Pharmacotherapy for Coronary Artery Disease and Acute Coronary Syndrome in the Aging Population.

PURPOSE OF REVIEW: To provide a comprehensive summary of relevant studies and evidence concerning the utilization of different pharmacotherapeutic and revascularization strategies in managing coronary artery disease and acute coronary syndrome specifically in the older adult population. RECENT FINDINGS: Approximately 30% to 40% of hospitalized patients with acute coronary syndrome are older adults, among whom the majority of cardiovascular-related deaths occur. When compared to younger patients, these individuals generally experience inferior clinical outcomes. Most clinical trials assessing the efficacy and safety of various therapeutics have primarily enrolled patients under the age of 75, in addition to excluding those with geriatric complexities. In this review, we emphasize the need for a personalized and comprehensive approach to pharmacotherapy for coronary heart disease and acute coronary syndrome in older adults, considering concomitant geriatric syndromes and age-related factors to optimize treatment outcomes while minimizing potential risks and complications. In the realm of clinical practice, cardiovascular and geriatric risks are closely intertwined, with both being significant factors in determining treatments aimed at reducing negative outcomes and attaining health conditions most valued by older adults.

Electronic ventricular pacing at the end of the QRS complex: Is it abnormal?

An 82-year-old man with ischemic cardiomyopathy, heart failure with reduced ejection fraction and Medtronic biventricular ICD presented with shortness of breath. His ECG is presented with shortness of breath. ECG shows atrial sensed, electronic ventricular pacing. At the end of each QRS complex there is another pacemaker stimulus. This represents typical case of cardiac contractility modulation therapy and not pacemaker malfunction.

Why do we keep missing left circumflex artery myocardial infarctions?

BACKGROUND: Diagnosis of left circumflex artery (LCx) myocardial infarctions via 12­lead electrocardiogram (ECG) has posed a challenge to healthcare professionals for many years. METHODS AND RESULTS: A retrospective observational study was performed to analyze patients admitted with myocardial infarction. The study used electronic medical records and specific ICD-10 codes to identify eligible patients, resulting in 2032 encounters. After independent adjudication of cardiac biomarkers, coronary angiography, and electrocardiographic changes, a final patient population of 58 encounters with acute occlusion myocardial infarction (OMI) with a culprit LCx lesion was established. OMI was defined as a lesion with either thrombolysis in myocardial infarction flow (TIMI) 0-2 or TIMI 3 with Troponin I > 1 ng/mL (Reference range 0.00-0.03 ng/mL). ECGs of these patients were then independently evaluated and grouped into 8 different classifications based on the presence or absence of ST elevation and/or depression in corresponding leads. ECG patterns and anatomical characteristics (proximal or distal to the first obtuse marginal artery) of the LCx lesions were then correlated. The appropriateness of triage and delay in reperfusion therapy were also assessed. Those with a left dominant or codominant circulation, and with LCx lesions proximal to the first obtuse marginal artery, were more likely to present with no or subtle ST-segment changes that led to delays in reperfusion therapy. CONCLUSIONS: Patients with left or codominant coronary artery circulation, with OMI proximal to the first obtuse marginal artery, may be less likely to have "classic" findings of ST-segment elevation on ECG due to cancellation forces in the limb leads.

Aspirin Blocks the Infarct-Size Limiting Effect of Ischemic Postconditioning in the Rat.

BACKGROUND: Ischemic postconditioning (PostC), repetitive cycles of re-occlusion, and reperfusion of the infarct-related artery immediately after reperfusion have been shown to limit myocardial infarct size in various animal models. Yet, translating the model into the clinical setting was disappointing, several clinical trials showing neutral effect. We hypothesized that aspirin loading could explain the differences between the pre-clinical and clinical studies. METHODS: Male Sprague Dawley rats were subjected to 30-min coronary artery ligation. At 25 min of ischemia, animals received intravenous aspirin (20 mg/kg) or vehicle. Upon reperfusion half of the rats were randomized to PostC (3 cycles of 10-s re-occlusion/10-s reperfusion. After 4-h reperfusion, rats were euthanized. Area at risk was assessed by blue dye and infarct size by 2,3,5-triphenyl-tetrazolium-chloride (TTC). RESULTS: Body weight and the size of the ischemic area at risk were comparable among groups. Infarct size expressed as a percentage of the ischemic area at risk was significantly smaller in the PostC group (13.9 ± 0.4%; p < 0.001) compared to the control group (31.0 ± 2.2%). Aspirin alone had no effect on infarct size (29.0 ± 2.6%). Yet, aspirin completely blocked the protective effect of PostC (33.3 ± 1.1%). CONCLUSIONS: Aspirin, administered before reperfusion, blocks the infarct size limiting effects of PostC in the rat.

