Myocardial infarction causes heart tissue damages; therefore, using non-invasive methods to regenerate the heart tissue could be very helpful. Recent studies claimed that the inhibition of the Wnt signaling could promote cardiac remodeling and induce cardiac regeneration. Therefore, a tankyrase inhibitor to stabilize the AXIN and inhibit the Wnt/β-catenin signaling pathway will induce cardiac regeneration after injury. In this regard, virtual screening procedure, using molecular docking of 9127 FDA and world approved drugs, including herbal medicine, was done over the crystal structures of tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) catalytic poly (ADP-ribose) polymerase (PARP) domains with PDB ID: 2RF5 and 3KR7, respectively, to find potential small molecule inhibitors to regenerate injured heart tissue. Subsequently, molecular dynamics simulations were done to assess the stability of selected ligands phenothrin and ethyl rosinate in the binding pocket of TNKS1 and TNKS2 for 100 ns, respectively. Both compounds show suitable interaction in their binding pocket. The molecular dynamics simulation results confirm their stability. The binding free energy of complexes was carried out by the MM-PBSA method. ADME properties also indicate the potential of drug-likeness of both compounds. Taking together both drugs may be promising for inducing cardiac regeneration after injury. Nevertheless, clinical approval remains.

Keywords: Cardiac tissue regeneration; Molecular dynamic simulation; Tankyrase inhibitor; Virtual screening; Wnt/β-catenin signaling.

Introduction: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) were individually proven to reduce major adverse cardiovascular events (MACE) in type 2 diabetes mellitus (T2DM) patients, but the relative magnitude of benefits from these two drug classes is debated. We aimed to review current available data on GLP1-RA and SGLT2i in T2DM patients and compare their efficacy and safety in this population.

Evidence acquisition: We systematically searched MEDLINE/PubMed, the Cochrane Library, Google Scholar, Embase, www.tctmd.com, www.clinicaltrials.gov, www.clinicaltrialresults.org, from inception to September 17, 2020 for randomized controlled trials (RCTs) comparing the effects of GLP1-RA vs SGLT2i vs optimal medical therapy (OMT) in adult T2DM patients. Three authors independently screened references and extracted data using a predefined data collection form. Outcomes were analyzed using an indirect comparison meta-analysis of aggregate study-level data. The primary combined efficacy outcome comprised cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary efficacy outcomes included all-cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, heart failure hospitalizations (HFH), and worsening renal function (WRF).

Evidence synthesis: 11 RCTs enrolling a total of 98572 patients were included; 56004 (57%) patients were derived from GLP1-RA RCTs and 42568 (43%) from SGLT2i RCTs. At a median follow-up of 3.0±1.3 years, compared with OMT, both GLP1-RA and SGLT2i similarly reduced the rate of the composite primary outcome (risk ratio [RR] 0.88; 95% confidence interval [95%CI] 0.83-0.93 and RR 0.88, 95%CI 0.82-0.95, respectively) with no difference between the drug classes (RR 1.00, 95%CI 0.92-1.10). Both classes similarly reduced MI rate, cardiovascular and all-cause mortality compared with OMT; stroke reduction was only observed with GLP1-RA with no difference in the indirect comparison with SGLT2i; conversely, only SGLT2i were effective in preventing HFH. Both GLP1-RA and SGLT2i were protective against WRF, with a major efficacy of SGLT2i in the indirect comparison.

Conclusions: This meta-analysis report that GLP1-RA and SGLT2i reduced with a similar efficacy not only MACE as MI, but also cardiovascular mortality and all-cause mortality at a median 3 years follow-up. SGLT2i were more protective in HFH and WRF than GLP1RA. These new data highlight the efficacy of SGLT2i not only in HF and chronic kidney disease (CKD) but also in ischemic heart diseases (IHD), with a homogeneity among the class, whereas the results observed with GLP1-RA are heterogenous. These findings will help clinical's decisions to optimize therapeutic strategies for diabetic patients.

Background: Fetuin-A is an anti-inflammatory and anti-calcification factor involved in the course of coronary artery disease (CAD). In line with these functions, fetuin-A has been investigated as a cardiovascular risk marker in many studies. However, the association between fetuin-A and the prognosis of CAD patients is still controversial.

Objectives: The present study was conducted to identify the association between serum fetuin-A level and long-term cardiovascular disease (CVD) and all-cause mortality of ST-elevation acute myocardial infarction (STEMI).

Methods: One hundred eigthy consecutive patients with STEMI were enrolled in the study. The study population was divided into subgroups (lower, ≤288 µg/ml; and higher, >288 µg/ml) according to the median fetuin-A level. Clinical follow-up data was obtained by annual contact with the patients or family members by telephone. The causes of death were also confirmed by the national health database. Two-sided p-values<0.05 were considered statistically significant.

