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Randomized controlled trials (RCTs) investigating the optimal screening strategy for atrial fibrillation (AF) have yielded conflicting results.To examine the comparative efficacy of different AF screening strategies in older adults.We searched MEDLINE, EMBASE and Cochrane without language restrictions through January 2022, for RCTs evaluating the outcomes of non-invasive AF screening approaches among adults ≥65 years. We conducted a pairwise meta-analysis comparing any AF screening approach versus no screening, and a network meta-analysis comparing systematic screening versus opportunistic screening versus no screening. The primary outcome was new AF detection.The final analysis included 9 RCTs with 85,209 patients. The weighted median follow-up was 12 months. The mean age was 73.4 years and men represented 45.6%. On pairwise meta-analysis, any AF screening (either systematic or opportunistic) was associated with higher AF detection (1.8% vs. 1.3%; risk ratio [RR] 2.10; 95% confidence interval [CI] 1.20-3.65) and initiation of oral anticoagulation (RR 3.26; 95%CI 1.15-9.23), compared with no screening. There was no significant difference between any AF screening versus no screening in all-cause mortality (RR 0.97; 95%CI 0.93-1.01) or acute cerebrovascular accident (CVA) (RR 0.92; 95%CI 0.84-1.01). On network meta-analysis, only systematic screening was associated with higher AF detection (RR 2.73; 95% CI 1.62-4.59) and initiation of oral anticoagulation (RR 5.67; 95% CI 2.68-11.99), but not with the opportunistic screening, compared with no screening.Systematic AF screening using non-invasive tools was associated with higher rate of new AF detection and initiation of OAC, but opportunistic screening was not associated with higher detection rates. There were no significant differences between the various AF screening approaches with respect to rates of all-cause mortality or CVA events. However, these analyses are likely underpowered and future RCTs are needed to examine the impact of systematic AF screening on mortality and CVA outcomes.None.

Despite being the mainstay for the initial noninvasive assessment of patients with symptomatic coronary artery disease, the 12‑lead 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.

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. Summary 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.

Patients with occlusion myocardial infarction (OMI) and no ST-elevation on presenting ECG are increasing in numbers. These patients have a poor prognosis and would benefit from immediate reperfusion therapy, but we currently have no accurate tools to identify them during initial triage. Herein, we report the first observational cohort study to develop machine learning models for the ECG diagnosis of OMI. Using 7,313 consecutive patients from multiple clinical sites, we derived and externally validated an intelligent model that outperformed practicing clinicians and other widely used commercial interpretation systems, significantly boosting both precision and sensitivity. Our derived OMI risk score provided superior rule-in and rule-out accuracy compared to routine care, and when combined with the clinical judgment of trained emergency personnel, this score helped correctly reclassify one in three patients with chest pain. ECG features driving our models were validated by clinical experts, providing plausible mechanistic links to myocardial injury.

The clinical significance of right bundle branch block (RBBB) or bifascicular block (BFB) in the setting of acute myocardial infarction (AMI) is uncertain. RBBB was found in 211 of 7,626 patients (2.8%), presenting to the ED (emergency department) with chest pain, of which 18 (8.5%) also had acute coronary syndrome (ACS). Incidences of ACS were not significantly different between new or presumed new RBBB and prior known RBBB or new or presumed new BFB and prior known BFB. In 2 patients, baseline ST-segment depression in leads V1-3 masked anterior ST-elevation detected on electrocardiogram (ECG). In opposition to the guidelines, the presence of RBBB or BFB does not appear to offer any clinical utility when evaluating patients with suspected AMI. Patients with suspected AMI who present with RBBB and any ST-elevation in leads V1-3 should be considered for emergent coronary angiography rather than RBBB alone.

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. 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). 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

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. 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. 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. 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.

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).

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 P2YWe 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 P2YData comparing dual therapy with OAC and a P2YThe addition of aspirin to OAC and a P2Y

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. 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. 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

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.