Effects of Dapagliflozin on Myocardial Gene Expression in BTBR Mice with Type 2 Diabetes.

BACKGROUND: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved for the treatment of type 2 diabetes, heart failure, and chronic kidney disease. DAPA-HF and DELIVER trial results demonstrate that the cardiovascular protective effect of dapagliflozin extends to non-diabetic patients. Hence, the mechanism-of-action may extend beyond glucose-lowering and is not completely elucidated. We have previously shown that dapagliflozin reduces cardiac hypertrophy, inflammation, fibrosis, and apoptosis and increases ejection fraction in BTBR mice with type 2 diabetes. METHODS: We conducted a follow-up RNA-sequencing study on the heart tissue of these animals and performed differential expression and Ingenuity Pathway analysis. Selected markers were confirmed by RT-PCR and Western blot. RESULTS: SGLT2 had negligible expression in heart tissue. Dapagliflozin improved cardiac metabolism by decreasing glycolysis and pyruvate utilization enzymes, induced antioxidant enzymes, and decreased expression of hypoxia markers. Expression of inflammation, apoptosis, and hypertrophy pathways was decreased. These observations corresponded to the effects of dapagliflozin in the clinical trials.

An Updated Review on the Role of Non-dihydropyridine Calcium Channel Blockers and Beta-blockers in Atrial Fibrillation and Acute Decompensated Heart Failure: Evidence and Gaps.

PURPOSE: The 2021 European Society of Cardiology guidelines on acute and chronic heart failure (HF) recommend that non-dihydropyridine calcium channel blockers (NDCC) should be avoided in patients with HF with reduced ejection fraction. It also emphasizes that beta-blockers only be initiated in clinically stable, euvolemic patients. Despite these recommendations, NDCC and beta-blockers are often still employed in patients with AF with rapid ventricular response and acute decompensated HF. The relative safety and efficacy of these therapies in this setting is unclear. METHODS: To address the question of the safety and efficacy of NDCC and beta-blockers for acute rate control in decompensated HF, we provide a perspective on the literature of NDCC and beta-blockers in chronic HF with reduced and preserved ejection fraction and AF, including trials on the management of AF with rapid ventricular response with and without HF. RESULTS: Robust data demonstrates mortality benefits when beta-blockers are used in patients with chronic HF with reduced ejection fraction. The data that inform the contraindication of NDCC in HF with reduced ejection fraction are outdated and were not primarily designed to address the efficacy and safety of rate control of AF in patients with HF. Several studies indicate that for acute rate control, NDCC and beta-blockers are both efficacious therapies, especially in the setting of tachycardia-induced cardiomyopathy. CONCLUSION: Future studies are needed to assess the safety and efficacy of beta-blockers and NDCC in both acute and chronic AF with HF with reduced and preserved ejection fraction.

Recombinant Apyrase (AZD3366) Against Myocardial Reperfusion Injury.

PURPOSE: Recombinant apyrase (AZD3366) increases adenosine production and ticagrelor inhibits adenosine reuptake. We investigated whether intravenous AZD3366 before reperfusion reduces myocardial infarct size (IS) and whether AZD3366 and ticagrelor have additive effects. METHODS: Sprague-Dawley rats underwent 30 min ischemia. At 25 min of ischemia, animals received intravenous AZD3366 or vehicle. Additional animals received intravenous CGS15943 (an adenosine receptor blocker) or intraperitoneal ticagrelor. At 24 h reperfusion, IS was assessed by triphenyltetrazolium chloride. Other rats were subjected to 30 min ischemia followed by 1 h or 24 h reperfusion. Myocardial samples were assessed for adenosine levels, RT-PCR, and immunoblotting. RESULTS: AZD3366 and ticagrelor reduced IS. The protective effect was blocked by CGS15943. The effect of AZD3366 + ticagrelor was significantly greater than AZD3366. One hour after infarction, myocardial adenosine levels significantly increased with AZD3366, but not with ticagrelor. In contrast, 24 h after infarction, adenosine levels were equally increased by AZD3366 and ticagrelor, and levels were higher in the AZD3366 + ticagrelor group. One hour after reperfusion, AZD3366 and ticagrelor equally attenuated the increase in interleukin-15 (an early inflammatory marker after ischemic cell death) levels, and their combined effects were additive. AZD3366, but not ticagrelor, significantly attenuated the increase in RIP1, RIP3, and P-MLKL (markers of necroptosis) 1 h after reperfusion. AZD3366, but not ticagrelor, significantly attenuated the increase in IL-6 and GSDMD-N (markers of pyroptosis) 1 h after reperfusion. At 24 h of reperfusion, both agents equally attenuated the increase in these markers, and their effects were additive. CONCLUSIONS: AZD3366 attenuated inflammation, necrosis, necroptosis, and pyroptosis and limited IS. The effects of AZD3366 and ticagrelor were additive.

