COVID-19 Vaccination-Associated Myocarditis in Adolescents.

OBJECTIVES: In this study, we aimed to characterize the clinical presentation, short-term prognosis, and myocardial tissue changes as noted on cardiovascular magnetic resonance (CMR) or cardiac MRI in pediatric patients with coronavirus disease 2019 vaccination-associated myocarditis (C-VAM). METHODS: In this retrospective multicenter study across 16 US hospitals, patients <21 years of age with a diagnosis of C-VAM were included and compared with a cohort with multisystem inflammatory syndrome in children. Younger children with C-VAM were compared with older adolescents. RESULTS: Sixty-three patients with a mean age of 15.6 years were included; 92% were male. All had received a messenger RNA vaccine and, except for one, presented after the second dose. Four patients had significant dysrhythmia; 14% had mild left ventricular dysfunction on echocardiography, which resolved on discharge; 88% met the diagnostic CMR Lake Louise criteria for myocarditis. Myocardial injury as evidenced by late gadolinium enhancement on CMR was more prevalent in comparison with multisystem inflammatory syndrome in children. None of the patients required inotropic, mechanical, or circulatory support. There were no deaths. Follow-up data obtained in 86% of patients at a mean of 35 days revealed resolution of symptoms, arrhythmias, and ventricular dysfunction. CONCLUSIONS: Clinical characteristics and early outcomes are similar between the different pediatric age groups in C-VAM. The hospital course is mild, with quick clinical recovery and excellent short-term outcomes. Myocardial injury and edema are noted on CMR. Close follow-up and further studies are needed to understand the long-term implications and mechanism of these myocardial tissue changes.

Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease.

BACKGROUND: Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. METHODS: 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4  M, 81 mcg over 3 minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140 ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR < 2.5, HMR ≥2, or ≤50% change in coronary blood flow with acetylcholine (CBFACH ). RESULTS: Seventy-two percent had endothelial-dependent epicardial dysfunction (response to ACH: % ∆ in coronary artery diameter and ∆%CBFACH ) and 92% had CMD. Among CMD patients, 65% had CFR < 2.5, 35% had HMR ≥2, and 60% had CBFACH change ≤50%. CFR modestly correlated with HMR (r = -0.38, p < .0001). Among patients with normal CFR, 26% had abnormal epicardial and 20% had abnormal microvascular endothelial dysfunction. Women had a lower CFR (p = .02), higher FFR (p = .03) compared to men. There were no differences in epicardial and microvascular function between patients with stable and unstable angina. CONCLUSION: In patients with no obstructive CAD: CMD is prevalent, abnormal CFR does not correlate with epicardial or microvascular endothelial dysfunction, women have lower CFR, higher FFR but similar endothelial function compared to men.

Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis: The MARINA Randomized, Double-Blinded, Controlled Pilot Trial.

BACKGROUND: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. METHODS: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. RESULTS: No significant differences in ΔSAQ angina frequency scores (P=0.53) or Duke Activity Status Index (P=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (P=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 (P=0.02). CONCLUSIONS: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

State of the Art: Imaging for Myocardial Viability: A Scientific Statement From the American Heart Association.

A substantial proportion of patients with acute myocardial infarction develop clinical heart failure, which remains a common and major healthcare burden. It has been shown that in patients with chronic coronary artery disease, ischemic episodes lead to a global pattern of cardiomyocyte remodeling and dedifferentiation, hallmarked by myolysis, glycogen accumulation, and alteration of structural proteins. These changes, in conjunction with an impaired global coronary reserve, may eventually become irreversible and result in ischemic cardiomyopathy. Moreover, noninvasive imaging of myocardial scar and hibernation can inform the risk of sudden cardiac death. Therefore, it would be intuitive that imaging of myocardial viability is an essential tool for the proper use of invasive treatment strategies and patient prognostication. However, this notion has been challenged by large-scale clinical trials demonstrating that, in the modern era of improved guideline-directed medical therapies, imaging of myocardial viability failed to deliver effective guidance of coronary bypass surgery to a reduction of adverse cardiac outcomes. In addition, current available imaging technologies in this regard are numerous, and they target diverse surrogates of structural or tissue substrates of myocardial viability. In this document, we examine these issues in the current clinical context, collect current evidence of imaging technology by modality, and inform future directions.