Results: During a median follow-up of 10 years, 71 deaths were recorded , 62 of whom died from CVD. Both CVD and all-cause mortality were found to be significantly higher in the lower fetuin-A group than the higher fetuin-A group (44% vs 24%, p= 0.005; 48% vs 31%, p= 0.022, respectively). In Cox regression proportional hazard analyses, fetuin-A was found to be an independent predictor of CVD and all-cause mortality.

Conclusions: Low fetuin-A concentration is associated with a poor long-term prognosis after STEMI, regardless of the traditional cardiovascular risk factors. Our findings have strengthened previous studies that consistently demonstrate the determining role of anti-inflammatory mediators in acute coronary syndromes.

Fundamento: A fetuína-A é um fator anti-inflamatório e anticalcificação envolvido no curso da doença arterial coronariana (DAC). Em alinhamento com essas funções, investigou-se a fetuína-A como marcador de risco cardiovascular em vários estudos. Porém, a associação entre a fetuína-A e o prognóstico dos pacientes com DAC ainda é controversa.

Objetivos: O presente estudo foi conduzido para identificar a associação entre o nível de fetuína-A sérica e doença cardiovascular (DCV) de longo prazo e a mortalidade global por infarto do agudo do miocárdio por supradesnivelamento do segmento ST (STEMI).

Métodos: Foram cadastrados no estudo cento e oitenta pacientes consecutivos com STEMI. A população do estudo foi dividida em subgrupos (mais baixo, ≤288 µg/ml; e mais alto, >288 µg/ml) de acordo com a mediana do nível de fetuína-A. Dados de acompanhamento clínico foram obtidos por contato telefônico anual com pacientes ou familiares. As causas das mortes também foram confirmadas pelo banco de dados de saúde nacional. P-valores bilaterais <0,05 foram considerados estatisticamente significativos.

Resultados: Durante um acompanhamento médio de 10 anos, foram registradas 71 mortes, das quais 62 foram devidas a DCV. Identificou-se um índice de mortalidade global e por DCV significativamente mais alto no grupo com nível de fetuína-A mais baixo que no grupo com nível de fetuína-A mais alto (44% versus 24%, p= 0,005; 48% versus 31%, p= 0,022, respectivamente). Nas análises de risco proporcionais por regressão de Cox, detectou-se que a fetuína-A era um preditor independente de mortalidade global e por DCV.

Conclusões: A baixa concentração de fetuína-A está associada ao prognóstico de longo prazo ruim pós-STEMI, independentemente de fatores de risco cardiovascular tradicionais. Nossos achados fortaleceram estudos prévios demonstrando consistentemente o papel determinante dos mediadores anti-inflamatórios em síndromes coronárias agudas.

Background: The smoking paradox has been a matter of debate for acute myocardial infarction patients for more than two decades. Although there is huge evidence claiming that is no real paradox, publications supporting better outcomes in post-MI smokers are still being released.

Objective: To explore the effect of smoking on very long-term mortality after ST Elevation myocardial infarction (STEMI).

Methods: This study included STEMI patients who were diagnosed between the years of 2004-2006 at three tertiary centers. Patients were categorized according to tobacco exposure (Group 1: non-smokers; Group 2: <20 package*years users, Group 3: 20-40 package*years users, Group 4: >40 package*years users). A Cox regression model was used to estimate the relative risks for very long-term mortality. P value <0.05 was considered as statistically significant.

Results: There were 313 patients (201 smokers, 112 non-smokers) who were followed-up for a median period of 174 months. Smokers were younger (54±9 vs. 62±11, p: <0.001), and the presence of cardiometabolic risk factors were more prevalent in non-smokers. A univariate analysis of the impact of the smoking habit on mortality revealed a better survival curve in Group 2 than in Group 1. However, after adjustment for confounders, it was observed that smokers had a significantly increased risk of death. The relative risk became higher with increased exposure (Group 2 vs. Group 1; HR: 1.141; 95% CI: 0.599 to 2.171, Group 3 vs Group 1; HR: 2.130; 95% CI: 1.236 to 3.670, Group 4 vs Group 1; HR: 2.602; 95% CI: 1.461 to 4.634).

Conclusion: Smoking gradually increases the risk of all-cause mortality after STEMI.

Fundamento: O paradoxo do fumante tem sido motivo de debate para pacientes com infarto agudo do miocárdio (IM) há mais de duas décadas. Embora haja muitas evidências demonstrando que não existe tal paradoxo, publicações defendendo desfechos melhores em fumantes pós-IM ainda são lançadas.