Acute chest pain in a patient with left bundle branch pacing.

We present a patient with left bundle branch (LBB) electronic ventricular pacing with chest pain. ECG showed ventricular pacing and ST elevation in the inferolateral leads. At first it was felt that the Sgarbossa criteria for STEMI in electronic ventricular pacing are not met. However, as symptoms persisted, emergency coronary angiography was performed showing complete occlusion of the left circumflex artery. As LBB pacing results in narrow QRS complexes with incomplete right bundle branch block, ST-segment deviation should not be ignored and the Sgarbossa criteria for patients with LBB block or right ventricular electronic pacing should not be applied.

Interpreting the ECG in patients with chest pain and right bundle branch block: A case report.

A patient with right bundle branch block (RBBB) presented with chest pain. An ECG showed ST-elevation in leads V1, V2, and aVR, with widespread ST-depression in leads II, aVF, I, aVL, and V4-6. The initial ECG interpretation missed ST-elevation myocardial infarction (STEMI), as ST-elevation thresholds were not reached. Non-urgent angiography showed severe left anterior descending artery stenosis requiring percutaneous coronary intervention. The course was complicated by cardiac arrest necessitating resuscitation and dual chamber pacemaker placement with left bundle branch pacing. This case report outlines the deficiencies of the current voltage criteria for identification of anterior STEMI in patients with RBBB.

Cilostazol: a Review of Basic Mechanisms and Clinical Uses.

Primarily used in the treatment of intermittent claudication, cilostazol is a 2-oxyquinolone derivative that works through the inhibition of phosphodiesterase III and related increases in cyclic adenosine monophosphate (cAMP) levels. However, cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. It has been observed to exhibit antiplatelet, antiproliferative, vasodilatory, and ischemic-reperfusion protective properties. As such, cilostazol has been investigated for clinical use in a variety of settings including intermittent claudication, as an adjunctive for reduction of restenosis after coronary and peripheral endovascular interventions, and in the prevention of secondary stroke, although its widespread implementation for indications other than intermittent claudication has been limited by relatively modest effect sizes and lack of studies in western populations. In this review, we highlight the pleiotropic effects of cilostazol and the evidence for its clinical use.

SGLT2 Inhibition by Dapagliflozin Attenuates Diabetic Ketoacidosis in Mice with Type-1 Diabetes.

BACKGROUND: SGLT2 inhibitors increase plasma ketone concentrations. It has been suggested that insulinopenia, along with an increase in the counter-regulatory hormones epinephrine, corticosterone, glucagon and growth hormone, can induce ketoacidosis, especially in type-1 diabetes (T1DM). Dehydration precipitates SGLT2 inhibitor-induced ketoacidosis in type-2 diabetes. We studied the effects of dapagliflozin and water deprivation on the development of ketoacidosis and the associated signaling pathways in T1DM mice. METHODS: C57BL/6 mice were fed a high-fat diet. After 7 days, some mice received intraperitoneal injection of streptozocin + alloxan (STZ/ALX). The treatment groups were control + water at lib; control + dapagloflozin + water at lib; control + dapagloflozin + water deprivation; STZ/ALX + water at lib; STZ/ALX + water deprivation; STZ/ALX + dapagloflozin + water at lib; STZ/ALX + dapagloflozin + water deprivation. Dapagliflozin was given for 7 days. In the morning of day 18, food was removed, and water was removed in the water deprivation groups. ELISA, rt-PCR, and immunoblotting were used to assess blood, heart, liver, white and brown adipose tissues. RESULTS: The T1DM mice had ketoacidosis even without water deprivation. Water deprivation increased plasma levels of ß-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1ß, IL-6, IL-8, and TNFα were also increased in the T1DM mice with water deprivation. Dapagliflozin attenuated the changes in the T1DM mice without and with water deprivation. Likewise, water deprivation increased the activation of the inflammasome in the heart, liver, and white fat of the T1DM mice and dapagliflozin attenuated these changes. Dapagliflozin reduced the mRNA levels of glucagon receptors in the liver and the increase in GPR109a in white and brown fat. In the liver, dapagliflozin increased AMPK phosphorylation, and attenuated the phosphorylation of TBK1 and the activation of NFκB. CONCLUSIONS: Dapagliflozin reduced ketone body levels and attenuated the activation of NFκB and the activation of the inflammasome in T1DM mice with ketoacidosis.

