Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects ...both sexes is largely unknown.
We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5-2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 95% confidence interval, 0.75-086 per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 95% confidence interval, 0.049-0.512), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041).
CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.
Diagnosing myocarditis is challenged by nonspecific clinical signs and symptoms and low accuracy of endomyocardial biopsy. Cardiac magnetic resonance imaging (CMR) provides both cardiac anatomy and ...tissue characterization in this setting, but the prognostic value of this method as a primary assessment tool in patients with suspected myocarditis remains limited.
This study sought to determine cardiac event-free survival of a consecutive cohort with suspected myocarditis with regard to CMR findings.
Six hundred seventy patients with suspected myocarditis underwent CMR including late gadolinium enhancement (LGE) parameters between 2002 and 2015 and were included and followed. We performed multivariable model for major adverse cardiovascular events (MACE) and determined the continuous net reclassification improvement by LGE markers.
At a median follow-up of 4.7 years (interquartile range IQR: 2.3 to 7.3 years), 98 patients experienced a MACE. Two hundred ninety-four (44%) patients showed LGE presence, which was associated with a more than doubling risk of MACE (hazard ratio HR: 2.22; 95% confidence interval CI: 1.47 to 3.35; p < 0.001). Annualized MACE rates were 4.8% and 2.1% corresponding to LGE presence and absence, respectively (p < 0.001). In the multivariable model, LGE presence maintained significant association with MACE (HR: 1.72; 95% CI: 1.08 to 2.76; p = 0.023). The computed continuous net reclassification improvement was 0.39 (95% CI: 0.10 to 0.67) when LGE presence was added to the multivariable model for MACE. Regarding location and pattern, septal and midwall LGE showed strongest associations with MACE (HR: 2.55; 95% CI: 1.77 to 3.83 and HR: 2.39; 95% CI: 1.54 to 3.69, respectively; both p < 0.001). A patchy distribution portended to a near 3-fold increased hazard to MACE (HR: 2.93; 95% CI: 1.79 to 4.80; p < 0.001). LGE extent (per 10% increase) corresponded to a 79% increase in risk of MACE (HR: 1.79; 95% CI: 1.25 to 2.57; p = 0.002). A normal CMR study corresponded to low annual MACE and death rates of 0.8% and 0.3%, respectively.
CMR tissue characterization provides effective risk stratification in patients with suspected myocarditis.
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Purpose Radiation therapy is a critical component in the care of patients with non-small-cell lung cancer (NSCLC), yet cardiac injury after treatment is a significant concern. Therefore, we wished to ...elucidate the incidence of cardiac events and their relationship to radiation dose to the heart. Patients and Materials Study eligibility criteria included patients with stage II to III NSCLC treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013. All cardiac events were reviewed and graded per Common Terminology Criteria for Adverse Events (v4.03). The primary end point was the development of a grade ≥ 3 cardiac event. Results In all, 125 patients met eligibility criteria; median follow-up was 51 months for surviving patients. Median prescription dose was 70 Gy, 84% received concurrent chemotherapy, and 27% had pre-existing cardiac disease. Nineteen patients had a grade ≥ 3 cardiac event at a median of 11 months (interquartile range, 6 to 24 months), and 24-month cumulative incidence was 11% (95% CI, 5% to 16%). On multivariable analysis (MVA), pre-existing cardiac disease (hazard ratio HR, 2.96; 95% CI, 1.07 to 8.21; P = .04) and mean heart dose (HR, 1.07/Gy; 95% CI, 1.02 to 1.13/Gy; P = .01) were significantly associated with grade ≥ 3 cardiac events. Analyzed as time-dependent variables on MVA analysis, both disease progression (HR, 2.15; 95% CI, 1.54 to 3.00) and grade ≥ 3 cardiac events (HR, 1.76; 95% CI, 1.04 to 2.99) were associated with decreased overall survival. However, disease progression (n = 71) was more common than grade ≥ 3 cardiac events (n = 19). Conclusion The 24-month cumulative incidence of grade ≥ 3 cardiac events exceeded 10% among patients with locally advanced NSCLC treated with definitive radiation. Pre-existing cardiac disease and higher mean heart dose were significantly associated with higher cardiac event rates. Caution should be used with cardiac dose to minimize risk of radiation-associated injury. However, cardiac risks should be balanced against tumor control, given the unfavorable prognosis associated with disease progression.