Objetivo: Explorar o efeito do fumo na mortalidade de longo prazo após infarto do miocárdio por elevação de ST (STEMI).

Métodos: Este estudo incluiu pacientes com STEMI que foram diagnosticados entre 2004 e 2006 em três centros terciários. Os pacientes foram categorizados de acordo com a exposição ao tabaco (Grupo 1: não-fumantes; Grupo 2: <20 pacotes*anos; Grupo 3: 2-040 pacotes*anos; Grupo 4: >40 pacotes*anos). Um modelo de regressão de Cox foi utilizado para estimar os riscos relativos para mortalidade de longo prazo. O valor de p <0,05 foi considerado como estatisticamente significativo.

Resultados: Trezentos e treze pacientes (201 fumantes e 112 não-fumantes) foram acompanhados por um período médio de 174 meses. Os fumantes eram mais novos (54±9 vs. 62±11, p: <0,001), e a presença de fatores de risco cardiometabólicos foi mais prevalente entre os não-fumantes. Uma análise univariada do impacto do hábito de fumar na mortalidade revelou uma curva de sobrevivência melhor no Grupo 2 do que no Grupo 1. Porém, após ajustes para fatores de confusão, observou-se que os fumantes tinham um risco de morte significativamente maior. O risco relativo tornou-se maior de acordo com a maior exposição (Grupo 2 vs. Grupo 1: RR: 1,141; IC95%: 0,599 a 2.171; Grupo 3 vs. Grupo 1: RR: 2,130; IC95%: 1,236 a 3,670; Grupo 4 vs. Grupo 1: RR: 2,602; IC95%: 1,461 a 4,634).

Conclusão: O hábito de fumar gradualmente aumenta o risco de mortalidade por todas as causas após STEMI.

The expression of various isoforms of aquaporins (AQPs) in different tissues and organs of the body makes it a viable candidate for being responsible for maintaining cell stability and integrity as their involvement has been well documented in a number of pathophysiological conditions of the human body. Any alteration in the cellular environment brought about by these AQPs creates severe downstream effects like changes in cellular osmolality, volume, ionic composition, signaling pathways and even in the levels of intracellular second messengers and, as such, facilitates the occurrence of diseases like cancer. The altered equilibrium of water, extracellular ions and amino acid neurotransmitters caused by neuronal destruction and oxidative stress in neurodegenerative diseases proposed the role of these AQPs in these diseased conditions as well. The association of AQPs in a variety of inflammatory processes like lung injury, brain edema, neuromyelitis optica, and colitis as manifested through their dysregulation both in animal and human diseases is truly an eye opener for their role in protection and reaction to various noxious stimuli including bacterial infection. Renal diseases like nephrogenic diabetes inspidus, autosomal dominant polycystic kidney disease and acute kidney injury are some of the pathophysiological conditions related to malfunctioning of aquaporins. Besides, the malfunctioning of aquaglyceroporins like AQP7 and AQP9 makes them responsible for disorders like obesity, nonalcoholic fatty liver disease and non-alcoholic steatohepatitis. In this review article, we present our current understanding of the role of AQPs in the causation of these metabolic disorders and how targeting them holds promising therapeutic potential for most of these diseases like cancer, renal diseases and even cardiovascular disorders.

Keywords: dysregulation; metabolic disorders; myocardial infarction; neurodegenerative; pathophysiological.

Background: Contemporary practices for hemodynamically supported high-risk percutaneous coronary intervention (HRPCI) have evolved over the last decade. This study sought to compare outcomes of the prospective, multicenter, PROTECT III study to historic patients treated with Impella in the PROTECT II randomized controlled trial (RCT).

Methods: Of 1,134 patients enrolled in PROTECT III from March 2017 to March 2020, 504 were "PROTECT II-like" (met eligibility for PROTECT II RCT) and are referred to as PROTECT III for comparative analysis. Major adverse cardiac and cerebrovascular events (MACCE), comprising all-cause mortality, stroke/transient ischemic attack, myocardial infarction (MI), and repeat revascularization, were compared at hospital discharge and 90 days.

