Prevalence and Predictors of Obstructive Coronary Artery Disease in Nonlow-risk Acute Chest Pain Patients Who Rule Out for Myocardial Infarction in the High-sensitivity Troponin Era.

OBJECTIVES: The best management approach for chest pain patients who rule out for myocardial infarction (MI) in the high-sensitivity troponin (hsTn) era remains elusive. Patients, especially those with nonlow clinical risk scores, are often referred for inpatient ischemic testing to uncover obstructive coronary artery disease (CAD). Whether the prevalence of obstructive CAD in this cohort is high enough to justify routine testing is not known. METHODS: We conducted a retrospective cohort analysis of 1517 emergency department chest pain patients who ruled out for MI by virtue of a stable high-sensitivity troponin T (hsTnT) levels (defined as <5 ng/L intermeasurements increase) and were admitted for inpatient testing. RESULTS: Abnormal ischemia evaluation (including 5.9% with evidence of fixed wall motion or perfusion defects) was 11.9%. Of those undergoing invasive angiography (n = 292), significant coronary stenoses (≥70% or unstable lesions) and multivessel CAD occurred in 16.8% and 5.5%, respectively. In a multivariate logistic regression model, known CAD, prior MI, chest pain character, mildly elevated hsTnT, and left ventricular ejection fraction <40% were predictive of an abnormal ischemia evaluation result, whereas electrocardiography findings and the modified History, EKG, Age, Risk factors, and troponin (HEART) score were not. Of note, 30-day adverse cardiac events were strikingly low at 0.4% with no deaths despite an overwhelming majority (>90%) of patients scoring intermediate or high on the modified HEART score. CONCLUSIONS: A considerable percentage of acute chest pain patients who rule out for MI by hsTn had evidence of obstructive CAD, and the modified HEART score was not predictive of an abnormal ischemia evaluation.

Acquired aortopulmonary fistula: a case report.

BACKGROUND: Aortopulmonary fistula is a rare complication of ascending aorta pathology. Presentation is most commonly dramatic with acute onset chest pain or heart failure secondary to left to right shunting. We describe a patient with acquired aortopulmonary fistula who had an insidious onset of heart failure as his presenting complaint. We also highlight the utility of multimodality cardiac imaging in establishing the diagnosis. CASE SUMMARY: A 79-year-old male patient with a history of coronary artery bypass graft surgery and mechanical aortic valve replacement, 23 years prior, presented with exertional dyspnoea of 7 months duration. An initial workup that included transthoracic and transoesophageal echocardiography as well as coronary and bypass graft angiography failed to diagnose an acquired aortopulmonary fistula complicating an ascending aortic pseudoaneurysm. Upon referral to our institution, the correct diagnosis was suspected on off-axis transthoracic echocardiography. The fistula was subsequently confirmed, and the extent of ascending aorta pathology defined via a multimodality imaging approach that consisted of transoesophageal echocardiography and cardiac computed tomography. The patient underwent successful surgical repair and was discharged in a stable condition. DISCUSSION: Acquired aortopulmonary fistula is a rare clinical entity. We describe a patient who had an insidious presentation of heart failure and found to have a large ascending aortic aneurysm that eroded into the main pulmonary artery creating a fistulous communication. The diagnosis was delayed and required a high index of suspicion and multimodality cardiac imaging.