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.

Identifying ischemic etiology of cardiomyopathy carries prognostic and therapeutic significance. Clinical and electrocardiographic parameters can predict ischemic cardiomyopathy. Positive T wave polarity in lead aVR (TPaVR) has been associated with adverse cardiac events and severity of coronary artery disease. Medical records of adults evaluated in an advanced heart failure referral clinic for cardiomyopathy with systolic dysfunction (ejection fraction ≤ 40%) were retrospectively reviewed. Patients with ventricular pacing were excluded. Significant predictors of ischemic cardiomyopathy from a univariate logistic regression model were entered simultaneously into a multivariate logistic regression model. A total of 180 patients met study inclusion criteria. Mean age of the population was 52.5 ± 15.3 years old and 65% were men. Ischemic cardiomyopathy was present in 52 patients (29%). Positive TPaVR was present in 57 patients (32%). Ischemic cardiomyopathy was more common in patients with positive TPaVR (63% vs 13%, plt; 0.001). Ischemic cardiomyopathy was independently predicted by male gender, diabetes, hyperlipidemia, absence of family history of cardiomyopathy, echocardiographic regional wall motion abnormality, and positive TPaVR. The strongest association was with positive TPaVR (odds ratio 30.5, 95% confidence interval 6.47 to 214; plt; 0.001). T wave amplitude of +0.025 mV in lead aVR was the optimal cutoff to distinguish ischemic and nonischemic cardiomyopathy in receiver operating characteristic analysis (sensitivity 69.2%, specificity 83.6%, area under curve = 0.747, 95% confidence interval 0.658 to 0.836). In conclusion, positive TPaVR was a strong predictor of ischemic etiology of cardiomyopathy.

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.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.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.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.

To assess the effects of electro-acupuncture (EA) on glycemic control, myocardial inflammation, and the progression of diabetic cardiomyopathy in mice with type 2 diabetes. Db/Db mice received EA at PC6+ST36 (DM-Acu), non-acupoint simulation (DM-Sham), or no treatment (DM). EA was applied for 30 min per day, 5 days a week for 4 weeks. Heart function was assessed by echocardiography. Myocardium was assessed by RT-PCR, immunoblotting, and histology. Serum TNF-α, IL-1α, IL-1β, IL-6, and IL-8 were measured. DM-Acu, but not DM-Sham, reduced fasting blood glucose without affecting body weight. DM decreased systolic function. DM-Acu, but not DM-Sham, attenuated the decrease in systolic function. Heart weight was significantly smaller in the DM-Acu than in the DM and DM-Sham groups. Percent fibrosis and apoptosis were reduced in the DM-Acu, but not the DM-Sham, group. Serum levels of IL-1α, IL-1β, IL-6, IL-8, ICAM-1, MCP-1, and TNF-α were significantly lower in the DM-Acu than in the DM or DM-Sham groups. Protein levels of P-Akt and P-AMPK and mRNA levels of phosphoinositide-3-kinase regulatory subunit 6 (PIK3r6) were significantly higher in the DM-Acu group. Myocardial mRNA and protein levels of insulin-like growth factor 1 receptor (IGF1R) were significantly lower in the DM and DM-Sham groups compared with the DM-Acu group. EA reduced serum glucose; prevented DM-induced hypertrophy and deterioration of systolic function, inflammation, and fibrosis; and restored IGF1R, P-Akt, and P-AMPK levels in mice with type 2 diabetes mellitus.

The pivotal studies that led to the recommendations for emergent reperfusion therapy for ST-elevation myocardial infarction (STEMI) were conducted for the most part over 25 years ago. At that time, contemporary standard treatments including aspirin, statin, and even anticoagulation were not commonly used. The 2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines and the 2017 European Society of Cardiology guidelines give a class I recommendation (with the level of evidence A) for primary percutaneous coronary intervention (pPCI) in patients with STEMI and ischemic symptoms of less than 12 h. However, if the patient presents to a hospital without pPCI capacity, and it is anticipated that pPCI cannot be performed within 120 min of first medical contact, fibrinolytic therapy is indicated (if there are no contraindications) (class I indication, level of evidence A). Our review of the pertinent literature shows that the current recommendation for inferior STEMI is based on the level of evidence lower than A. We can consider level B even C, supporting the recommendation for fibrinolytic therapy if pPCI is not available for inferior STEMI.

