Transcriptomic Biomarkers for the Accurate Diagnosis of Myocarditis Growth-Differentiation Factor-15 Is a Robust, Independent Predictor of 11-Year Mortality Risk in Community-Dwelling Older Adults: The Rancho Bernardo Study Circulation Editors’ Picks Most Read Articles on the of Biomarkers

Summary— New diagnostic tools based on gene signatures derived from the entire complement of messenger RNAs in a cell or tissue have become established in the clinical management of certain disorders, particularly cancer. The comprehensiveness of this approach contributes to its accuracy. Myocarditis is a disorder that causes a substantial proportion of patients presenting with new-onset heart failure and left ventricular dysfunction. Typically diagnosed by endomyocardial biopsy and evaluated with histological criteria called the Dallas criteria, clinical management is hampered by low sensitivity and specificity and the need for multiple cardiac biopsies. The present study suggests that the application of a transcriptomic based biomarker can substantially improve the diagnostic accuracy of heart biopsy for myocarditis. Using endomyocardial biopsy tissue obtained at the time of clinical presentation, we developed a molecular signa-ture comprising 62 genes that predicted with high accuracy the presence of myocarditis in a population of 48 patients. Importantly, this required evaluation of tissue from a single endomyocardial biopsy sample and therefore is clinically practical. The present results could provide treating physicians with important and accurate diagnostic information about individual patients and could provide tools for per-sonalized treatment or monitoring. Given emerging treatment strategies for viral and inflammatory myocarditis, accurate diagnostic tools are of increased importance. Conclusions— Together, these findings demonstrate that transcriptomic biomarkers from a single endomyocardial biopsy can improve the clinical detection of patients with inflammatory diseases of the heart. This approach advances the clinical management and treatment of cardiac disorders with highly variable outcome. 1 about how PAD differs from atherosclerosis of other vascular territories. Studies of biomarkers and future disease risk can improve our ability to detect patients at heightened risk and our understanding of disease pathogenesis and, by extension, may identify potential novel modalities for treatment. Adiponectin is secreted from adipose tissue and is known to be inversely correlated with future diabetes mellitus risk. It may also be antiatherogenic. This study is the first to examine the relationship between adiponectin and PAD as a specific vascular end point. A large population of initially healthy women aged ≥ 45 years without existing cardiovascular disease was studied. After traditional cardiovascular risk factors were taken into account, women with high-molecular-weight or total adiponectin levels in the highest tertile had a 59% (high-molecular-weight) or 63% (total) reduced risk for future symptomatic PAD (intermittent claudication or lower-extremity revascularization) compared with women with levels in the lowest tertile. Given the lack of a consistently demonstrated relationship between adiponectin and other cardiovascular end points, this strik-ing result, if confirmed, suggests a unique relationship of adiponectin in PAD development that may reflect a more prominent role of adipo-kines in peripheral atherosclerosis. adiponectin associated These prospective data support a protective role for this adipokine in atherosclerosis Summary— The goal of risk stratification for primary prevention of cardiovascular disease is to identify individuals who may be candi-dates for interventions that could improve outcomes. Current risk stratification tools remain imperfect, and biomarkers that reflect novel pathophysiological pathways could improve risk assessment as well as provide insight into potential therapeutic targets. Growth differentiation factor-15 (GDF-15) is a divergent member of the trans-forming growth factor- β cytokine superfamily that is upregulated in the myocardium after ischemic injury. Previous community-based studies have shown that higher levels of GDF-15 are associated with prevalent cardiovascular disease. The present study of older from the Rancho Bernardo Study evaluated the association of GDF-15 levels with cardiovascular outcomes and mortality and found that GDF-15 was a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality even after adjustment for traditional cardiovascular disease risk factors, renal function, and body size. In models containing all 3 markers, both GDF-15 and N-terminal pro-B-type natriuretic peptide, but not C-reactive protein, added incremental value for prediction of cardiovascular and all-cause mortality. When associations are confirmed in other cohorts and when further studies clarify the mechanism of action, GDF-15 may ultimately be a worthy target for therapeutic interventions to prevent cardiovascular and all-cause death. Conclusions— Growth differentiation factor-15 is a strong predictor of all-cause, cardiovascular, and noncardiovascular mortality in com-munity-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and C-reactive protein levels. 3 Summary— Community-level event rates are the ultimate measures of successful clinical and public health efforts to reduce major causes of mortality. Studies of acute myocardial infarction (AMI) incidence and survival after AMI ratio, 1.09; 95% confidence interval, 0.74–1.59; P interaction =0.012). Thus, in patients with stable coronary artery disease and preserved left ventricular ejection fraction, elevated levels of novel biomarkers of cardiovascular stress identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy. Conclusions— In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy. Summary— The atherogenic process has important determinants early in life. Childhood exposure to ozone may be a novel risk factor for carotid artery intima-media thickness in young adults. Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. Early life exposure to ozone has been associated with childhood lung function development. Systemic inflammation induced first in the lung may be propagated throughout the body to target other organ systems. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals to potentially reduce atherosclerotic burden and its consequences. Conclusions— Childhood exposure to O 3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals. 10 Summary— The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) phase 2 randomized, double-blind trial evaluated adeno-associated virus type 1 (AAV1)/sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2a) versus placebo in 39 patients. A deficiency in SERCA2a has been identified in cardiomyocytes from failing human hearts. AAV1/SERCA2a is a viral vector delivering the deficient SERCA2a gene by intracoronary infusion into patients with advanced heart failure. AAV1/SERCA2a in this study population demonstrated no untoward safety findings; there appeared to be fewer cardiovascular adverse events in the high-dose group compared with placebo. The study met the prospectively defined efficacy end points comprising 7 different parameters in 5 clinically relevant domains. All 3 predefined analyses were met at the individual-level, group-level (in functional and left ventricular func-tion/remodeling domains), and clinical outcomes (duration of cardiovascular hospitalizations). High-dose AAV1/SERCA2a compared with placebo also demonstrated significantly delayed and reduced frequency of adverse cardiovascular events per patient, reaching statisti-cal significance at 12 months ( P =0.003). The positive signals across 5 domains support the contention that high-dose AAV1/SERCA2a induced meaningful biological activity. Results from this small study indicate a decrease in symptoms of heart failure, augmented functional status, a decrease in natriuretic peptide levels, beneficial ventricular reverse remodeling, and a significant increase in time to and decreased frequency of adjudicated cardiovascular events in the high-dose group versus placebo. The totality of the data, limited by the small study size, strongly supports moving forward with confirmatory clinical studies of AAV1/SERCA2a for patients with severe heart failure. This CUPID trial represents a new approach to the treatment of heart failure with enzyme replacement via gene therapy. Administration of Gene Therapy in Cardiac Disease study safety and suggested benefit of adeno-associated reticulum advanced Summary— The initial diagnosis of new nonacute heart failure is as difficult as it is important, especially in settings where more advanced diagnostic tests, notably echocardiography, are not read-ily available. This diagnostic study demonstrates the importance of history taking and, in particular, physical examination in a large cohort of 721 patients suspected of having nonacute heart failure, 207 (28.7%) of whom were diagnosed with heart failure. When a primary care physician is confronted with a patient suspected of having nonacute heart failure, a diagnostic rule including age, objective evidence of prior coronary artery disease, use of a loop diuretic, displaced apex beat, basal or more pulmonary rales, irregu-larly heart The rule comparable in 2 validation datasets. additio