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Takotsubo syndrome (TS) has become an important clinical entity over the last decade. However, high-quality outcomes data from randomized control clinical trials and large TS cohorts about the impact of pharmacological interventions on prognosis in TS is scarce. This study aimed to evaluate the

Recent trials in multivessel STEMI patients show that a strategy of complete revascularization in the acute or sub-acute phase guided by angiography (PRAMI, CvLPRIT) or FFR (PRIMULTI, COMPARE-ACUTE) improves the composite endpoint of MACE in comparison to an infarct related artery (IRA) only

Bivalirudin (Angiomax®, The Medicines Company, NJ, USA) is a direct-acting synthetic antithrombotic agent that has been approved as an alternative treatment to unfractionated heparin for patients with acute coronary syndromes who are undergoing percutaneous coronary intervention (PCI). Both European Society of Cardiology and American College of Cardiology/American Heart Association guidelines recommend this antithrombotic agent for the treatment of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) in the setting of PCI.

The failing heart is characterized by disturbed myocardial energy metabolism and creatine depletion. The aims of this study were to evaluate in vivo the effects of creatine (Cr) depletion on 1) left ventricular (LV) function, morphology, and lipid metabolism and 2) to test whether functional, morphologic, and metabolic disturbances induced by Cr depletion are reversible.Male Balb/c mice approximately 20 g were used. Two groups were studied: the mice treated with creatine analogue beta-guanidinopropionic acid (BGP) (n = 30) and controls (n = 30). BGP (1 M) were administered by subcutaneously implanted osmotic minipumps for 4 weeks. The mice were examined in vivo using echocardiography. High-performance liquid chromatography was used for measurements of the myocardial creatine, adenosine nucleotides, and lipids. BGP was discontinued in a subgroup of mice and these animals were followed for an additional 4 weeks, after which echocardiography was performed under resting and stress conditions. Body weight was lower in BGP mice (P.001) compared with the controls after 4 weeks. The total myocardial Cr pool was approximately 40% lower (P.001), whereas total nucleotide pool (TAN) was 18% lower (P = n.s.) in the BGP group. LV systolic function was disturbed at rest and stress in the BGP mice (both P.05). LV dimensions and LV mass were increased in the BGP group (P.05). There was an accumulation of intracellular triglycerides in the BGP-treated mice (P.05). Four weeks after BGP discontinuation Cr, TAN and TG content were restored to the normal levels while LV function, dimension, and mass were normalized.Myocardial Cr depletion results in LV dysfunction, pathologic remodeling, and lipid accumulation. These alterations are completely reversible on normalization of Cr content. Cr metabolism may be an important target for pharmacologic intervention to increase myocardial efficiency and structural integrity of the failing heart.

Excessive sympathetic activity is believed to be the key arrhythmogenic factor both in the setting of acute myocardial infarction and during chronic heart failure. The aim of this study was to evaluate the effect of neuropeptide Y2 blockade on malignant ventricular arrhythmias in rats with acute myocardial infarction. Vagotonic dose-finding study for neuropeptide Y2 receptor antagonist, (S)-N2-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl] cylopentyl] acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamid (AR-H05359) was conducted in guinea pigs (n=50) and rats (n=3). Induction of postinfarction arrhythmias was conducted in Sprague-Dawley rats that were randomized into 3 groups. Neuropeptide Y2 antagonist treated rats (n=7), placebo group (n=10) and amiodarone treated rats (n=8). Myocardial infarction was induced by ligation of the left coronary artery. Computerized telemetric ECG tracings were obtained continuously before induction of myocardial infarction and up to 120 min postinfarction. Occurrence of ventricular arrhythmias was analyzed according to a 10-point arrhythmia score. There was no difference in the arrhythmia scores between the neuropeptide Y2 and the saline group. The amiodarone treated animals had lower score compared to the neuropeptide Y2 and the placebo group (p

BACKGROUND: Instantaneous wave-free ratio (iFR) is a new hemodynamic resting index for assessment of coronary artery stenosis severity. iFR uses high frequency sampling to calculate a gradient across a coronary lesion during a period of diastole. The index has been tested against fractional flow reserve (FFR) and found to have an overall classification agreement of 80% to 85%. Whether the level of disagreement is clinically relevant is unknown. Clinical outcome data on iFR are scarce. This study is a registry-based randomized clinical trial, which is a novel strategy using health quality registries as on-line platforms for randomization, case record forms, and follow-up.DESIGN/METHODS: iFR-SWEDEHEART is a multicenter, prospective, randomized, controlled, clinical open-label clinical trial. Two thousand patients with stable angina or acute coronary syndrome and an indication for physiology-guided assessment of one or more coronary stenoses will be randomized 1:1 to either iFR- or FFR-guided intervention. The randomization will be conducted online in the Swedish web-based system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART) registry. The trial has a non-inferiority design, with a primary combined end point of all-cause death, non-fatal myocardial infarction, and unplanned revascularization at 12 months. End points will be identified through national registries and undergo central blind adjudication to ensure data quality.DISCUSSION: The iFR-SWEDEHEART trial is an registry-based randomized clinical trial evaluating the safety and efficacy of the diagnostic method iFR compared to FFR.