Beta blockers and renin-angiotensin-aldosterone-inhibitors (RAAS-i) including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been a mainstay of guideline-based medical therapy for heart failure with reduced ejection fraction (HFrEF) for decades. However, initial evidence supporting each of the aforenoted class of drug for heart failure indications was largely found independently of the other two classes with the exception of the addition of BBs to ACEIs. In the initial ACEI trials for HFrEF, few participants were on BBs as BBs were seen as contraindicated in HFrEF at the time. The seminal BB in HFrEF trials had high prevalence of ACEIs use as ACEIs for HF were standard of care by then, but ARBs as a class were still in their infancy. We closely examine the evidence for combinations of BB and ACEIs versus ARBs in HFrEF. In doing so, we demonstrate the lack of evidence for consideration of ARBs to be interchangeable with ACEIs when used in combination with BB and provide evidence that calls in to question the validity of assuming benefits from each drug class are independently cumulative, widening the gap between ACEIs and ARBs when used with BBs. Modern guidelines should emphasize this lack of evidence for the combination use of ARB and BB in HFrEF, except for candesartan. Even as practice moves towards the widespread uptake of angiotensin receptor-neprilysin inhibitors (which contain the ARB valsartan) in heart failure, the distinction has important implications for the ongoing role of combination therapy with BB, which thus far has been assumed, but not proven.

Background: In patients with pulmonary hypertension (PHT), the assessment of left ventricular (LV) diastolic function by echocardiography may not be reliable. PHT can affect Doppler parameters of LV diastolic function such as mitral inflow velocities and mitral annular velocities. The current guidelines for the assessment of LV diastolic function do not recommend specific adjustments for patients with PHT. Methods: We analyzed 36 patients from the PHT clinic that had an echocardiogram and right heart catheterization performed within 6 months of each other. Early mitral inflow velocity (E), lateral mitral annular velocity (lateral e’), septal mitral annular velocity (septal e’), tricuspid free wall annular velocity (RV e’) were measured and compared to the invasively measured intracardiac pressures including pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure, and right ventricular end-diastolic pressure. Results: Among patients with PHT, the specificity of the septal e’ for LV diastolic dysfunction was 0.19, and the positive predictive value was 0.13 (lower than the lateral e’ or E/average e’). By receiver-operating characteristic curve analysis, the area under the curve (AUC) of lateral and septal e’ was just 0.64 (p = 0.9) and 0.53 (p = 0.6), respectively, while the AUC of average E/e’ was 0.94 (p < 0.001). The septal e’ was paradoxically lower at 6.5 ± 1.9 cm/s for normal PCWP compared to 6.9 ± 1.7 cm/s for elevated PCWP (p = 0.04). 81 versus 40% (p = 0.017) of patients with normal versus elevated PCWP had an abnormal septal e’ Conclusion: Our study suggests E/average e’ may be the only reliable tissue Doppler parameter of LV diastolic dysfunction in patients with PHT, and that septal e’ is paradoxically decreased in patients with PHT and normal left-sided filling pressures.

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.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.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.AZD3366 attenuated inflammation, necrosis, necroptosis, and pyroptosis and limited IS. The effects of AZD3366 and ticagrelor were additive.

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.