Ticagrelor and Dapagliflozin Have Additive Effects in Ameliorating Diabetic Nephropathy in Mice with Type-2 Diabetes Mellitus.

PURPOSE: Ticagrelor and dapagliflozin can suppress the activation of the NOD-like receptor 3 (NLRP3)-inflammasome and activate AMP-activated protein kinase (AMPK). The anti-inflammatory effects of dapagliflozin has been shown to depend on AMPK activation. Dapagliflozin and ticagrelor have been shown to have additive effects on the progression of diabetic cardiomyopathy in BTBR ob/ob mice with type-2 diabetes. We assessed whether dapagliflozin and ticagrelor have additive effects on the activation of the NLRP3-inflammasome and the progression of diabetic nephropathy in mice with type-2 diabetes. METHODS: Eight-week-old BTBR received either no-drug, dapagliflozin (1.5 mg/kg/d), ticagrelor (100 mg/kg/d), or their combination for 12 weeks. Blood was assessed weekly for glucose and urine for glucose and albumin. After 12 weeks, blood creatinine, cystatin C, inflammasome activation, and insulin were assessed by ELISA. Renal cortex samples were assessed by hematoxylin and eosin and periodic acid-Schiff staining. RT-PCR and immunoblotting were used to evaluate fibrosis and the activation of Akt, AMPK and the inflammasome. RESULTS: Both ticagrelor and dapagliflozin reduced serum creatinine and cystatin C levels and urinary albumin. Both drugs attenuated the increase in glomerular area and mesangial matrix index. Both drugs decreased collagen-1 and collagen-3 expression and the activation of the NLRP3-inflammasome. Both drugs increased P-AMPK levels, but only dapagliflozin increased P-Akt levels. Overall, the protective effects of dapagliflozin and ticagrelor were additive. CONCLUSIONS: Dapagliflozin and ticagrelor attenuated the progression of diabetic nephropathy in BTBR ob/ob mice with additive effects of the combination. This was associated with AMPK activation and reduced activation of the NLRP3 inflammasome, whereas only dapagliflozin increased Akt activation.

Antacid Therapy in Coronary Artery Disease and Heart Failure: Proton Pump Inhibitors vs. H2 Receptor Blockers.

PURPOSE: Acid suppressive therapy using histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) can be utilized for the prevention of gastrointestinal bleeding (GIB) among patients with cardiovascular disease receiving dual antiplatelet therapy (DAPT). However, emerging data suggests underlying associations between PPI or H2RA use and cardiovascular disease incidence, progression, and mortality. This review explores the history of acid suppressive therapies and their use in cardiovascular disease patients and the growing evidence in support of H2RA use. RECENT FINDINGS: PPIs were originally championed as better than H2RAs for preventing GIB events in cardiovascular disease patients on DAPT therapy, but there is evidence to suggest that drug-drug interactions between clopidogrel and PPIs may translate to worse cardiovascular outcomes. Studies demonstrating PPI superiority in the setting of DAPT were also limited due to small sample sizes and high levels of bias. Consequently, there is renewed interest in H2RAs for patients on DAPT with some data demonstrating similar or improved clinical outcomes over PPI therapy. Additionally, studies have discovered a possible role for H2RAs in the management of heart failure (HF) incidence, symptoms, and mortality. Studies comparing H2RAs and PPIs in patients on DAPT have demonstrated mixed results for cardiovascular and GIB outcomes, with several studies being underpowered and limited by biases. Recent clinical and pre-clinical studies now support the noninferiority of H2RAs for major outcomes and even utility in HF. These findings suggest that H2RAs may warrant reconsideration as an acid suppressive therapy over PPIs for patients on DAPT or with HF.