Results: Compared with PROTECT II (N=216), PROTECT III patients were less often Caucasian (77.1% vs 83.8%, p=0.045), with less prior CABG (13.7% vs 39.4%; p<0.001) and prior MI (40.7% vs 69.3%; p<0.001). More PROTECT III patients underwent rotational atherectomy (37.1% vs 14.8%, p<0.001) and duration of support was longer (median 1.6 vs 1.3 hours; p<0.001), with greater improvement achieved in myocardial ischemia jeopardy scores (7.0±2.4 vs 4.4±2.9; p<0.001) and SYNTAX scores (21.4±10.8 vs 15.7±9.5; p<0.001). In-hospital bleeding requiring transfusion was significantly lower in PROTECT III (1.8% vs 9.3%; p<0.001), as was procedural hypotension (2.2% vs 10.1%; p<0.001) and cardiopulmonary resuscitation or ventricular arrhythmia (1.6% vs 6.9%; p<0.001). At 90 days, MACCE was 15.1% and 21.9% in PROTECT III and PROTECT II, respectively (p=0.037). Following propensity score matching, Kaplan-Meier analysis showed improved 90-day MACCE rates in PROTECT III (10.4% vs 16.9%, p=0.048).

Conclusions: The PROTECT III study demonstrates improved completeness of revascularization, less bleeding, and improved 90-day clinical outcomes compared to PROTECT II for Impella-supported HRPCI among patients with severely depressed LVEF.

Keywords: Impella; ejection fraction; left ventricular dysfunction; mechanical circulatory support; percutaneous coronary intervention.

Variations in high-sensitivity cardiac troponin I (hs-cTnI) by age and sex along with various sampling times can make the evaluation for acute myocardial infarction (AMI) challenging. Machine learning integrates these variables to allow a more accurate evaluation for possible AMI. The goal was to test the diagnostic and prognostic utility of a machine learning algorithm in the evaluation of possible AMI. We applied a machine learning algorithm (myocardial-ischemic-injury-index [MI3]) that incorporates age, sex, and hs-cTnI levels at time 0 and 30 minutes in 529 patients evaluated for possible AMI in a single urban emergency department. MI3 generates an index value from 0-100 reflecting the likelihood of AMI. Patients were followed at 30-45 days for major adverse cardiac events (MACE). There were 42 (7.9%) patients that had an AMI. Patients were divided into 3 groups by the MI3 score: low-risk (≤ 3.13), intermediate-risk (> 3.13-51.0), and high-risk (> 51.0). The sensitivity for AMI was 100% with a MI3 value ≤ 3.13 and 353 (67%) ruled-out for AMI at 30 minutes. At 30-45 days there were 2 (0.6%) MACEs (2 non-cardiac deaths) in the low-risk group, in the intermediate-risk group 4 (3.0%) MACEs (3 AMIs, 1 cardiac death), and in the high-risk group 4 (9.1%) MACEs (4 AMIs, 2 cardiac deaths). The MI3 algorithm had 100% sensitivity for AMI at 30 minutes and identified a low-risk cohort who may be considered for early discharge.

Ventricular septum defect (VSD) is an often lethal complication caused by myocardial infarction. We report a rare case of post-myocardial infarction ventricular septum rupture in a patient after extracorporeal cardiopulmonary resuscitation (eCPR). In the bedside echocardiography after VA ECMO cannulation, we noticed the circular, hypertrophied left ventricle with the disintegrated inter-ventricular septum (maximum dehiscence 3.3 cm), accompanied by decreased left-ventricular ejection fraction and the right ventricle being compressed by the left ventricle's free septal wall. There was no pressure-relevant inter-ventricular separation resulting in left-to-right-shunting and therefore resulting in a fully functional uni-ventricular heart.

Keywords: STEMI; TEE; VSD; myorcadial infarction.

Background: In patients with ST-segment elevation myocardial infarction (STEMI) who have multivessel disease, the FLOWER-MI trial found no significant clinical benefit to fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) compared to angiography-guided PCI.

Aims: Our aim was to estimate the cost-effectiveness and cost-utility of FFR-guided PCI, the secondary endpoint of the FLOWER-MI trial.

Methods: Costs, major adverse cardiovascular events (composite of all-cause death, non-fatal myocardial infarction [MI], and unplanned hospitalisation leading to urgent revascularisation), and quality-adjusted life years were calculated in both groups. The incremental cost-effectiveness and cost-utility ratios were estimated. Uncertainty was explored by probabilistic bootstrapping. The analysis was conducted from the perspective of the health care provider with a time horizon of one year.

Results: At one year, the average cost per patient was 7,560€ (±2,218) in the FFR-guided group and 7,089€ (±1,991) in the angiography-guided group (p-value<0.01). The point estimates for the incremental cost-effectiveness and cost-utility ratios found that the angiography-guided strategy was cost saving and improved outcomes, with a probabilistic sensitivity analysis confirming dominance.

Conclusions: The FFR-guided strategy at one year is unlikely to be cost effective compared to the angiography-guided strategy on both clinical and quality of life outcomes.

