intense investigation over decades. Since the function of endothelial cells is a gauge of vascular health, assessment of vascular function is emerging as a useful tool for predicting cardiovascular risk and as a surrogate outcome measure for cardiovascular reduction intervention studies. This review highlights techniques for assessing endothelial function, focusing on a novel method of determining peripheral vascular reactivity via arterial tonometry.

Assessment of peripheral vascular endothelial function in the ambulatory setting.

Until now, peripheral vascular endothelial function testing has been performed in research laboratories under highly controlled conditions, thus limiting its clinical applicability. In this study, we evaluated endothelial function in two peripheral vascular beds before and during reactive hyperemia in an outpatient clinic setting. The brachial artery was imaged with a portable ultrasound device and changes in vessel diameter were expressed as percent flow-mediated dilation (%FMD). Pulse wave amplitude of the finger was detected by peripheral arterial tonometry (PAT) and PAT hyperemia was defined as the maximal plethysmographic recording compared to baseline. Sixty individuals (43 men) were enrolled with an average age 53 +/- 2 years (mean +/- SE). The 31 individuals with more than two cardiac risk factors (CRF) had lower FMD (7.0 +/- 1.1%) and PAT hyperemia (2.1 +/- 0.9) compared to the 29 individuals with 0-2 CRF (FMD 11.3 +/- 0.8%, PAT hyperemia 2.4 +/- 0.1; p < 0.05 for both). The 32 individuals with coronary artery disease (CAD) had lower FMD (6.8 +/- 1.1%) and PAT hyperemia (2.0 +/- 0.1) compared to the 28 individuals without CAD (FMD 11.5 +/- 0.8%, PAT hyperemia 2.4 +/- 0.1; p < 0.05 for both). Thus, peripheral vascular endothelial function testing in the ambulatory setting correlates with the extent of CAD risk and the presence or absence of CAD. In conclusion, these data suggest that peripheral vascular endothelial function testing is feasible in ambulatory patients, and this is an important next step in bringing this technology to clinical applicability.

What is the best approach for the assessment of left atrial size? Comparison of various unidimensional and two-dimensional parameters with three-dimensional echocardiographically determined left atrial volume.

BACKGROUND: Left atrial (LA) size has prognostic importance in a variety of cardiac conditions. Diameters, area, or volume derived from 2-dimensional (2D) echocardiography (2DE) are commonly used to measure LA size, but involve numerous assumptions. This study examined the accuracy of these 2DE parameters compared to 3-dimensional echocardiographic LA volume (3DV). METHODS: LA diameters, area, and volume measured from 2DE were correlated with 3DV in 118 patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, or without structural heart disease. RESULTS: Diameter (anterior-posterior, superior-inferior, and medial-lateral) and 2DE area measurements had statistically significant, but modest, correlations with 3DV, and exhibited a large degree of scatter in comparison with 3DV. The 2DE-derived volume had an excellent correlation with 3DV, but consistently underestimated LA volume. CONCLUSION: The 2DE LA volume correlates better than other parameters with 3DV, but often results in underestimation. Thus, caution should be exercised when using unidimensional and 2D measurements of LA size.

Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.

OBJECTIVES: We investigated the value of reactive hyperemia peripheral arterial tonometry (RH-PAT) as a noninvasive tool to identify individuals with coronary microvascular endothelial dysfunction. BACKGROUND: Coronary endothelial dysfunction, a systemic disorder, represents an early stage of atherosclerosis; RH-PAT is a technique to assess peripheral microvascular endothelial function. METHODS: Using RH-PAT, digital pulse volume changes during reactive hyperemia were assessed in 94 patients without obstructive coronary artery disease and either normal (n = 39) or abnormal (n = 55) coronary microvascular endothelial function; RH-PAT index, a measure of reactive hyperemia, was calculated as the ratio of the digital pulse volume during reactive hyperemia divided by that at baseline. RESULTS: Average RH-PAT index was lower in patients with coronary endothelial dysfunction compared with those with normal coronary endothelial function (1.27 +/- 0.05 vs. 1.78 +/- 0.08: p < 0.001). An RH-PAT index <1.35 was found to have a sensitivity of 80% and a specificity of 85% to identify patients with coronary endothelial dysfunction. CONCLUSIONS: Digital hyperemic response, as measured by RH-PAT, is attenuated in patients with coronary microvascular endothelial dysfunction, suggesting a role for RH-PAT as a noninvasive test to identify patients with this disorder.

Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude.

BACKGROUND: Abnormalities in pulse wave amplitude (PWA) have been described in subjects with atherosclerosis and may be a marker of future cardiac events. We evaluated the relationship between changes in PWA of the finger and peripheral endothelial function. METHODS: We performed measurements of PWA with a novel finger plethysmograph (peripheral arterial tonometry [PAT]) and compared the findings with a simultaneous noninvasive measurement of peripheral endothelial function with brachial artery ultrasound scanning (BAUS) in 89 subjects. The PAT hyperemia ratio was defined as the ratio of PWA during reactive hyperemia relative to the baseline. Flow-mediated dilation (FMD) was defined by BAUS as the ratio of the brachial artery diameter during reactive hyperemia relative to the baseline. Sixty-eight subjects underwent exercise myocardial perfusion imaging (ExMPI). RESULTS: Fifty-four men and 35 women were examined. There was a linear relationship between the PAT hyperemia ratio and FMD during the same episode of reactive hyperemia (r = 0.55, P <.0001). Subjects in the lowest FMD quartile had the lowest PAT hyperemia ratio, whereas subjects in the highest FMD quartile had the highest PAT hyperemia ratio (P <.001 for trend). Similar to BAUS, the PAT hyperemia ratio was more impaired in subjects with cardiovascular risk factors and in subjects with ExMPI studies that were indicative of coronary artery disease. CONCLUSIONS: Assessment of PWA with PAT demonstrates patterns of abnormality similar to that of BAUS assessment of FMD. PWA during reactive hyperemia is influenced by factors known to affect endothelial function, including cardiovascular risk factors and coronary artery disease. These findings support the concept that analysis of PWA with PAT during reactive hyperemia may be used to study peripheral vascular endothelial function.