Acute ST-elevation myocardial infarction (STEMI) is associated with a high incidence of complications as well as a considerable hospitalization rate and economic burden. Preliminary evidence suggests that remote ischemic conditioning (RIC) is a promising non-invasive intervention that may effectively and safely reduce myocardial infarct size, subsequent cardiac events and complications, and mortality. However, RIC's cardio-protective effect remains under debate, especially for single timepoint RIC programs. Adequately powered large-scale randomized controlled trials investigating clinical outcomes are thus needed to clarify the role of full disease cycle RIC programs.The intelligent "Internet Plus"-based full disease cycle remote ischemic conditioning (i-RIC) trial is a pragmatic, multicenter, randomized controlled, parallel group, clinical trial. The term, intelligent "Internet Plus"-based full disease cycle, refers to smart devices aided automatic and real-time monitoring of remote ischemic pre-, per- or post-conditioning intervention for patients with STEMI undergoing percutaneous coronary intervention (PCI). Based on this perspective, 4700 STEMI patients from five hospitals in China will be randomized to a control and an intervention group. The control group will receive PCI and usual care, including pharmacotherapy, before and after PCI. The intervention group will receive pre-, per-, and post-operative RIC combined with long-term i-RIC over a one-month period in addition. A smartphone application, an automated cuff inflation/deflation device and "Internet Plus"-based administration will be used in the long-term phase. The primary outcome is the combined cardiac death or hospitalization for heart failure rate. Secondary outcomes include clinical and functional outcomes: major adverse cardiac and cerebrovascular events rate, all-cause mortality, myocardial reinfarction rate, readmission rate for heart failure and ischemic stroke rate, unplanned revascularization rate, plasma concentration of myocardial infarction-related key biomarkers, infarct size, cardiac function, cardiopulmonary endurance, health-related quality of life, total hospital length of stay, total medical cost, and compliance with treatment regime.The i-RIC trial is designed to test the hypothesis that clinical and functional outcomes can be improved with the i-RIC program in STEMI patients undergoing PCI. The concept of RIC is expected to be enhanced with this intelligent "Internet Plus"-based program focusing on the full disease cycle. If the i-RIC program results in superior improvement in primary and secondary outcomes, it will offer an innovative treatment option for STEMI patients and form the basis of future recommendations.Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR2000031550, 04 April 2020.

Publishe d decades after several randomized controlled trials (RCT) demonstrating decreased hospitalizations and no effect on all-cause mortality with digoxin use, a series of meta-analyses linking digoxin treatment and mortality have contributed to a narrower application of this medication for the management of heart failure (HF) and atrial fibrillation (AF). Given the conflicting data from the earlier RCTs and more recent meta-analyses, there is a growing polarization among providers for and against the use of digoxin in managing these conditions. To help close this divide, we provide a perspective on the literature with special attention to the quality of both older and more recent studies on this subject. The data from the highest quality studies we have, RCTs, suggest that digoxin use in patients with HF and/or AF is associated with improvement in several areas of outcomes including functional capacity, symptom management, reduced hospitalizations, fewer deaths due to HF, and treatment of refractory chronic heart failure with rEF, and may even have overall mortality benefit when serum digoxin concentrations are within therapeutic range. These effects are more pronounced in patients with EF

A number of criteria have been developed to aid with the diagnosis of occlusion myocardial infarction (OMI) in patients with left bundle branch block (LBBB) and ventricular paced rhythms (VPR). The current guidelines do not provide clear preference for any specific ECG criteria in LBBB and paced rhythm patients. This review delineates the difficulties of electrocardiographic diagnosis of OMI in both LBBB and VPR patients. We describe the original Sgarbossa and the newer criteria and their diagnostic performances. We highlight the expected changes of newer pacing modalities and how they may interfere with the electrocardiographic diagnosis of OMI. We recommend utilizing the Cai et al. algorithm, which combines clinical assessment with the Smith Modified Sgarbossa ECG criteria, for both LBBB and right ventricular pacing patients with suspected OMI. There is limited data concerning ECG changes of OMI in patients with the newer pacing modalities, such as biventricular, His-bundle, or left bundle branch pacing.