Context: As many as 14% of patients transported by ambulance with chest pain die prior to hospital discharge. To date, no high-quality controlled trials have revealed that prehospital advanced life support interventions affect survival for these patients.Objective: The Ontario Prehospital Advanced Life Support (OPALS) Study assessed the effect of adding an advance life support service to an existing basic life support emergency medical service program, on the rate of mortality and morbidity for patients with out-of-hospital chest pain.Design: Controlled clinical trial comparing survival for 9 months before and 9 after instituting an advanced life support program.Setting: Thirteen urban and suburban Ontario communities (populations ranging from 30,000 to 750,000; total, 2.5 million).Patients: All adult patients with a primary complaint of chest pain and transported by paramedics to the emergency department.Intervention: Paramedics were trained in standard advanced life support, which includes endotracheal intubation, intravenous furosemide and morphine, oral ASA, and sublingual NTG. Emergency medical services within each community had to meet predefined criteria in order to qualify for the advanced life support phase.Main Outcome Measure: Survival to hospital discharge.Results: Overall, 12,168 patients were enrolled in either the basic life support phase (N = 5,788) or the advanced life support phase (N = 6,380). The rate of mortality significantly decreased from 4.3% in the basic life support phase to 3.2% in the advanced life support phase (absolute change 1.1, 95% CI 0.4-1.8, P = 0.0013). We also demonstrated a decrease in mortality for the subgroup of patients with a discharge diagnosis of myocardial infarction (13.1 percent vs 8.2 percent, P = 0.002).Conclusions: The addition of a prehospital advanced life support program to an existing basic life support emergency medical service was associated with a significant decrease in the mortality rate among patients complaining of chest pain. Future research should clarify the most effective interventions and target specific populations.ClinicalTrials.gov Identifier: NCT00212953.

Keywords: Emergency medical services; advanced life support; basic life support; chest pain; myocardial infarction; paramedic; prehospital.

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.

Keywords: Adenosine; Animal model; Apyrase; Infarct size; Myocardial infarction; Necroptosis; Necrosis; Pyroptosis.

Multiplexed assays are essential for the detection of biomarker panels. Differentiating signals from different biomarkers in a single test zone makes the detection more efficient. In this paper, a new method is designed for the synthesis of gap-enhanced nanoparticles (GeNPs) using Raman reporter molecules (RRM) and 6-amino-1-hexanethiol (6-AHT) as the spacer. The GeNPs show a nanometer-size gap, generate strong surface-enhanced Raman scattering (SERS) attributed to the gap, and exhibit discriminative spectral peaks. The strong Au-S bonds on both core and shell sides and the covalent bond between RRM and 6-AHT led to a stable structure, which ensured the stable SERS signal generation from the GeNPs. Using the GeNPs, a spectrally multiplexed assay for the detection of a biomarker panel is developed. The biomarker panel is composed of cardiac troponin I (cTnI), copeptin, and heart-type fatty acid-binding protein (h-FABP), which improves myocardial infarction (MI) diagnostic performance. A paper-based platform that is more amenable to point-of-care diagnostic analysis is used. The developed single biomarker assay achieves limits of detection of 0.01 ng mL^-1, 0.86 ng mL^-1, 0.004 ng mL^-1 for cTnI, h-FABP, and copeptin in buffer solutions. The dynamic range of the assay in human serum samples also covers the clinically relevant range of the biomarkers. The cross interference in the multiplexed assay is low. These results show the strong potential of the developed GeNPs in multiplexed detection of biomarkers and the developed simple-to-use multiplexed assay in the diagnosis of MI at the point of care.

Keywords: Gap-enhanced nanoparticle; Multiplex detection; Myocardial infarction; Paper-based biosensor; Spacer for nanogap; Surface-enhanced Raman spectroscopy.

Objective: Autonomic imbalance in patients with chronic heart failure (CHF) and cardiovascular diseases (CVD) is characterized by reduced parasympathetic and enhanced sympathetic activity. Aerobic exercise improves autonomic function in patients with CHF and CVD. However, little is known about the effects of resistance training (RT) on cardiac autonomic function. Therefore, we aimed to investigate the effects of RT added on aerobic training on autonomic function in patients with CHF and CVD.

Data sources: The relevant clinical trials were searched in PubMed, Physiotherapy evidence Database (PEDro, Science Direct and Google Scholar databases using the following keywords, "resistance or strength training", "chronic heart failure", "coronary artery disease", "myocardial infarction", "hypertension", "cardiovascular disease", "heart rate variability (HRV)", "heart rate recovery (HRR)", "muscle sympathetic nerve activity (MSNA)", and "autonomic function".