The Cost of Breaking Even: a Perspective on the Net Clinical Impact of Adding Aspirin to Antithrombotic Therapies in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

PURPOSE: Outcomes from randomized controlled trials (RCTs) inform the latest recommendations on percutaneous coronary intervention (PCI) management of a short period of oral anticoagulation (OAC), a P2Y12 receptor inhibitor, and aspirin for 1 week or until hospital discharge in patients with atrial fibrillation (AF) undergoing PCI, and up to 4 weeks in individuals considered to be at high-risk for ischemic events, followed by discontinuation of aspirin and continuation of OAC and a P2Y12 inhibitor for up to 12 months. METHODS: We examined and summarized the outcomes of bleeding and major adverse cardiac events (MACEs) from RCTs and meta-analyses, published between 2013 and 2022, comparing therapy with OAC and a P2Y12 inhibitor with and without aspirin in AF patients undergoing PCI with stenting. RESULTS: Data comparing dual therapy with OAC and a P2Y12 inhibitor alone to triple therapy with OAC, a P2Y12 inhibitor, and aspirin with respect to the risks of MACEs, including stent thrombosis within the first 30 days, are underpowered and inconclusive. The addition of aspirin does not appear to be associated with a decreased risk of ischemic events, even in patients with high-risk CHA2DS2-VASc scores, but does significantly increase bleeding hazards. The increased safety of newer generation drug-eluting stents may have further minimized any theoretical anti-ischemic benefits of aspirin. The possible attenuation of the pleiotropic effects of concomitant cardiovascular medications by aspirin may also have been a contributing factor. CONCLUSION: The addition of aspirin to OAC and a P2Y12 inhibitor is likely associated with a net clinical harm in patients with AF who undergo PCI with stenting, even within the first 1-4 weeks after PCI. Revisiting the guideline recommendations to administer aspirin in this timeframe may be warranted.

Do We Really Need Aspirin Loading for STEMI?

Aspirin loading (chewable or intravenous) as soon as possible after presentation is a class I recommendation by current ST elevation myocardial infarction (STEMI) guidelines. Earlier achievement of therapeutic antiplatelet effects by aspirin loading has long been considered the standard of care. However, the effects of the loading dose of aspirin (alone or in addition to a chronic maintenance oral dose) have not been studied. A large proportion of myocardial cell death occurs upon and after reperfusion (reperfusion injury). Numerous agents and interventions have been shown to limit infarct size in animal models when administered before or immediately after reperfusion. However, these interventions have predominantly failed to show significant protection in clinical studies. In the current review, we raise the hypothesis that aspirin loading may be the culprit. Data obtained from animal models consistently show that statins, ticagrelor, opiates, and ischemic postconditioning limit myocardial infarct size. In most of these studies, aspirin was not administered. However, when aspirin was administered before reperfusion (as is the case in the majority of studies enrolling STEMI patients), the protective effects of statin, ticagrelor, morphine, and ischemic postconditioning were attenuated, which can be plausibly attributable to aspirin loading. We therefore suggest studying the effects of aspirin loading before reperfusion on the infarct size limiting effects of statins, ticagrelor, morphine, and/ or postconditioning in large animal models using long reperfusion periods (at least 24 h). If indeed aspirin attenuates the protective effects, clinical trials should be conducted comparing aspirin loading to alternative antiplatelet regimens without aspirin loading in patients with STEMI undergoing primary percutaneous coronary intervention.

A Comprehensive Review of the Pleiotropic Effects of Ticagrelor.

AIMS: This review summarizes the findings of preclinical studies evaluating the pleiotropic effects of ticagrelor. These include attenuation of ischemia-reperfusion injury (IRI), inflammation, adverse cardiac remodeling, and atherosclerosis. In doing so, it aims to provide novel insights into ticagrelor's mechanisms and benefits over other P2Y12 inhibitors. It also generates viable hypotheses for the results of seminal clinical trials assessing ticagrelor use in acute and chronic coronary syndromes. METHODS AND RESULTS: A comprehensive review of the preclinical literature demonstrates that ticagrelor protects against IRI in the setting of both an acute myocardial infarction (MI), and when MI occurs while on chronic treatment. Maintenance therapy with ticagrelor also likely mitigates adverse inflammation, cardiac remodeling, and atherosclerosis, while improving stem cell recruitment. These effects are probably mediated by ticagrelor's ability to increase local interstitial adenosine levels which activate downstream cardio-protective molecules. Attenuation and augmentation of these pleiotropic effects by high-dose aspirin and caffeine, and statins respectively may help explain variable outcomes in PLATO and subsequent randomized controlled trials (RCTs). CONCLUSION: Most RCTs and meta-analyses have not evaluated the pleiotropic effects of ticagrelor. We need further studies comparing cardiovascular outcomes in patients treated with ticagrelor versus other P2Y12 inhibitors that are mindful of the unique pleiotropic advantages afforded by ticagrelor, as well as possible interactions with other therapies (e.g., aspirin, statins, caffeine).