OBJECTIVE There is mounting evidence regarding the cardiovascular benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) among patients with atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM). There is paucity of data assessing real-world practice patterns for these drug classes. We aimed to assess utilization rates of these drug classes and facility-level variation in their use. RESEARCH DESIGN AND METHODS We used the nationwide Veterans Affairs (VA) health care system data set from 1 January 2020 to 31 December 2020 and included patients with established ASCVD and T2DM. Among these patients, we assessed the use of SGLT2i and GLP-1 RA and the facility-level variation in their use. Facility-level variation was computed using median rate ratios (MRR), a measure of likelihood that two random facilities differ in use of SGLT2i and GLP-1 RA in patients with ASCVD and T2DM. RESULTS Among 537,980 patients with ASCVD and T2DM across 130 VA facilities, 11.2% of patients received an SGLT2i while 8.0% of patients received a GLP-1 RA. Patients receiving these cardioprotective glucose-lowering drug classes were on average younger and had a higher proportion of non-Hispanic Whites. Overall, median (10th–90th percentile) facility-level rates were 14.92% (9.31–22.50) for SGLT2i and 10.88% (4.44–17.07) for GLP-1 RA. There was significant facility-level variation among SGLT2i use—MRRunadjusted: 1.41 (95% CI 1.35–1.47) and MRRadjusted: 1.55 (95% CI 1.46 –1.63). Similar facility-level variation was observed for use of GLP-1 RA—MRRunadjusted: 1.34 (95% CI 1.29–1.38) and MRRadjusted: 1.78 (95% CI 1.65–1.90). CONCLUSIONS Overall utilization rates of SGLT2i and GLP-1 RA among eligible patients are low, with significantly higher residual facility-level variation in the use of these drug classes. Our results suggest opportunities to optimize their use to prevent future adverse cardiovascular events among these patients.

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 β-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1β, 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.

ST elevation on ECGs immediately after cardiac surgery is usually considered to be non-specific. However, these ST changes can be the first clues to serious condition such as graft occlusion and myocardial infarction. We present two patients with ST elevation on ECGs immediately following coronary artery bypass surgery to illustrate that ST changes early after surgery can represent significant pathology and true ischemia after cardiac surgery, which warrants prompt investigation. More studies are needed to see if different thresholds for ST elevation should be used for detecting STEMI after heart surgery.

Background In the standard ECG display, limb leads are presented in a non-anatomical sequence: I, II, III, aVR, aVL, aVF. The Cabrera system is a display format which instead presents the limb leads in a cranial/left-to-caudal/right sequence, i.e. in an anatomically sequential order. Lead aVR is replaced in the Cabrera display by its inverted version, −aVR, which is presented in its logical place between lead I and lead II. Main text In this debate article possible implications of using the Cabrera display, instead of the standard, non-contiguous lead display, are presented, focusing on its use in patients with possible acute coronary syndrome. The importance of appreciating reciprocal limb-lead ECG changes and the diagnostic and prognostic value of including aVR or lead −aVR in ECG interpretation in acute coronary syndrome is covered. Illustrative cases and ECGs are presented with both the standard and contiguous limb lead display for each ECG. A contiguous lead display is useful when diagnosing acute coronary syndrome in at least 3 ways: 1) when contiguous leads are present adjacent to each other, identification of ST elevation in two contiguous leads is simple; 2) a contiguous lead display facilitates understanding of lead relationships as well as reciprocal changes; 3) it makes the common neglect of lead aVR unlikely. Conlusions It is logical to display the limb leads in their sequential anatomical order and it may have advantages both in diagnostics and ECG learning.