New-Onset Uncontrolled Hypertension and Renal Failure in a Young Woman.

This report describes the case of a previously healthy 30-year-old woman who presented with uncontrolled hypertension and renal failure. This case emphasizes the importance of considering renal artery disease. The differential diagnosis for renal artery stenosis is discussed, and the diagnosis and management of Takayasu's arteritis in this patient are highlighted. (Level of Difficulty: Beginner.).

The influence of multidirectional shear stress on plaque progression and composition changes in human coronary arteries.

AIMS: Local wall shear stress (WSS) plays an important role in the onset of atherosclerotic plaque formation; however, it does not fully explain plaque progression and destabilisation. We aimed to investigate for the first time the influence of multidirectional WSS features on plaque progression and plaque composition changes in human coronary arteries. METHODS AND RESULTS: Coronary artery imaging using biplane angiography and virtual histology intravascular ultrasound (VH-IVUS) was performed in twenty patients with coronary artery disease at baseline and after six-month follow-up. Three-dimensional surfaces of the coronary arteries were generated using the coronary imaging and, together with patient-specific flow measurements, different WSS features (multidirectional and conventional time-averaged WSS [TAWSS]) were determined at baseline using computational fluid dynamics (CFD). The changes in plaque component area over the six-month period were determined from VH-IVUS. Changes in plaque composition rather than plaque size were primarily associated with the (multidirectional) WSS at baseline. Interestingly, regions simultaneously exposed to low TAWSS and low multidirectional WSS showed the greatest plaque progression (p<0.001). CONCLUSIONS: In this patient study, several multidirectional WSS features were found to contribute significantly to coronary plaque progression and changes in plaque composition.

Drug-Eluting Balloons Versus Everolimus-Eluting Stents for In-Stent Restenosis: A Meta-Analysis of Randomized Trials.

OBJECTIVES: Individual randomized trials comparing drug-eluting balloons (DEB) versus everolimus-eluting stents (EES) for in-stent restenosis (ISR) were underpowered for clinical end-points. The objective of this study was to compare the clinical outcomes of DEB versus EES for any ISR. MATERIALS & METHODS: Electronic databases were searched for randomized trials which compared DEB versus EES for any ISR (i.e., drug eluting or bare metal stents). Summary estimate risk ratios (RRs) were constructed using a DerSimonian and Laird random effects model. RESULTS: Five trials with 962 patients were included. In-segment minimum lumen diameter (MLD) was lower with DEB (standardized mean difference -0.24, 95% confidence interval [CI] -0.46 - -0.01) on angiographic follow-up at a mean of 8.6 months. There was no statistically significant difference in the risk of target vessel revascularization (TVR) at 1 year (RR 1.15, 95% CI 0.60-2.19), but TVR was increased with DEB at 3 years (RR 1.87, 95% CI 1.15-3.03). The risk of target lesion revascularization (TLR) was statistically increased with DEB (RR 2.17, 95% CI 1.13-4.19) at a mean of 24.4 months. There was no difference in the risk of MI, stent thrombosis, cardiac mortality and all-cause mortality between both groups. CONCLUSION: In patients with any type of ISR, DEB was associated a similar risk of TVR at 1-year, but increased risk of TVR and TLR at longer follow-up, as compared with EES. The quality of evidence was moderate, suggesting the need for further randomized trials with longer follow-up to confirm the role of DEB in the management of ISR.

Low Coronary Wall Shear Stress Is Associated With Severe Endothelial Dysfunction in Patients With Nonobstructive Coronary Artery Disease.