Tako-tsubo cardiomyopathy (TCM) is an acute cardiac syndrome with severe hypokinesia of the left ventricle (LV), often affecting the apex causing apical ballooning and heart failure. Sympathetic stress is a trigger of TCM and is probably underdiagnosed and not uncommon in ICU patients [1]. We have developed an experimental rat model of TCM, in which LV apical akinesia develops after intraperitoneal (i.p.) injection of isoprenaline with many similarities to clinical TCM [2]. We recently demonstrated that pre-treatment with isoflurane could prevent the development of LV apical akinesia in this TCM animal model [3].

The aim of this study was to determine the prognostic impact of chronic total occlusion (CTO) on long-term mortality in a large prospective cohort.CTO is present in many patients with coronary artery disease and is difficult to treat with percutaneous coronary intervention.The study population consisted of all consecutive patients who underwent coronary angiography in Sweden between January 1, 2005 and January 1, 2012, who were registered in SCAAR (Swedish Coronary Angiography and Angioplasty Registry). The patient population was heterogeneous with regard to indication for angiography (stable angina, ST-segment elevation myocardial infarction [STEMI], unstable angina or non-STEMI, and other) and treatment options. The long-term mortality rates of patients with and without CTO were compared by using shared frailty Cox proportional hazards regression adjusted for confounders. Tests were conducted for interactions between CTO and several pre-specified characteristics: indication for angiography and percutaneous coronary intervention (stable angina, STEMI, unstable angina or non-STEMI, and other), severity of coronary artery disease (1-, 2-, and 3-vessel and/or left main coronary artery disease), age, sex, and diabetes.During the study period, 14,441 patients with CTO and 75,431 patients without CTO were registered in SCAAR. CTO was associated with higher mortality (hazard ratio: 1.29; 95% confidence interval: 1.22 to 1.37; p 0.001). In subgroup analyses, the risk attributable to CTO was lowest in patients with stable angina and highest in those with STEMI. In addition, CTO was associated with highest risk in patients under 60 years of age and with lowest risk in octogenarians. There was no interaction between CTO and either diabetes or sex, suggesting an equally adverse effect in both groups.In this large prospective observational study of patients with coronary artery disease, CTO was associated with increased mortality. This association was most prominent in younger patients and in those with acute coronary syndromes.

Background Cardiovascular disease is the most common cause of death for both genders. Debates are ongoing as to whether gender‐specific differences in clinical course, diagnosis, and management of acute myocardial infarction (MI) exist. Methods and Results We compared all men and women who were treated for acute MI at cardiac care units in Västra Götaland, Sweden, between January 1995 and October 2014 by obtaining data from the prospective SWEDEHEART (Swedish Web‐System for Enhancement of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) registry. We performed unadjusted and adjusted Cox proportional hazards and logistic regression analyses on complete case data and on imputed data sets. Overall, 48 118 patients (35.4% women) were diagnosed with acute MI. Women as a group had better age‐adjusted prognosis than men, but this survival benefit was absent for younger women (aged P P P 12 antagonists). Differences in treatment between the genders did not decrease over the study period ( P >0.1 for all treatments). Conclusions Women on average have better adjusted prognosis than men after acute MI; however, younger women and women with ST‐segment elevation MI have disproportionately poor prognosis and are less likely to be prescribed evidence‐based treatment.