Data synthesis: Twelve articles with 323 subjects were eligible to be evaluated. The outcome measures included HRV, HRR, and MSNA. There were seven studies on CHF, two on CAD, and three studies on hypertension. Meta-analysis of all the studies showed that combined RT and aerobic training decreased MSNA significantly in patients with CHF and CAD (mean difference: -3.796; CI: -6.779 to 0.813; p=0.013; I2 =93.5%). No study evaluated the effects of RT or combined training on HRR.

Conclusion: We could not find sufficient data about the effects of RT alone on HRV and HRR, but the results showed that combined RT and aerobic training improved MSNA in patients with CHF and CAD, significantly. Further studies with similar methodological principles on the same patient population are needed.

Circular RNAs (circRNAs) are a class of non-coding RNA molecules that are associated with not only normal physiological functions but also various diseases, including cardiac diseases such as myocardial infarction (MI). The present study explored the potential role of circRNA_0007059 (circ_0007059) during MI pathogenesis using in vitro studies. Microarray and quantitative PCR analyses demonstrated elevated circ_0007059 expression and downregulated miR-378 and miR-383 expression in H₂O₂-treated mice cardiomyocytes and infarcted hearts of MI mouse model as compared those in relevant controls. Moreover, circ_0007059 knockdown improved cardiomyocyte viability after H₂O₂ treatment as revealed by the CCK-8 and colony formation assays. Flow cytometry and caspase activity assays demonstrated that circ_0007059 suppressed H₂O₂-induced cardiomyocyte apoptosis. Enzyme-linked immunosorbent assays and Western blotting revealed that inflammatory cytokine (interleukin-1β, interleukin-18 and C-C motif chemokine ligand 5) expression was induced by H₂O₂ treatment and that circ_0007059 repressed H₂O₂-induced inflammation. Bioinformatics analyses and dual-luciferase reporter assays showed that circ_0000759 acts as a miR-378 and miR-383 sponge. Furthermore, the upregulation or suppression of miR-378 and miR-383 expression in H₂O₂-treated cardiomyocytes had similar effects on the apoptosis and inflammation of cardiomyocytes as that of circ_0007059 knockdown or overexpression, respectively. Additionally, lentiviral shRNA-circ_0007059 administration to mice with MI considerably reduced the size of infarcted regions and promoted cardiac activity. Collectively, our findings suggest that circ_0007059 expression is upregulated in mice cardiomyocytes in response to oxidative stress and cardiac tissues of MI mouse model, suggesting its involvement in the pathogenesis of MI by targeting miR-378 and miR-383.

Keywords: Myocardial infarction; apoptosis; circ_0007059; inflammation; miR-378; miR-383.

Background: Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of non-vaccine induced TTS in 6 European countries.

Methods: Electronic medical records from France, the Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction or ischemic stroke, all with concurrent thrombocytopenia, were estimated among the general population of persons in a database between 2017 to 2019. A range of additional potential adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner.

Findings: A total of 38,611,617 individuals were included. Background rates ranged from 1.0 (95% CI: 0.7 to 1.4) to 8.5 (7.4 to 9.9) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 20.8 (18.9 to 22.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 2.5 (2.2 to 2.7) for SVT with thrombocytopenia, and from 1.0 (0.8 to 1.2) to 43.4 (40.7 to 46.3) for myocardial infarction or ischemic stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1 to 0.2) per 100,000 person-years. The incidence of non-vaccine induced TTS increased with age, and is typically greater among those with more comorbidities and greater medication use than the general population. It was also more often seen in men than women. A large proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their event.

Interpretation: Although rates vary across databases, non-vaccine induced TTS has consistently been seen to be a very rare event among the general population. While still remaining very rare, rates were typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population. This article is protected by copyright. All rights reserved.

Objective: Severely calcified coronary stenoses remain a significant challenge during contemporary percutaneous coronary intervention (PCI), often requiring advanced therapies to circumvent suboptimal lesion preparation and major adverse cardiac events (MACEs). Recent reports suggest combined coronary atherectomy and intravascular lithotripsy (IVL) may achieve superior preparation of severely calcified coronary stenoses during PCI. We sought to evaluate the safety and utility of combined orbital atherectomy (OA) and IVL for the modification of coronary artery calcification (CAC) prior to drug-eluting stent (DES) implantation in PCI.

Methods: We performed a retrospective review of all patients who underwent coronary OA and IVL within a single PCI procedure at our institution. The primary outcome was procedural success, defined as successful DES implantation with a residual percent diameter stenosis of <30% and Thrombolysis in Myocardial Infarction (TIMI) 3 flow following PCI without occurrence of in-hospital MACE (cardiac death, myocardial infarction, or target-vessel revascularization). MACE was additionally assessed at 30 days post intervention.