OBJECTIVES: This study investigated the relationship between low wall shear stress (WSS) and severe endothelial dysfunction (EDFx). BACKGROUND: Local hemodynamic forces such as WSS play an important role in atherogenesis through their effect on endothelial cells. The study hypothesized that low WSS independently predicts severe EDFx in patients with coronary artery disease (CAD). METHODS: Forty-four patients with CAD underwent coronary angiography, fractional flow reserve, and endothelial function testing. Segments with >10% vasoconstriction after acetylcholine (Ach) infusion were defined as having severe EDFx. WSS, calculated using 3-dimensional angiography, velocity measurements, and computational fluid dynamics, was defined as low (<1 Pa), intermediate (1 to 2.5 Pa), or high (>2.5 Pa). RESULTS: Median age was 52 years, 73% were women. Mean fractional flow reserve was 0.94 ± 0.06. In 4,510 coronary segments, median WSS was 3.67 Pa. A total of 24% had severe EDFx. A higher proportion of segments with low WSS had severe EDFx (71%) compared with intermediate WSS (22%) or high WSS (23%) (p < 0.001). Segments with low WSS demonstrated greater vasoconstriction in response to Ach than did intermediate or high WSS segments (-10.7% vs. -2.5% vs. +1.3%, respectively; p < 0.001). In a multivariable logistic regression analysis, female sex (odds ratio [OR]: 2.44; p = 0.04), diabetes (OR: 5.01; p = 0.007), and low WSS (OR: 9.14; p < 0.001) were independent predictors of severe EDFx. CONCLUSIONS: In patients with nonobstructive CAD, segments with low WSS demonstrated more vasoconstriction in response to Ach than did intermediate or high WSS segments. Low WSS was independently associated with severe EDFx.

Prognostic Significance of Nonobstructive Left Main Coronary Artery Disease in Women Versus Men: Long-Term Outcomes From the CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) Registry.

BACKGROUND: Patients with obstructive (≥50% stenosis) left main (LM) coronary artery disease (CAD) are at high risk for adverse events; prior studies have also documented worse outcomes among women than men with severe multivessel/LM CAD. However, the prognostic significance of nonobstructive (1%-49% stenosis) LM CAD, including sex-specific differences, has not been previously examined. METHODS AND RESULTS: In the long-term CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) registry, patients underwent elective coronary computed tomographic angiography for suspected CAD and were followed for 5 years. After excluding those with obstructive LM CAD, 5166 patients were categorized as having normal LM or nonobstructive LM (18% of cohort). Cumulative 5-year incidence of death, myocardial infarction, or revascularization was higher among patients with nonobstructive LM than normal LM in both women and men: women (34.3% versus 15.4%; P<0.0001); men (24.6% versus 18.2%; P<0.0001). A significant interaction existed between sex and LM status for the composite outcome (P=0.001). In multivariable Cox regression, the presence of nonobstructive LM plaque increased the risk for the composite outcome in women (adjusted hazard ratio, 1.48; P=0.005) but not in men (adjusted hazard ratio, 0.98, P=0.806). In subgroup analysis, women with nonobstructive LM CAD had a nearly 80% higher risk for events than men with nonobstructive LM CAD (adjusted hazard ratio, 1.78; P=0.017); sex-specific interactions were not observed across other patterns (eg, location or extent) of nonobstructive plaque. CONCLUSION: Nonobstructive LM CAD was frequently detected on coronary computed tomographic angiography and strongly associated with adverse events among women. Recognizing the sex-specific prognostic significance of nonobstructive LM plaque may augment risk stratification efforts.

Discordance Between Fractional Flow Reserve and Coronary Flow Reserve: Insights From Intracoronary Imaging and Physiological Assessment.