In the randomized rapid intravascular cooling in myocardial infarction as adjunctive to percutaneous coronary intervention (RAPID MI-ICE) and rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction CHILL-MI studies, hypothermia was rapidly induced in conscious patients with ST-elevation myocardial infarction (STEMI) by a combination of cold saline and endovascular cooling. Twenty patients in RAPID MI-ICE and 120 in CHILL-MI with large STEMIs, scheduled for primary percutaneous coronary intervention (PCI) within 30% of the left ventricle) exhibited significantly reduced IS/MaR in the hypothermia group (40.5, 27.0-57.6 vs. 55.1, 41.1-64.4, median, IQR; hypothermia n=42 vs. control n=37, p=0.03), while patients with MaR

Takotsubo syndrome is an acute cardiovascular condition that predominantly affects women. In this study, we compared patients with takotsubo syndrome and those with acute myocardial infarction with respect to patient characteristics, angiographic findings, and short- and long-term mortality.From the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA), we obtained and merged data on patients undergoing coronary angiography in Västra Götaland County in western Sweden between January 2005 and May 2013. Short- and long-term mortality in patients with takotsubo (n=302) and patients with ST-elevation myocardial infarction (STEMI, n=6595) and non-ST-elevation myocardial infarction (NSTEMI, n=8207) were compared by modeling unadjusted and propensity score-adjusted logistic and Cox proportional-hazards regression.The proportion of the patients diagnosed with takotsubo increased from 0.16% in 2005 to 2.2% in 2012 (P0.05); 14% of these patients also had significant coronary artery disease. Cardiogenic shock developed more frequently in patients with takotsubo than NSTEMI (adjusted OR 3.08, 95% CI 1.80-5.28, P0.001). Thirty-day mortality was 4.1% and was comparable to STEMI and NSTEMI. The long-term risk of dying from takotsubo (median follow-up 25 months) was also comparable to NSTEMI (adjusted HR 1.01, 95% CI 0.70-1.46, P=0.955) STEMI (adjusted HR 0.83, 95% CI 0.57-1.20, P=0.328).The proportion of acute coronary syndromes attributed to takotsubo syndrome in Western Sweden has increased over the last decade. The prognosis of takotsubo syndrome is poor, with similar early and late mortality as STEMI and NSTEMI.

Patients developing stress-induced cardiomyopathy (SIC) after subarachnoid hemorrhage (SAH) have increased risk of vasospasm, delayed cerebral ischemia and death. We evaluated whether high-sensitive troponin T (hsTnT) and N-terminal pro B-type natriuretic peptide (NTproBNP) are useful biomarkers for early detection of SIC after SAH.Medical records of all patients admitted to our NICU with suspected or verified SAH from January 2010 to August 2014 were reviewed. Patients in whom echocardiography was performed and blood samples for measurements of hsTnT and/or NTproBNP were obtained, within 72 and 48 h, respectively, after onset of symptoms, were included. SIC was defined as reversible left ventricular segmental hypokinesia diagnosed by echocardiography.A total of 502 SAH patients were admitted during the study period, 112 patients fulfilled inclusion criteria and 25 patients fulfilled SIC criteria. Peak levels of hsTnT and NTproBNP were higher in patients with SIC (p0.001). hsTnT had its peak on admission, while NTproBNP peaked at days 2-4 after onset of symptoms. A hsTnT89 ng/l or a NTproBNP2,615 ng/l obtained within 48 h after onset of symptoms had a sensitivity of 100% and a specificity of 79% in detecting SIC.The cardiac biomarkers, hsTnT and NTproBNP, are increased early after SAH and levels are considerably higher in patients with SIC. These biomarkers are useful for screening of SIC, which could make earlier diagnosis and treatment of SIC in SAH patients possible.

To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110α catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110α but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.

Takotsubo syndrome is an acute reversible heart failure syndrome that is increasingly recognized in modern cardiology practice. This Position Statement from the European Society of Cardiology Heart Failure Association provides a comprehensive review of the various clinical and pathophysiological facets of Takotsubo syndrome, including nomenclature, definition, and diagnosis, primary and secondary clinical subtypes, anatomical variants, triggers, epidemiology, pathophysiology, clinical presentation, complications, prognosis, clinical investigations, and treatment approaches. Novel structured approaches to diagnosis, risk stratification, and management are presented, with new algorithms to aid decision-making by practising clinicians. These also cover more complex areas (e.g. uncertain diagnosis and delayed presentation) and the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation. The unmet needs and future directions for research in this syndrome are also discussed.