Types 1 and 2 myocardial infarction (MI) may occur in the setting of gastrointestinal bleeding (GIB). There is a paucity of data pertinent to the contemporary prevalence and impact of types 1 and 2 MI following GIB. We examined clinical profiles and the prognostic impact of both MI types on outcomes of patients hospitalized with GIB.The 2018 Nationwide Readmission Database was queried for patients hospitalized for the primary diagnosis of GIB and had concomitant diagnoses of type 1 or type 2 MI. Baseline characteristics, in-hospital mortality, resource utilization, and 30-day all-cause readmissions were compared among groups.Of 381,867 primary GIB hospitalizations, 2902 (0.75%) had type 1 MI and 3963 (1.0%) had type 2 MI. GIB patients with type 1 and type 2 MI had significantly higher in-hospital mortality compared to their counterparts without MI (adjusted odds ratios [aOR]: 4.72, 95% confidence interval [CI] 3.43-6.48; and aOR: 2.17, 95% CI 1.48-3.16, respectively). Both types 1 and 2 MI were associated with higher rates of discharge to a nursing facility (aOR of type 1 vs. no MI: 1.65, 95% CI 1.45-1.89, and aOR of type 2 vs no MI: 1.37, 95% CI 1.22-1.54), longer length of stay, higher hospital costs, and more 30-day all-cause readmissions (aOR of type 1 vs no MI: 1.22, 95% CI 1.08-1.38; aOR of type 2 vs no MI: 1.17, 95% CI 1.05-1.30).Types 1 and 2 MI are associated with higher in-hospital mortality and resource utilization among patients hospitalized with GIB in the United States.

Acute myocardial infarction (MI) is still a large source of morbidity and mortality worldwide. Although early reperfusion therapy has been prioritized in the modern era of percutaneous coronary intervention and thrombolysis, attempts at incremental improvements in clinical outcomes by reducing MI size have not been successful so far. Herein, we review the studies that have evaluated immediate-onset antiplatelet therapy as attempts to improve meaningful clinical outcomes in ST-segment elevation MI (STEMI). Unfortunately, many of the adjunctive pharmacotherapies have proven to be disappointing. Recent studies performed in the background of routine oral administration of P2Y12 adenosine receptor inhibitors, which may take several hours to take full effect, and aspirin have largely shown no improvement in outcomes, despite an earlier onset of antiplatelet activity of the investigative agents. Further progress in improving outcomes during STEMI may depend on exploring therapeutics that modulate the pathophysiology of microvascular damage during ischemia–reperfusion injury, a phenomenon whose effects evolve over hours to days. We speculate that the dynamic nature of the no-reflow phenomenon may be an explanation for these disappointing results with the intravenous antiplatelet agents. We hope that appreciation for what has not worked in this domain may direct future research efforts to focus on novel pathways. Myocardial ischemia and reperfusion injury are very much still a lingering issue. Despite significant improvements in door-to-balloon times, rates of in-hospital mortality for STEMI remain unchanged. Outcomes following successfully reperfused STEMI are likely determined by the initial size of myocardial necrosis (ie, cardiomyocyte death during the period of ongoing ischemia), patency of the infarct-related epicardial coronary artery, possible reperfusion injury, the microvascular no-reflow phenomenon, and adverse remodeling after infarction.

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.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.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).While overall AF event rates were low, n-3 FA treatment is associated with increased risk for AF.

Dipyridamole is an old anti-platelet and coronary vasodilator agent that inhibits platelet phosphodiesterase and increases interstitial adenosine levels. Its use in coronary artery disease (CAD) has fallen out of practice in the modern era with the advent of new anti-platelet agents, and most modern guidelines on the management of CAD either neglect to comment on its utility or outright recommend against it. The majority of the studies used in these guidelines are outdated and took place in an era when high doses of aspirin were used and statins were not widely utilized. There is growing evidence in rat models of dipyridamole’s synergy with statins through adenosine modulation resulting in significant myocardial protection against ischemia–reperfusion injury and limitation of infract size. The data in human studies are limited but show a similar potential synergy between dipyridamole and statins. It would thus be prudent to reconsider the recommendations against the use of dipyridamole in CAD and to re-evaluate its possible role and potential benefits through well-designed randomized trials combining it with statins, low-dose aspirin, and/or other anti-platelet agents.