OBJECTIVES: The aim of this study was to investigate the epicardial and microvascular substrates associated with discordances between fractional flow reserve (FFR) and coronary flow reserve (CFR) values. BACKGROUND: Discordances between FFR and CFR remain poorly characterized. METHODS: FFR, hyperemic stenosis resistance (HSR), and intravascular ultrasound were performed as indexes of epicardial function and CFR and hyperemic microvascular resistance (HMR) as measures of microvascular function in 94 patients with moderate coronary stenosis. Maximal plaque burden (PBmax), HSR, and HMR were calculated in 4 quadrants based on values of FFR ≤0.80 and CFR ≤2.0 as follows: concordant normal (preserved FFR and CFR), concordant abnormal (low FFR and CFR), discordant low FFR and preserved CFR, and discordant preserved FFR and low CFR. RESULTS: Sixty-four patients (68%) had concordant FFR and CFR findings, and 30 patients (32%) had discordant FFR and CFR. Compared with patients with preserved FFR and CFR, those with low FFR and CFR had higher PBmax (p = 0.003), higher HSR (p < 0.001), and similar HMR. Among patients with preserved FFR, those with reduced CFR had similar PBmax and HSR but a trend toward higher HMR (p = 0.058) compared with patients with preserved CFR. Among patients with reduced FFR, those with preserved CFR had lower PBmax (p = 0.004), a trend toward lower HSR (p = 0.065), and lower HMR (p = 0.03) compared with patients with reduced CFR. Furthermore, compared with patients with preserved FFR and low CFR, those with low FFR and preserved CFR had higher HSR (p = 0.022) but lower HMR (p = 0.003). CONCLUSIONS: In patients with moderate coronary stenosis, preserved FFR and low CFR is associated with increased microvascular resistance, while low FFR and preserved CFR has modest epicardial stenosis and preserved microvascular function.

Percutaneous coronary intervention or coronary artery bypass grafting for unprotected left main coronary artery disease.

BACKGROUND: Recent trials comparing PCI with CABG for unprotected left main disease yielded discrepant evidence. OBJECTIVES: To perform an updated meta-analysis of randomized trials comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with unprotected left main coronary artery disease. METHODS: Randomized trials comparing PCI versus CABG for patients with unprotected left main coronary artery disease were included. Summary estimates risk ratios (RRs) were performed with a DerSimonian and Laird model at short-term, intermediate and long-term follow-up periods (i.e., 30-days, 1-year, and >1-year). Outcomes evaluated were major adverse cardiac and cerebrovascular events (MACCE), all-cause mortality, myocardial infarction, stroke, revascularization and stent thrombosis or symptomatic graft occlusion. RESULTS: Six trials with 4,700 patients and a mean SYNTAX score of 23 were included. At short-term follow-up, the risk of MACCE was lower with PCI (RR 0.55, 95% confidence interval [CI] 0.39-0.76) driven by the lower risk of myocardial infarction (RR 0.67, 95% CI 0.46-0.99), and stroke (RR 0.38, 95% CI 0.16-0.90). The risk of MACCE was similar at the intermediate follow-up (RR 1.21, 95% CI 0.97-1.51). At long-term follow-up, PCI was associated with a higher risk of MACCE (RR 1.19, 95% CI 1.01-1.41), due to a higher risk of revascularization (RR 1.62, 95% CI 1.34-1.94), while the risk of all-cause mortality, myocardial infarction, and stroke were similar. CONCLUSIONS: In patients with unprotected left main coronary disease and low to intermediate SYNTAX score, PCI might be an acceptable alternative to CABG. © 2017 Wiley Periodicals, Inc.

Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study.