Results: Eight patients underwent combined coronary OA and IVL within a single PCI procedure. The mean percent diameter stenosis prior to intervention was 80.5 ± 8.3%, with a mean calcific arc of 338 ± 42°. Procedural success was achieved in 7 of 8 cases (87.5%). Both in-hospital and 30-day MACE rates were 0%.

Conclusion: We report the safe and effective use of combined coronary OA and IVL for the preparation of severely calcified coronary stenoses during PCI. Through their distinct yet complementary mechanisms of action, the combined use of these therapies may achieve superior preparation of severely calcified coronary stenoses during PCI.

Keywords: PCI; coronary artery disease; interventional devices; percutaneous coronary intervention.

Objectives: Distal radial artery (DRA) access is a novel alternative to conventional radial artery access for coronary catheterization. This study investigated the incidence of vascular complications with percutaneous coronary intervention (PCI) from DRA access among patients with acute myocardial infarction (AMI) with and without ST-segment elevation.

Methods: Between April 2018 and October 2019, a total of 131 consecutive patients underwent primary PCI for AMI, among whom DRA access was used in 116 (88.5%), comprising 77 with ST-segment elevation myocardial infarction (STEMI) and 39 with non-ST-segment elevation myocardial infarction. The mean patient age was 70.4 ± 12.9 years and 71.6% were male. Right DRA was used in 110 patients (94.8%). A 5 or 6 Fr sheath was used in the PCI procedure. Patient backgrounds, procedural characteristics, and procedural complications were retrospectively analyzed. Patency of the radial artery was examined using Doppler ultrasound.

Results: Minor bleeding (Bleeding Academic Research Consortium [BARC] 2) was observed in 2 patients (1.7%) while no major bleedings (BARC 3a, 3b, 3c, and 5) were observed. On the Early Discharge After Transradial Stenting of Coronary Arteries Study (EASY) hematoma scale, a grade III hematoma (≥10 cm) was observed in 1 patient (0.9%), and no patients with hematoma were > grade IV. Doppler ultrasound of the radial artery was performed on 95 patients (81.9%). The incidence of radial artery occlusion was 1.1% (n = 1). The door-to-balloon time for STEMI patients was 40.0 ± 30.8 minutes.

Conclusions: The current study demonstrated that DRA access was associated with a low incidence of access-site complications within optimal revascularization time among patients with AMI who underwent PCI.

Keywords: distal radial artery; radial artery occlusion; vascular complication.

Objective: To study the long-term effectiveness of case-management rehabilitation intervention on vocational reintegration of patients after myocardial infarction (MI).

Design: Blinded simple randomization was used to construct an intervention and control groups that were followed up for two years.

Subjects and setting: 151 patients, aged 50.3 ± 5.9 years, who experienced uncomplicated MI and were enrolled in a cardiac rehabilitation program were recruited.

Interventions: included an early referral to an occupational physician, tailoring an occupational rehabilitation program, based on individual patient needs, coordination with relevant parties, psychosocial intervention, intensive follow-up sessions during a two-year follow-up.

Main measures: Return to work within six months of hospitalization and maintenance of employment at one and two years of follow-up.

Results: Return-to-work (RTW) rate in the intervention group was 89% and nearly all maintained employment at one year of follow-up (92%) and two years of follow-up (87%). Moreover, almost all of them returned to and maintained their previous jobs. The corresponding figures were: 98%, 94% and 98%, respectively. The figures for the RTW and employment maintenance for the control group were: 74%, 75%, and 72%, respectively. Only about 75%, in this group kept their previous job. The case-management intervention was associated with increased odds of maintaining employment at follow-up of one year (OR = 5.89, 95% CI 1.42-24.30) and two years (OR = 3.12, 95% CI 1.01-10.03).

Conclusions: The extended case-management rehabilitation intervention had a substantial positive impact on both the RTW of MI patients and their maintenance of employment at one and two years of follow-up.

Trial registration: This trial is registered at US National Institutes of Health #NCT04934735.

Keywords: Myocardial infarction; case-management; randomized controlled trial; rehabilitation; return to work.

Background: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination.

Methods and findings: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding.

Conclusions: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

An 84-year-old man was admitted with urinary tract infection and chest discomfort. He initially responded to conservative acute coronary syndrome management and antibiotics.On day 6 of admission, he developed acute severe abdominal pain; 12-lead electrocardiography showed widespread ST-segment depression in the anterior chest leads with ST-elevation in the posterior leads (V7-9) suggestive of an acute posterior myocardial infarction. Arterial blood gases showed severe metabolic acidosis with a lactate of 11 mmol/L.An urgent computed tomography angiography suggested acute small bowel ischaemia. The case was discussed with the on-call surgical team, who advised that, due to severe frailty, he was not fit for surgical intervention and should be managed conservatively. He was managed with intravenous heparin infusion and supportive measures, but sadly continued to deteriorate and was palliated. He died shortly afterwards.