Studies have shown that drug-eluting stents (DES) differ in safety and efficacy. Long-term effects of DES are not well-studied. The aim of this study was to compare commonly used DES in regard to long-term risk of restenosis and stent thrombosis. We used data from the SCAAR registry (Swedish

Routine intracoronary thrombus aspiration before primary percutaneous coronary intervention (PCI) in STEMI patients does not seem to reduce mortality but may reduce stent thrombosis and reinfarction. The aim of this observational study was to evaluate the impact of thrombus aspiration on mortality

Recent reports indicate that patients with STEMI who undergo primary PCI during off-hours may have worse prognosis compared to procedures performed during regular-hours. The aim of this study was to compare outcome between patients with STEMI who underwent primary PCI during off-hours and regular

Growth hormone has been proposed as a potential new therapeutic agent for treatment of myocardial infarction (MI) and congestive heart failure (CHF). The purpose of this study was to evaluate the effects of GH on: (a) myocardial expression of creatine transporter (CreaT) during early postinfarct remodeling, (b) myocardial levels of total creatine (TCr) and adenine pool (TAN) and (c) plasma levels of inflammatory cytokines interleukin-1beta (IL-1beta), tumor-necrosis-factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in rat model of postinfarct cardiac remodeling. Myocardial infarction (MI) was induced by ligation of the left coronary artery in male Sprague-Dawley rats (200-250 g). Three different groups were studied: MI rats treated with GH (n=11) (3 mg/kg/day), MI rats treated with saline (n=10), and sham operated rats (n=7). In the myocardium from GH treated rats the level of mRNA CreaT expression was significantly increased (p

Aims In myocardial ischaemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling pathway that includes VEGF receptor 2 (VEGFR2), resulting in increased oedema and inflammation and thereby expanding the area of tissue damage. In this study, we investigated the role of receptor-interacting protein 2 (Rip2) in VEGF signalling and myocardial ischaemia/reperfusion injury. Methods and results To determine whether Rip2 has a role in VEGF signalling, we used cultured endothelial cells in which Rip2 was or was not inactivated. In Rip2-deficient endothelial cells, stimulation with VEGF resulted in more rapid kinetics of VEGFR2 phosphorylation than in control cells. Rip2 deficiency also enhanced VEGF-induced activation of ERK1/2, suggesting an increased propensity for endothelial permeability. In a mouse model of myocardial ischaemia, Rip2 deficiency resulted in enhanced vascular permeability, increased oedema and expanding area of myocardial damage, and markedly reduced heart function after long-term follow-up. Conclusion Our results show that Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischaemia. These findings indicate that Rip2 may be a promising novel therapeutic target to reduce excess vascular permeability in ischaemic heart disease.

AIM: Sudden cardiac arrest (SCA) accounts for more than half of all deaths from coronary heart disease. Time to return of spontaneous circulation is the most important determinant of outcome but successful resuscitation also requires percutaneous coronary intervention in selected patients. However, proper selection of patients is difficult. We describe data on angiographic finding and survival from a prospectively followed SCA patient cohort.METHODS: We merged the RIKS-HIA registry (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) and SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for patients hospitalized in cardiac care units in Western Sweden between January 2005 and March 2013. We performed propensity score-adjusted logistic and Cox proportional-hazards regression analyses on complete-case data as well as on imputed data sets.RESULTS: 638 consecutive patients underwent coronary angiography due to SCA. Severity of coronary artery disease was similar among SCA patients and patients undergoing coronary angiography due to suspected coronary artery disease (n=37,142). An acute occlusion was reported in the majority of SCA patients and was present in 37% of patients who did not have ST-elevation on the post resuscitation ECG. 31% of SCA patients died within 30 days. Long-term risk of death among patients who survived the first 30 days was higher in patients with SCA compared to patients with acute coronary syndromes (P

AIMS Takotsubo syndrome, also known as stress-induced cardiomyopathy, is an important differential diagnosis in patients presenting with chest pain and is associated with significant morbidity and mortality. Beyond adrenergic overstimulation the pathophysiology behind Takotsubo is poorly known and the syndrome cannot be differentiated from acute myocardial infarction (AMI) by non-invasive tests. Despite the facts that Takotsubo syndrome and AMI may differ in many important aspects and that potential mechanistic similarities and/or differences between Takotsubo syndrome and AMI have not been established, Takotsubo syndrome patients are treated according to guidelines developed for AMI and acute heart failure. The aim of this article was to assess whether cardiac function and hemodynamic indices differ between rat models of Takotsubo syndrome and AMI. METHODS Male Sprague-Dawley rats were randomized to the Takotsubo syndrome (50 mg/kg intraperitoneally isoprenaline) or AMI [permanent left anterior descending coronary artery (LAD) ligation] models. Two hours post-isoprenaline or LAD ligation, arterial and intraventricular pressures were recorded and cardiac function was studied by echocardiography. In another subset of Takotsubo syndrome rats, pharmacological intervention aimed at maintaining systolic blood pressure more than 90 mmHg with either norepinephrine or phenylephrine was compared with saline. RESULTS Left ventricular end-diastolic pressure was significantly lower and estimates of cardiac function were significantly better in Takotsubo syndrome rats compared with AMI rats. Vasopressor treatment was associated with increased mortality in Takotsubo syndrome rats (P