Although the number of clinical applications for fluorine-18 fluorodeoxyglucose (18F-FDG) cardiac positron emission tomography (PET) has continued to grow, there remains a lack of consensus regarding ...the ideal method of suppressing normal myocardial glucose utilization for image optimization. This review describes various patient preparation protocols that have been used as well as the success rates achieved in different studies. Collectively, the available literature supports using a high-fat, no-carbohydrate diet for at least two meals with a fast of 4-12 hours prior to 18F-FDG PET imaging and suggests that isolated fasting for less than 12 hours and supplementation with food or drink just prior to imaging should be avoided. Each institution should adopt a protocol and continuously monitor its effectiveness with a goal to achieve adequate myocardial suppression in greater than 80% of patients.
Objectives This study sought to relate imaging findings on positron emission tomography (PET) to adverse cardiac events in patients referred for evaluation of known or suspected cardiac sarcoidosis. ...Background Although cardiac PET is commonly used to evaluate patients with suspected cardiac sarcoidosis, the relationship between PET findings and clinical outcomes has not been reported. Methods We studied 118 consecutive patients with no history of coronary artery disease, who were referred for PET, using 18 Ffluorodeoxyglucose (FDG) to assess for inflammation and rubidium-82 to evaluate for perfusion defects (PD), following a high-fat/low-carbohydrate diet to suppress normal myocardial glucose uptake. Blind readings of PET data categorized cardiac findings as normal, positive PD or FDG, positive PD and FDG. Images were also used to identify whether findings of extra-cardiac sarcoidosis were present. Adverse events (AE)—death or sustained ventricular tachycardia (VT)—were ascertained by electronic medical records, defibrillator interrogation, patient questionnaires, and telephone interviews. Results Among the 118 patients (age 52 ± 11 years; 57% males; mean ejection fraction: 47 ± 16%), 47 (40%) had normal and 71 (60%) had abnormal cardiac PET findings. Over a median follow-up of 1.5 years, there were 31 (26%) adverse events (27 VT and 8 deaths). Cardiac PET findings were predictive of AE, and the presence of both a PD and abnormal FDG (29% of patients) was associated with hazard ratio of 3.9 (p < 0.01) and remained significant after adjusting for left ventricular ejection fraction (LVEF) and clinical criteria. Extra-cardiac FDG uptake (26% of patients) was not associated with AE. Conclusions The presence of focal PD and FDG uptake on cardiac PET identifies patients at higher risk of death or VT. These findings offer prognostic value beyond Japanese Ministry of Health and Welfare clinical criteria, the presence of extra-cardiac sarcoidosis and LVEF.
Myocardial perfusion imaging has limited sensitivity for the detection of high-risk coronary artery disease (CAD). We tested the hypothesis that a normal coronary flow reserve (CFR) would be helpful ...for excluding the presence of high-risk CAD on angiography.
We studied 290 consecutive patients undergoing (82)Rb PET within 180 d of invasive coronary angiography. High-risk CAD on angiography was defined as 2-vessel disease (≥ 70% stenosis), including the proximal left anterior descending artery; 3-vessel disease; or left main CAD (≥ 50% stenosis). Patients with prior Q wave myocardial infarction, elevated troponin levels between studies, prior coronary artery bypass grafting, a left ventricular ejection fraction of less than 40%, or severe valvular heart disease were excluded.