The Role of ECG in the Diagnosis and Risk Stratification of Acute Coronary Syndromes: an Old but Indispensable Tool.

PURPOSE OF REVIEW: Since its inception in 1902 by Willem Einthoven, the electrocardiogram (ECG) has fundamentally undergone minimal technological advances. Nevertheless, its clinical utility is critical, and it remains an essential tool to diagnose, risk stratify, and guide reperfusion and invasive strategies in patients with suspected acute coronary syndromes. ECG reading can be demanding, with many healthcare professionals lacking the necessary expertise to accurately interpret them. This is exacerbated by the need to constantly revisit old dogmas pertinent to the interpretation of ECGs. RECENT FINDINGS: Notably, ECG leads record the global electrical activity of the heart toward and away from each electrode rather than local events. The long-held central paradigm that the various ECG leads record local events underneath specific electrodes should therefore be reassessed. For example, ST segment elevation in leads V1 and V2 usually denote antero-apical rather than septal infarction, often a misnomer utilized by the majority of clinicians. The ECG diagnosis of ST-elevation myocardial infarction (STEMI) is sometimes challenging and discerning it from non-ST-elevation myocardial infarction (NSTEMI) is of paramount importance to implement timely acute reperfusion therapy. In fact, when qualifications for emergency reperfusion therapy are based on STEMI ECG criteria, nearly one-third of cases with acute coronary occlusion are missed. Diagnostic ST elevation in the absence of left ventricular (LV) hypertrophy or left bundle-branch block (LBBB) is defined by a specific set of sex-specific criteria for new ST elevation at the J point in contiguous precordial or limb leads. However, other ECG criteria need to be kept in mind. These include, but are not limited to, new or presumably new left bundle branch block (LBBB), which is often considered as an STEMI-equivalent; ST depression in two or more precordial leads (V1-V4), denoting a true inferolateral transmural myocardial infarction; and the infrequent presentation with hyperacute T-wave changes. As our understanding of the pathology of ischemic reperfusion injury has evolved and following the introduction of new imaging modalities such as cardiac magnetic resonance imaging, we need to re-assess the old dogmas pertinent to the interpretation of ECGs and update the terms and classifications.

Emerging ECG methods for acute coronary syndrome detection: Recommendations & future opportunities.

Despite being the mainstay for the initial noninvasive assessment of patients with symptomatic coronary artery disease, the 12­lead ECG remains a suboptimal diagnostic tool for myocardial ischemia detection with only acceptable sensitivity and specificity scores. Although myocardial ischemia affects the configuration of the QRS complex and the STT waveform, current guidelines primarily focus on ST segment amplitude, which constitutes a missed opportunity and may explain the suboptimal diagnostic performance of the ECG. This possible opportunity and the low cost and ease of use of the ECG provide compelling motivation to enhance the diagnostic accuracy of the ECG to ischemia detection. This paper describes numerous computational ECG methods and approaches that have been shown to dramatically increase ECG sensitivity to ischemia detection. Briefly, these emerging approaches can be conceptually grouped into one of the following four approaches: (1) leveraging novel ECG waveform features and signatures indicative of ischemic injury other than the classical ST-T amplitude measures; (2) applying body surface potentials mapping (BSPM)-based approaches to enhance the spatial coverage of the surface ECG to detecting ischemia; (3) developing an inverse ECG solution to reconstruct anatomical models of activation and recovery pathways to detect and localize injury currents; and (4) exploring artificial intelligence (AI)-based techniques to harvest ECG waveform signatures of ischemia. We present recent advances, shortcomings, and future opportunities for each of these emerging ECG methods. Future research should focus on the prospective clinical testing of these approaches to establish clinical utility and to expedite potential translation into clinical practice.