The randomised RAPID MI-ICE and CHILL-MI studies rapidly induced hypothermia in awake patients with ST-elevation myocardial infarction (STEMI) by a combination of cold saline and endovascular cooling. 20 patients in RAPID MI-ICE and 120 in CHILL-MI with large STEMIs, planned to undergo primary PCI

Aims In the present study, we investigated the prognostic value of radial artery intima-media thickness (rIMT) in patients with suspected coronary artery disease (CAD). Carotid artery intima-media thickness is a well-known surrogate marker of atherosclerosis. Recently, using very high-resolution ultrasound, we showed rIMT can be imaged with great precision and is related to various cardiovascular risk factors. Methods and results We recruited a total of 416 patients (62 ± 9 years, 44% male) with suspected CAD, referred to myocardial perfusion scintigraphy (MPS). Among these patients, 133 underwent coronary angiography on clinical indication. Two-dimensional images of carotid and radial arteries were acquired bilaterally (using 8 and 55 MHz ultrasound, respectively). All patients were followed regarding major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, stroke, and coronary revascularization. A group of 20 healthy subjects (aged 61 ± 3, 50% male) were recruited for reference. During 3 years of follow-up, 77 MACE occurred. Patients with MACE exhibited significantly thicker rIMT vs. those without (0.35 ± 0.06 vs. 0.32 ± 0.07 mm, P < 0.001). Increased rIMT was associated with an increased occurrence of significant coronary artery narrowing, diagnosed by coronary angiography ( P = 0.028). Patients with rIMT values above the median had a nearly three-fold increased risk for MACE (hazard ratio 2.8, 95% confidence interval 1.6–4.8). In multivariate analysis, rIMT ( P = 0.011) remained a significant predictor of MACE, along with type II diabetes ( P = 0.012), body mass index ( P = 0.024), and MPS-verified ischaemia ( P < 0.001). Conclusion Radial artery IMT, assessed by very high-resolution ultrasound, confers prognostic information in patients with suspected CAD.

Echocardiography is frequently the initial noninvasive imaging modality used to assess patients with takotsubo cardiomyopathy (TTC). Standard transthoracic echocardiography can provide, even in the acute care setting, useful information about left ventricular (LV) morphology as well as regional and global systolic or diastolic function. It allows the differentiation of different LV morphologic patterns according to the localization of wall motion abnormalities. A "circumferential pattern" of LV myocardial dysfunction characterized by symmetric wall motion abnormalities involving the midventricular segments of the anterior, inferior, and lateral walls should be considered suggestive of TTC and included in the differential diagnosis of acute coronary syndromes. Moreover, advanced echocardiographic techniques, including speckle-tracking, myocardial contrast, and coronary flow studies, are providing mechanistic and pathophysiologic insights into this unique syndrome. Early identification of any potential complications (i.e., LV outflow tract obstruction, reversible moderate to severe mitral regurgitation, right ventricular involvement, thrombus formation, and cardiac rupture) are crucial for the management, risk stratification, and follow-up of patients with TTC. Because of the dynamic evolution of the syndrome, comprehensive serial echocardiographic examinations should be systematically performed. This review focuses on these aspects of imaging and the increasing understanding of the clinical and prognostic utility of echocardiography in TTC.