Fifty-five patients (19%) had high-risk CAD on angiography. As expected, the trade-off between the sensitivity and the specificity of the CFR for identifying high-risk CAD varied substantially depending on the cutoff selected. In multivariable analysis, a binary CFR of less than or equal to 1.93 provided incremental diagnostic information for the identification of high-risk CAD beyond the model with the Duke clinical risk score (>25%), percentage of left ventricular ischemia (>10%), transient ischemic dilation index (>1.07), and change in the left ventricular ejection fraction during stress (<2) (P = 0.0009). In patients with normal or slightly to moderately abnormal results on perfusion scans (<10% of left ventricular mass) during stress (n = 136), a preserved CFR (>1.93) excluded high-risk CAD with a high sensitivity (86%) and a high negative predictive value (97%).
A normal CFR has a high negative predictive value for excluding high-risk CAD on angiography. Although an abnormal CFR increases the probability of significant obstructive CAD, it cannot reliably distinguish significant epicardial stenosis from nonobstructive, diffuse atherosclerosis or microvascular dysfunction.
Coronary flow reserve (CFR), an integrated measure of focal, diffuse, and small-vessel coronary artery disease (CAD), identifies patients at risk for cardiac death. We sought to determine the ...association between CFR, angiographic CAD, and cardiovascular outcomes.
Consecutive patients (n=329) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography were followed (median 3.1 years) for cardiovascular death and heart failure admission. The extent and severity of angiographic disease were estimated with the use of the CAD prognostic index, and CFR was measured noninvasively by positron emission tomography. A modest inverse correlation was seen between CFR and CAD prognostic index (r=-0.26; P<0.0001). After adjustment for clinical risk score, ejection fraction, global ischemia, and early revascularization, CFR and CAD prognostic index were independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95% confidence interval, 1.20-3.40; P=0.008; hazard ratio for 10-U increase in CAD prognostic index, 1.17; 95% confidence interval, 1.01-1.34; P=0.032). Subjects with low CFR experienced rates of events similar to those of subjects with high angiographic scores, and those with low CFR or high CAD prognostic index showed the highest risk of events (P=0.001). There was a significant interaction (P=0.039) between CFR and early revascularization by coronary artery bypass grafting, such that patients with low CFR who underwent coronary artery bypass grafting, but not percutaneous coronary intervention, experienced event rates comparable to those with preserved CFR, independently of revascularization.
CFR was associated with outcomes independently of angiographic CAD and modified the effect of early revascularization. Diffuse atherosclerosis and associated microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact the outcomes of revascularization.
Poor reproducibility within and across studies arising from lack of knowledge regarding the performance of extracellular RNA (exRNA) isolation methods has hindered progress in the exRNA field. A ...systematic comparison of 10 exRNA isolation methods across 5 biofluids revealed marked differences in the complexity and reproducibility of the resulting small RNA-seq profiles. The relative efficiency with which each method accessed different exRNA carrier subclasses was determined by estimating the proportions of extracellular vesicle (EV)-, ribonucleoprotein (RNP)-, and high-density lipoprotein (HDL)-specific miRNA signatures in each profile. An interactive web-based application (miRDaR) was developed to help investigators select the optimal exRNA isolation method for their studies. miRDar provides comparative statistics for all expressed miRNAs or a selected subset of miRNAs in the desired biofluid for each exRNA isolation method and returns a ranked list of exRNA isolation methods prioritized by complexity, expression level, and reproducibility. These results will improve reproducibility and stimulate further progress in exRNA biomarker development.
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•exRNA sequencing complexity and reproducibility varies across isolation methods•Deconvolution shows differential access to exRNA carriers by different methods•Performance of exRNA isolation methods vary across biofluids and RNA species•miRDaR enables customized selection of optimal exRNA isolation methods
A systematic comparison of 10 extracellular RNA isolation methods across 5 biofluids will aid researchers in selecting optimal approaches for individual studies with the overall goal of enhancing reliability and reproducibility for a rapidly growing field.
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