Inflammation is an increasingly recognized hallmark of pulmonary hypertension (PH). Statins have been shown to attenuate key pathologic mechanisms via pleiotropic effects in animal models. However, clinical benefit of statins in patients with PH is unknown and their effect on mortality has not been studied. We performed a retrospective analysis of patients between January 2002 to January 2012, with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%), defined by transthoracic echocardiograms. Patients were divided into two groups based on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed. Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality and hospitalization. 2363 patients (age 71 ± 16; 31% male) were included; 140 (6%) were on statin therapy. Overall 1-year mortality was 34%. Following propensity score matching, 138 patients were included in the statin group and 624 patients in the no-statin group; all-cause mortality was significantly lower in the statin group compared with the no-statin group [15.2 vs. 33.8%, HR 0.42 (95% CI 0.27, 0.66), p < 0.001], but hospitalization was comparable between two groups. After stratifying patients based on COPD status, patients with COPD showed a marginally significant survival benefit from statins [HR 0.53 (95% CI 0.26, 1.10), p = 0.09]; and statins significantly reduced 1-year all-cause mortality in patients without COPD [HR 0.36 (95% CI 0.19, 0.67), p = 0.001]. We found no significant difference in the effect of statins on patients with COPD compared to those without (p = 0.16). Statin therapy is associated with reduced mortality risk in patients with severe PH and preserved left ventricular function. This beneficial effect was not found to be dependent on COPD status. These novel findings should be confirmed in large randomized trials.

Oscillatory wall shear stress is a dominant flow characteristic affecting lesion progression patterns and plaque vulnerability in patients with coronary artery disease.

Although experimental studies suggest that low and oscillatory wall shear stress (WSS) promotes plaque transformation to a more vulnerable phenotype, this relationship has not been examined in human atherosclerosis progression. Thus, the aim of this investigation was to examine the association between oscillatory WSS, in combination with WSS magnitude, and coronary atherosclerosis progression. We hypothesized that regions of low and oscillatory WSS will demonstrate progression towards more vulnerable lesions, while regions exposed to low and non-oscillatory WSS will exhibit progression towards more stable lesions. Patients (n = 20) with non-flow-limiting coronary artery disease (CAD) underwent baseline and six-month follow-up angiography, Doppler velocity and radiofrequency intravascular ultrasound (VH-IVUS) acquisition. Computational fluid dynamics models were constructed to compute time-averaged WSS magnitude and oscillatory WSS. Changes in VH-IVUS-defined total plaque and constituent areas were quantified in focal regions (i.e. sectors; n = 14 235) and compared across haemodynamic categories. Compared with sectors exposed to low WSS magnitude, high WSS sectors demonstrated regression of total plaque area (p < 0.001) and fibrous tissue (p < 0.001), and similar progression of necrotic core. Sectors subjected to low and oscillatory WSS exhibited total plaque area regression, while low and non-oscillatory WSS sectors demonstrated total plaque progression (p < 0.001). Furthermore, compared with low and non-oscillatory WSS areas, sectors exposed to low and oscillatory WSS demonstrated regression of fibrous (p < 0.001) and fibrofatty (p < 0.001) tissue and similar progression of necrotic core (p = 0.82) and dense calcium (p = 0.40). Herein, we demonstrate that, in patients with non-obstructive CAD, sectors subjected to low and oscillatory WSS demonstrated regression of total plaque, fibrous and fibrofatty tissue, and progression of necrotic core and dense calcium, which suggest a transformation to a more vulnerable phenotype.

High wall shear stress and high-risk plaque: an emerging concept.

In recent years, there has been a significant effort to identify high-risk plaques in vivo prior to acute events. While number of imaging modalities have been developed to identify morphologic characteristics of high-risk plaques, prospective natural-history observational studies suggest that vulnerability is not solely dependent on plaque morphology and likely involves additional contributing mechanisms. High wall shear stress (WSS) has recently been proposed as one possible causative factor, promoting the development of high-risk plaques. High WSS has been shown to induce specific changes in endothelial cell behavior, exacerbating inflammation and stimulating progression of the atherosclerotic lipid core. In line with experimental and autopsy studies, several human studies have shown associations between high WSS and known morphological features of high-risk plaques. However, despite increasing evidence, there is still no longitudinal data linking high WSS to clinical events. As the interplay between atherosclerotic plaque, artery, and WSS is highly dynamic, large natural history studies of atherosclerosis that include WSS measurements are now warranted. This review will summarize the available clinical evidence on high WSS as a possible etiological mechanism underlying high-risk plaque development.