In the normally contracting heart, the contractile apparatus consumes the great majority of myocardial energy metabolites and oxygen. In fact, non-contractile myocardial functions, including cardiac action potentials as well as maintenance of cellular homeostasis, require less than 20% as much oxygen [1]. It is therefore apparent that shutting down the hearts' mechanical activities during severe oxygen deprivation could preserve energy metabolites. In fact, this is what happens during ischemic stunning. We believe that the same mechanisms are at play in takotsubo, another conditions in which the cardiomyocytes sense relative oxygen deprivation. The heart relies almost entirely on aerobic metabolism and is dependent on a continuous supply of oxygen. In healthy subjects the heart can increase regional blood flow at least 5-fold through socalled autoregulatory mechanisms and can therefore tolerate fluctuations in myocardial oxygen demand. However, situations can arise where autoregulatory mechanisms fail to maintain adequate tissue perfusion. This leads to myocardial ischemia. If the supply:demand mismatch is of sufficient magnitude and duration cardiomyocyte cell death ensues. Following complete occlusion of a coronary artery, cardiomyocytes supplied by that artery stop contracting within seconds. Energy metabolites decrease to 50% of their initial levels within 10 min and within 20 min irreversible cell injury ensues. Thus, contractile activities cease well before the cell is depleted of energy, a phenomenon coined “ischemic stunning”. Such a hierarchical order of cellular functions is reasonable from an evolutionary perspective and is common in biology. By downprioritizing contractile activities the cell preserves energy and is able to sustain longer periods of oxygen deprivation. Hence, although it inherently leads to impaired cardiac function with potential complications, ischemic stunning is likely an important protective mechanism in acute ischemic syndromes, including acute myocardial infarction. Pre-, perand postconditioning are terms used to describe the protective effect on the myocardium of brief episodes of ischemia against subsequent, simultaneous, or preceding greater ischemic insults. A great myriad of molecules have been postulated to mediate conditioning but none have been successfully translated to clinical praxis. It is clear from earlier studies that ischemic conditioning phenomena entail more thanmerely ischemic stunning, i.e. preservation of energy metabolites otherwise destined to be consumed by the contractile apparatus. Studies have shown that brief episodes of ischemia preceding an ischemic event are associated with cardioprotection independent on the degree of functional impairment still present at the onset of the indexevent [2]. This is not surprising since ischemic stunning likely ensues immediately upon coronary artery occlusion. Thus, since little energy is lost before stunning ensues, little if any benefit would be expected if the myocardium was already stunned beforehand. Instead, conditioning more likely probes the heart towards more efficient “stunning” once the ischemic insult occurs. This is most likely accomplished by complex intracellular alterations, some of which have been thoroughly studied. Takotsubo is characterized by regional contractile dysfunction that develops in the absence of an explanatory vascular culprit lesion and that often extends beyond the territory supplied by a single main coronary artery. Catecholamines are strongly implicated in the pathogenesis and a strong emotional and/or physical stressor can be identified in the majority of patients [3]. Although the mechanisms underlying takotsubo are incompletely understood, there is indirect support in the literature for a causative role of relative ischemia. First, microvascular resistance has been shown to be increased in patients with takotsubo [4]. Second, and more important, left ventricular outflow obstruction can be observed at the time of echocardiographic assessment in approximately 1/4 of patients that present with typical takotsubo, i.e. apical akinesia with preserved basal function [5]. The combination of strong inotropic drive and outflow obstruction could be expected to greatly increase LV afterload, particularly in apical regions. Cardiomyocytes within

BACKGROUND: Routine intracoronary thrombus aspiration before primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) has not been proved to reduce short-term mortality. We evaluated clinical outcomes at 1 year after thrombus aspiration.METHODS: We randomly assigned 7244 patients with STEMI to undergo manual thrombus aspiration followed by PCI or to undergo PCI alone, in a registry-based, randomized clinical trial. The primary end point of all-cause mortality at 30 days has been reported previously. Death from any cause at 1 year was a prespecified secondary end point of the trial.RESULTS: No patients were lost to follow-up. Death from any cause occurred in 5.3% of the patients (191 of 3621 patients) in the thrombus-aspiration group, as compared with 5.6% (202 of 3623) in the PCI-only group (hazard ratio, 0.94; 95% confidence interval [CI], 0.78 to 1.15; P=0.57). Rehospitalization for myocardial infarction at 1 year occurred in 2.7% and 2.7% of the patients, respectively (hazard ratio, 0.97; 95% CI, 0.73 to 1.28; P=0.81), and stent thrombosis in 0.7% and 0.9%, respectively (hazard ratio, 0.84; 95% CI, 0.50 to 1.40; P=0.51). The composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis occurred in 8.0% and 8.5% of the patients, respectively (hazard ratio, 0.94; 95% CI, 0.80 to 1.11; P=0.48). The results were consistent across all the major subgroups, including grade of thrombus burden and coronary flow before PCI.CONCLUSIONS: Routine thrombus aspiration before PCI in patients with STEMI did not reduce the rate of death from any cause or the composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis at 1 year. (Funded by the Swedish Research Council and others; TASTE ClinicalTrials.gov number, NCT01093404.).

Takotsubo cardiomyopathy (TTC) is a distinct clinical entity characterized by the presence of transient left ventricular wall dysfunction without significant culprit obstructive coronary artery disease. Invasive coronary angiography and ventriculography are the 'gold standard' for definitive diagnosis, with an integrated multi-modality imaging approach offering advantages in various clinical scenarios. Echocardiography is a widely available, first-line, non-invasive imaging technique appropriate both in emergency setting to confirm diagnosis, assess for various potential acute complications, and in serial follow-up to track myocardial recovery. Cardiac magnetic resonance (CMR) may be helpful to discriminate TTC from other acute cardiac syndromes with troponin elevation and ventricular dysfunction. Echocardiography, CMR, and nuclear imaging may also provide new insights into possible underlying pathophysiological mechanisms, and myocardial (123)I-metaiodobenzyl-guanidine imaging may have a role for retrospective diagnosis in the subacute phase of late-presenting cases. The potential diagnostic role of coronary computed tomography angiography in the emergency room requires a further study.