Efficacy of Long-Term Oral Beta-Blocker Therapy in Patients Who Underwent Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction With Preserved Left Ventricular Ejection Fraction: A Systematic Review and Meta-analysis.

ABSTRACT: After the results of the first multicenter, prospective randomized clinical trial (RCT) evaluating long-term efficacy of oral beta-blockers in patients with preserved left ventricular ejection fraction (LVEF) after ST elevation myocardial infarction (STEMI), we decided to conduct an updated systematic review and meta-analysis to evaluate the long-term efficacy of oral beta-blocker use in patients with preserved LVEF who underwent percutaneous coronary intervention (PCI) for STEMI. A time-limited search from January 1, 1999, to April 16, 2020, on PubMed and EMBASE was conducted on April 16, 2020, for observational studies and clinical trials evaluating the efficacy of long-term oral beta-blockers in patients with preserved LVEF after STEMI treated with PCI. The comparative outcomes between beta-blockers and non-beta-blockers were assessed by pooling weighted odds ratio (OR) with 95% confidence interval (CI) using random-effects model. The outcomes of interest were all-cause mortality and major adverse cardiac event (MACE). Twelve studies (11 observational and 1 RCT) comprising 32,108 patients (19,740 on beta-blocker therapy and 12,368 without beta-blocker therapy) were included. Of which, 75% percent were male (mean age of 64 years: 63.87 ± 3.01 years on beta-blocker therapy and 64.76 ± 3.02 years on non-beta-blocker therapy; P = 0.129) with a follow-up of up to 4.7 years. Unadjusted all-cause mortality [OR = 0.58 (95% CI: 0.42-0.79)] and adjusted all-cause mortality [OR = 0.64 (95% CI: 0.48-0.87)] were significantly lower in patients on the long-term beta-blocker therapy group. However, unadjusted MACE [OR = 0.87 (95% CI: 0.70-1.08)] was not reduced with beta-blocker therapy in these patients. Patients with preserved LVEF after STEMI treated with PCI on long-term oral beta-blocker therapy have a significant reduction in risk of all-cause mortality, without an effect on MACE rates. The only RCT included showed neutral effect, so results of ongoing RCTs are anticipated. Considering that the only high-quality data (RCT) suggest a neutral effect, one should be cautious in interpreting the conclusion.

Association Between Omega-3 Fatty Acid Treatment and Atrial Fibrillation in Cardiovascular Outcome Trials: A Systematic Review and Meta-Analysis.

PURPOSE: Data on the relationship between omega-3 fatty acid (n-3 FA) therapy with atrial fibrillation (AF) have been inconsistent. We investigate the association between n-3 FA and risk for AF by pooling data from available large, cardiovascular outcome trials. METHODS: We performed a systematic search on PubMed and Embase for studies on n-3 FA with AF as an outcome measure. Large (≥ 1000 participants) randomized controlled trials with ≥ 1-year follow-up period were included. The association between n-3 FA and risk of AF or stroke was assessed. Mantel-Haenszel random effects model was used to calculate risk ratios (RR) with 95% confidence intervals (CI). We then performed meta-regression to evaluate effect on AF by dose of n-3 FA therapy. RESULTS: A total of 8 randomized control trials encompassing 83,112 participants were included in the meta-analysis. Of these, five trials assessed a lower dose of n-3 FA (≤ 1 g daily, n = 61,096) while 3 trials assessed a higher dose (> 1 g daily, n = 22,016). In meta-analysis, a significant association was noted between n-3 FA treatment and risk of AF (4.0% vs 3.3%; RR 1.24, 95% CI 1.11-1.38, p = 0.0002). There was a modest but still significant association in the lower dose (n-3 FA ≤ 1 g daily) sub-group (RR 1.12, 95% CI 1.04-1.21, p = 0.004) and stronger association in the higher dose (n-3 FA > 1 g daily) sub-group (RR 1.51, 95% CI 1.26-1.80, p < 0.001; p-interaction between low versus high subgroups = 0.003). There was no increase in stroke risk (RR 1.04, 95% CI 0.90-1.20). Meta-regression demonstrated a significant association between dose of n-3 FA with risk for AF events (log RR 0.103, 95% CI 0.048-0.159, p < 0.001). CONCLUSION: While overall AF event rates were low, n-3 FA treatment is associated with increased risk for AF.