Effects of Febuxostat on Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To investigate the association between using febuxostat and cardiovascular events. METHODS: Systematic search of randomized controlled trials was performed using PubMed/MEDLINE, Cochrane review, and EMBASE databases through April 17, 2019. Meta-analysis was performed using random effect model and estimates were reported as risk difference (RD) with 95% CIs. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. The main outcomes of interest were cardiovascular mortality and all-cause mortality. RESULTS: A total of 15 randomized controlled trials (16,070 participants) were included. The mean ± SD age was 58.1±11.7 years. At the median follow-up of 6.4 months, use of febuxostat was not associated with statistically significant risk of cardiovascular mortality (RD, 0.12%; 95% CI, -0.25% to 0.49%; I 2 =48%; low certainty evidence), all-cause mortality (RD, 0.20%; 95% CI, -0.28% to 0.68%; I 2  =60%; very low certainty evidence), major adverse cardiovascular events (RD, 0.40%; 95% CI, -0.34% to 1.13%; I 2 =26%; low certainty evidence), myocardial infarction (RD, -0.06%; 95% CI, -0.29% to 0.17%; I 2  =0%; moderate certainty evidence), stroke (RD, 0.10%; 95% CI, -0.15% to 0.35%; I 2 =0%; moderate certainty evidence), or new-onset hypertension (RD, 1.58%; 95% CI, -0.63% to 3.78%; I 2 =58%; very low certainty evidence). These findings were consistent in patients with existing cardiovascular disease. CONCLUSION: This meta-analysis suggested that use of febuxostat was not associated with higher risk of mortality or adverse cardiovascular outcomes in patients with gout and hyperuricemia. The results were limited by low to moderate certainty of evidence.

Comparative outcome analysis of stable mildly elevated high sensitivity troponin T in patients presenting with chest pain. A single-center retrospective cohort study.

BACKGROUND: The ideal high-sensitivity troponin (hsTn) cutoff for identifying those at low risk of 30 days events is debated; however, the 99th percentile overall or gender-specific upper reference limit (URL) is most commonly used. The magnitude of risk and the best management strategy for those with low-level hsTn elevation hasn't been extensively studied. METHODS: We conducted a retrospective cohort analysis including 4396 chest pain patients (542 with low-level hsTn elevation) who ruled out for myocardial infarction (MI), had a stable high-sensitivity troponin T (hsTnT) levels (defined as < 5 ng/l inter-measurements increase in hsTnT levels), and were discharged from the emergency department without further ischemic testing. The aim of the study was to compare the 30-day incidence of adverse cardiac events (ACE) between patients with undetectable high-sensitivity troponin T (hsTnT) (group 1), patients with hsTnT within the 99th percentile sex-specific URL (group 2), and patients with low-level hsTnT elevation (between the 99th percentile URL and ≤ 50 ng/l) (group 3). RESULTS: 30-day event rates were very low 0.1%, 0.6%, and 0.4% for hsTnT groups 1, 2, and 3 respectively (overall P = 0.041, for groups 2 & 3 interaction P = 0.74). 30-day all-cause mortality, as well as 1-year all-cause and cardiovascular mortalities, occurred more frequently in those with low-level hsTnT elevation as did 1-year composite ACE. CONCLUSION: In conclusion, 30-day adverse event rates were very low in those with stable low-level hsTnT elevation who ruled out for MI and were discharged from the emergency department without further inpatient testing.

A comparative 30-day outcome analysis of inpatient evaluation vs outpatient testing in patients presenting with chest pain in the high-sensitivity troponin era. A propensity score matched case-control retrospective study.

BACKGROUND: The best disposition of chest pain patients who rule out for myocardial infarction (MI) but have non-low clinical risk scores in the high-sensitivity troponin era is not well studied. HYPOTHESIS: In carefully selected patients who rule out for MI, and have a high-sensitivity troponin T ≤ 50 ng/L with an absolute increase less than 5 ng/L on repeat measurements, early emergency room (ER) discharge might be equivalent to inpatient evaluation in regards to 30-day incidence of adverse cardiac events (ACEs) regardless of the clinical risk score. METHODS: A total of 12 847 chest pain patients presenting to our health system ERs from January 2017 to September 2019 were retrospectively investigated. A propensity score matching algorithm was used to account for baseline differences between admitted and discharged cohorts. We then estimated and compared the incidence of 30-day and 1-year composite ACEs (MI, urgent revascularization, or cardiovascular death) between both groups. A multivariate Cox regression model was used to evaluate the effect of admission on outcomes. RESULTS: A total of 2060 patients were matched in 1:1 fashion. The primary endpoint of 30-day composite ACEs occurred in 0.6% and 0.4% of the admission and the discharged cohorts, respectively (P = .76). One-year composite ACEs was also similar between both groups (4% vs 3.7%, P = .75). In a multivariate Cox regression model, the effect of inpatient evaluation was neutral (hazard ratio 1.1, confidence interval 0.62-1.9, P = .75). CONCLUSIONS: Inpatient evaluation was not associated with better outcomes in our selected group of patients. Larger-scale randomized trials are needed to confirm our findings.