The aim of this study was to confirm the cardioprotective effects of hypothermia using a combination of cold saline and endovascular cooling.Hypothermia has been reported to reduce infarct size (IS) in patients with ST-segment elevation myocardial infarctions.In a multicenter study, 120 patients with ST-segment elevation myocardial infarctions (6 h) scheduled to undergo percutaneous coronary intervention were randomized to hypothermia induced by the rapid infusion of 600 to 2,000 ml cold saline and endovascular cooling or standard of care. Hypothermia was initiated before percutaneous coronary intervention and continued for 1 h after reperfusion. The primary end point was IS as a percent of myocardium at risk (MaR), assessed by cardiac magnetic resonance imaging at 4 ± 2 days.Mean times from symptom onset to randomization were 129 ± 56 min in patients receiving hypothermia and 132 ± 64 min in controls. Patients randomized to hypothermia achieved a core body temperature of 34.7°C before reperfusion, with a 9-min longer door-to-balloon time. Median IS/MaR was not significantly reduced (hypothermia: 40.5% [interquartile range: 29.3% to 57.8%; control: 46.6% [interquartile range: 37.8% to 63.4%]; relative reduction 13%; p = 0.15). The incidence of heart failure was lower with hypothermia at 45 ± 15 days (3% vs. 14%, p 0.05), with no mortality. Exploratory analysis of early anterior infarctions (0 to 4 h) found a reduction in IS/MaR of 33% (p 0.05) and an absolute reduction of IS/left ventricular volume of 6.2% (p = 0.15).Hypothermia induced by cold saline and endovascular cooling was feasible and safe, and it rapidly reduced core temperature with minor reperfusion delay. The primary end point of IS/MaR was not significantly reduced. Lower incidence of heart failure and a possible effect in patients with early anterior ST-segment elevation myocardial infarctions need confirmation. (Efficacy of Endovascular Catheter Cooling Combined With Cold Saline for the Treatment of Acute Myocardial Infarction [CHILL-MI]; NCT01379261).

Chronic total coronary occlusion (CTO) is a frequent finding in patients with ischemic heart disease. Our aim was to evaluate the prognostic impact of CTO on long-term survival in patients with different severity of ischemic heart disease at the level of one whole nation. The study population

Sedating animals is sometimes necessary in experimental research. This paper presents and discusses the influence of four of the most common anesthetic agents on cardiovascular parameters in rats. We also studied the influence of body temperature. Ten-week-old Sprague-Dawley rats were anesthetized with either isoflurane, pentobarbital, ketamine/xylazine or tiletamine/zolazepam ( n = 12 in each group). A pressure-sensing catheter was placed in the right carotid artery for the continuous measurement of arterial pressure, and echocardiography was performed. Indices of cardiac function were significantly higher in the tiletamine/zolazepam rats compared with the other groups. Heart rate was highest but stroke volume lowest with pentobarbital. Left ventricular diastolic dimension was lower in the pentobarbital and tiletamine/zolazepam rats compared with the isoflurane or ketamine/xylazine rats. Intraventricular diastolic pressure was similar in all groups whereas intraventricular systolic pressure, as well as both systolic and diastolic aortic pressures, was significantly higher in the tiletamine/zolazepam rats compared with the other groups. No hemodynamic indices differed significantly among the isoflurane, pentobarbital and ketamine/xylazine rats. Lowering body temperature significantly reduced heart rate and cardiac output but had no apparent effect on hemodynamic parameters. In conclusion, although cardiac functional parameters differed between the different anesthetic agents in ways that could be of relevance to the researcher, they may all have a role in experimental cardiology. Importantly, tiletamine/zolazepam anesthesia resulted in significantly higher indices of cardiac function and elevated blood pressures compared with the other anesthetic agents, a finding that should be kept in mind when interpreting data obtained in rats sedated on this regimen.