Keywords: mesenteric ischaemia; posterior myocardial infarction.

Objective: The effect of malnutrition in patients with ST segment elevation myocardial infarction (STEMI) is not fully understood. In this study, we tried to investigate the prognostic consequence of the Controlling Nutritional Status (CONUT) score in patients with STEMI.

Methods: In this study, we evaluated the CONUT scores of 1,028 patients with STEMI and examined its relationship with major adverse cardiovascular events (MACE) (all-cause mortality, myocardial reinfarction, and vessel revascularization) during a period of 19.9±10.3 months. Patients with CONUT score ≥5 were defined as severely malnourished. Predictors of MACE were assessed by Cox regression analysis, and p<0.05 was considered to indicate statistical significance.

Results: MACE was observed in a total of 147 (14.3%) patients. MACE was more frequent in the group with a higher CONUT score (33.3% vs. 10.9%, p<0.001). CONUT score ≥5 was an independent predictor of MACE in the Cox regression analysis (hazard ratio=2.50, 95% confidence interval: 1.61-3.90, p<0.001). Low ejection fraction, Killip class ≥3 at presentation, thrombolysis in myocardial infarction flow grade <3 after intervention, left main artery involvement, and low hemoglobin levels were other independent predictors of MACE in the long-term follow-up. Kaplan-Meier curves showed decreased MACE free survival rates in the high CONUT score group at a mean 19.9±10.3 months' follow-up duration (log-rank p<0.01).

Conclusion: Malnutrition was strongly associated with poor outcomes in patients with STEMI treated using primary percutaneous coronary intervention.

Background: High blood cholesterol accelerates the progression of atherosclerosis that is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis that results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease (ASCVD). Methods: Low-density lipoprotein (LDL) receptor (LDLR) was used as the bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK, encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo, we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice, as well as knocked Klkb1 down using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and PCSK9 inhibition was evaluated as well. We also applied the anti-PK neutralizing antibody that blocked PK and LDLR interaction to mice. Mice lacking both PK and Apolipoprotein e (Klkb1^-/-Apoe^-/-) were generated to assess the role of PK in atherosclerosis. Results: PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of PCSK9 with Evolocumab further decreased plasma LDL cholesterol levels in Klkb1-deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed down the progression of atherosclerosis in mice on Apoe-deficient background. Conclusions: PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat ASCVD.

Both cardiogenic shock (CS) and critical culprit lesion locations (CCLLs), defined as the left main trunk and proximal left anterior descending coronary artery, are associated with worse outcomes in ST-elevation myocardial infarctions (STEMIs). We aimed to examine how the combination of CS and/or CCLLs affected the prognosis in Japanese STEMI patients in the primary percutaneous coronary intervention era (PPCI-era). The subjects included 624 STEMI patients admitted to our hospital between January 2013 and April 2020. They were divided into four groups according to the combination of CS and CCLLs: CS (-) CCLL (-) group [n = 405], CS (-) CCLL (+) group [n = 150], CS (+) CCLL (-) group [n = 25], and CS (+) CCLL (+) group [n = 44]. The cumulative incidences of all-cause death at 30 days and 1 year were 3.5% and 6.4% in the CS (-) CCLL (-), 3.3% and 5.6% in the CS (-) CCLL (+), 32.0% and 32.0% in the CS (+) CCLL (-), and 50.0% and 65.9% in the CS (+) CCLL (+) group, respectively. After a multivariate adjustment, the CS (+) CCLL (+) group was independently associated with all-cause death (hazard ratio: 17.00, 95% confidence interval: 7.12-40.59 versus the CS (-) CCLL (-) group). In the CS (+) CCLL (+) group, compared to years 2013-2017, the IMPELLA begun to be used (44.4% versus 0%), and intra-aortic balloon pumps significantly decreased (44.4% versus 92.3%) during years 2018-2020, while the medications upon discharge did not significantly differ. The 30-day mortality was numerically lower during years 2018-2020 than years 2013-2017 (Log-rank test, P = 0.092). In conclusion, the prognosis of STEMIs varies greatly depending on the combination of CS and CCLLs, and in particular, patients with both CS and CCLLs had the poorest prognosis during the modern PPCI-era.

Keywords: Broad-anterior STEMI; Cause of death; Short- and mid-term mortality.