Complete Revascularization in Patients With STEMI and Multi-Vessel Disease: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Percutaneous coronary intervention (PCI) is the treatment of choice for ST-elevation myocardial infarction (STEMI). However, efficacy of complete vs culprit only revascularization in patients with STEMI and multivessel disease remains unclear. METHODS: We searched PubMed/MEDLINE, and Cochrane library. The primary endpoint was major adverse cardiovascular events (MACE). Secondary outcomes were all-cause mortality, cardiovascular mortality, myocardial infarction (MI), repeat revascularization, stroke, major bleeding, and contrast induced nephropathy. Estimates were calculated as random effects hazard ratios (HRs) with 95% confidence intervals (CI). RESULTS: Twelve trials with 7592 patients were included. There was a significantly lower risk of MACE [HR 0.61; 95% CI (0.43-0.60); p = 0.0009; I2 = 72%], cardiovascular mortality [HR 0.74; 95% CI (0.56-0.99); p = 0.04; I2 = 2%], and repeat revascularization [HR 0.43; 95% CI (0.31-0.59); p < 0.00001; I2 = 67%] in patients treated with complete compared with culprit-only revascularization. There was no statistically significant difference in MI [HR 0.77; 95% CI (0.52-1.12); p = 0.17; I2 = 49%], all-cause mortality [HR 0.86; 95% CI (0.65-1.13); p = 0.28; I2 = 14%], heart failure [HR 0.82 95% CI (0.51-1.32); p = 0.42; I2 = 26%], major bleeding [HR 1.07; 95% CI (0.66-1.75); p = 0.78; I2 = 25%], stroke [HR 0.67; 95% CI (0.24-1.89); p = 0.45; I2 = 54%], or contrast induced nephropathy, although higher contrast volumes were used in the complete revascularization group [HR 1.22; 95% CI (0.78-1.92); p = 0.39; I2 = 0%]. CONCLUSION: Complete revascularization was associated with a significantly lower risk of MACE, cardiovascular mortality, and repeat revascularization compared with culprit-only revascularization. These results suggest complete revascularization with PCI following STEMI and multivessel disease should be considered.

Transcatheter Aortic Valve Replacement in Low-Risk Patients: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) has become the standard treatment option for patients with symptomatic severe aortic stenosis (AS) with high surgical risk and a reasonable option for intermediate surgical risk as an alternative to surgical aortic valve replacement (SAVR). The role of TAVR in lower risk patients is less established but has been the focus of recent randomized controlled trials (RCTs). We performed a meta-analysis of RCTs to assess TAVR outcomes among low surgical risk patients. METHODS AND RESULTS: Systematic search of RCTs was done using PubMed, EMBASE, and Cochrane Library databases. Statistical analysis was performed with RevMan v5.3 software using a random effects model to report risk ratio (RR) with 95% confidence interval (CI). A total of three RCTs including 2698 patients (1375 TAVR and 1323 SAVR) were analyzed. Compared to SAVR, TAVR was not associated with all-cause mortality [RR 0.86 (95% CI 0.61-1.19); P = 0.36; I2 = 8%] or stroke [RR 0.82 (0.48-1.43); P = 0.49; I2 = 42%]. However, TAVR was significantly associated with lower risk of acute kidney injury [RR 0.27 (0.13-0.54); P = 0.0002; I2 = 0%], new-onset atrial fibrillation [RR 0.26 (0.18-0.39); P < 0.00001; I2 = 80%], and life-threatening or disabling bleeding [RR 0.35 (0.22-0.55); P < 0.00001; I2 = 57%], but a higher risk of moderate-severe paravalvular leak [RR 4.40 (1.22-15.86); P = 0.02; I2 = 26%] and permanent pacemaker insertion [RR 2.73 (1.41-5.28); P = 0.003; I2 = 83%]. CONCLUSIONS: There is no difference in all-cause mortality or stroke between TAVR and SAVR, but TAVR is associated with lower risk of other perioperative complications except for moderate-severe paravalvular leak and the need for permanent pacemaker implantation.

Managing cardiotoxicity associated with immune checkpoint inhibitors.

Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied in the past and clear guidelines for management of these side effects are available in the literature. However, cardiotoxicity with novel agents such as ICIs has been fairly under-reported and/or underestimated and we are yet to formulate clear guidelines for management of these rare side effects. In the last few years, there has been an overall increase in the number of cases of cardiotoxicity related to ICIs. In this literature review, we describe the mechanism of action of the most widely used ICIs and their related cardiotoxicities. The increase in number of case reports about the potential of cardiotoxicities with these novel agents clearly indicates the need for a new insight into the field of cardio-immuno-oncology.

A novel method for monitoring functional lesion-specific recruitment of repair proteins in live cells.

DNA-protein relationships have been studied by numerous methods, but a particular gap in methodology lies in the study of DNA adduct-specific interactions with proteins in vivo, which particularly affects the field of DNA repair. Using the repair of a well-characterized and ubiquitous adduct, the abasic (AP) site, as a model, we have developed a comprehensive method of monitoring DNA lesion-specific recruitment of proteins in vivo over time. We utilized a surrogate system in which a Cy3-labeled plasmid containing a single AP-site was transfected into cells, and the interaction of the labeled DNA with BER enzymes, including APE1, Polß, LIG1, and FEN1, was monitored by immunofluorescent staining of the enzymes by Alexafluor-488-conjugated secondary antibody. The recruitment of enzymes was characterized by quantification of Cy3-Alexafluor-488 co-localization. To validate the microscopy-based method, repair of the transfected AP-site DNA was also quantified at various time points post-transfection using a real time PCR-based method. Notably, the recruitment time kinetics for each enzyme were consistent with AP-site repair time kinetics. This microscopy-based methodology is reliable in detecting the recruitment of proteins to specific DNA substrates and can be extended to study other in vivo DNA-protein relationships in any DNA sequence and in the context of any DNA structure in transfectable proliferating or quiescent cells. The method may be applied to a variety of disciplines of nucleic acid transaction pathways, including repair, replication, transcription, and recombination.

Development of a novel assay for human tyrosyl DNA phosphodiesterase 2.

Tyrosyl DNA phosphodiesterase 2 (TDP2), a newly discovered enzyme that cleaves 5'-phosphotyrosyl bonds, is a potential target for chemotherapy. TDP2 possesses both 3'- and 5'-tyrosyl-DNA phosphodiesterase activity, which is generally measured in a gel-based assay using 3'- and 5'-phosphotyrosyl linkage at the 3' and 5' ends of an oligonucleotide. To understand the enzymatic mechanism of this novel enzyme, the gel-based assay is useful, but this technique is cumbersome for TDP2 inhibitor screening. For this reason, we have designed a novel assay using p-nitrophenyl-thymidine-5'-phosphate (T5PNP) as a substrate. This assay can be used in continuous colorimetric assays in a 96-well format. We compared the salt and pH effect on product formation with the colorimetric and gel-based assays and showed that they behave similarly. Steady-state kinetic studies showed that the 5' activity of TDP2 is 1000-fold more efficient than T5PNP. Tyrosyl DNA phosphodiesterase 1 (TDP1) and human AP-endonuclease 1 (APE1) could not hydrolyze T5PNP. Sodium orthovanadate, a known inhibitor of TDP2, inhibits product formation from T5PNP by TDP2 (IC(50)=40 mM). Our results suggest that this novel assay system with this new TDP2 substrate can be used for inhibitor screening in a high-throughput manner.