Atrial fibrillation (AF) is the most common form of arrhythmia in humans and is associated with substantial morbidity and mortality. Obesity and diabetes have been linked to myocardial lipotoxicity - a condition where the heart accumulates and produces toxic lipid species. We hypothesized that obesity and diabetes were involved in the pathophysiology of AF by means of promoting a lipotoxic phenotype in atrial muscle, and that AF predicts mortality in cardiac care patients.Our study consists of two parts. The first part is a registry study based on prospective data obtained through the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA) from hospitals in western Sweden. All consecutive patients between 2006 and 2011 admitted to coronary care unit (CCU) with sinus rhythm (SR) or AF were included in the analysis. Multivariate logistic regression and Cox proportional-hazards regression were used to test whether diabetes and obesity were independent predictors of AF at admission to CCU and whether AF was associated with increased one-year mortality. In the second part we obtained atrial biopsies from 54 patients undergoing cardiac surgery and performed lipidomic analysis for a detailed qualitative and quantitative analysis of lipid species including triglycerides (TAG), ceramides (CER), phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylethanolamine (PE), sphyngomyelins (SM), free cholesterol (FC), cholesterol esters (CEs) and diacylglycerols (DAGs).Between 2006 and 2011, 35232 patients were admitted to CCUs in western Sweden, mostly due to ischemic heart disease, heart failure, arrhythmia, syncope and chest pain. The mean age was 66years and 58.7% were male. There was a high prevalence of obesity (20.3%) and diabetes (16.8%). Obesity (OR 1.35, 95% CI 1.17-1.56, P0.001) and severe obesity (1.6, 95% CI 1.29-1.99, P0.001) were independent predictors of AF but diabetes was not (OR=0.92, 95% CI=0.82-1.04). AF increased one-year mortality (HR 1.32, 95% CI 1.16-1.50, P0.001). Lipidomic analysis revealed that atrial TAG content was substantially lower in the AF patients (P0.05). No quantitative difference was found in the content of CER, PC, LPC, PE, SM, FC, CE and DAG, between the patients who had AF or sinus rhythm at admission to the CCU. AF patients had greater proportion of polyunsaturated DAG (P0.05) while no difference was found in saturated DAG.Obesity but not diabetes is an independent predictor of AF and AF is associated with increased one-year mortality in this CCU population. AF is associated with quantitative and qualitative alterations in atrial lipid content but not with lipotoxicity.

Aims Stress-induced cardiomyopathy (SIC) is an important differential diagnosis to acute myocardial infarction (AMI) that is associated with significant morbidity and mortality. The typical hallmark of SIC is left-ventricular apical akinesia but preserved function in basal segments. Catecholamines are postulated to play an important role in SIC but the precise pathophysiology is incompletely understood. Whether myocardial perfusion of the affected segments is impaired in SIC has been debated and remains unknown. Methods and results Myocardial contrast echocardiography (MCE) was used to study regional myocardial perfusion in a rat model of SIC. Twelve rats received 50 mg/kg isoproterenol (ISO) i.p. and were continuously monitored by MCE. Apical and basal perfusion were estimated and expressed as a ratio at baseline, 5, 10, 20, 30, 40, 50, 60, 70, 80, and 90 min post-ISO. The rats developed typical apical ballooning after 43 ± 9 min post-ISO injection. The ratio of apical:basal perfusion was close to 1.00 at all time-points and never dropped below 0.89 (95% CI never extended below 0.73). Light and electron microcoscopical investigation revealed no structural damage of myocardial vessels. Conclusion Apical perfusion is not impaired in the early phase of SIC in this rat model.

Cardiac dysfunction is common in ICU patients and is a poor prognostic factor [1,2]. Acute myocardial infarction (AMI) is commonly diagnosed in ICU patients and cardiospecific proteins are detected in up to 47% of these patients. An AMI diagnosis is often based only on detection of cardiospecific proteins in plasma and/or ECG and echocardiographic findings. Angiographic evidence is rarely present [2]. Furthermore, reported plasma troponin levels are often mildly to moderately elevated, a laboratory finding that is consistent not only with a small or moderately sized AMI but also with stress-induced cardiomyopathy (SIC). It is thus possible that many or perhaps most cases of myocardial infarction diagnosed in the ICU may in fact be SIC. SICwas first described in 1990 but is nowan increasingly recognized acute cardiac syndrome and an important differential diagnosis in patients presenting with chest pain [3]. SIC is characterized by severe regional myocardial hypokinesia or akinesia, often but not always involving apical segments, in the absence of an explanatory coronary lesion [4]. Although the pathomechanisms behind SIC is believed to differ substantially from that of AMI the two conditions appear clinically similar and cannot, as yet, be differentiated by non-invasive modalities [5]. However, plasma troponin levels are typically mildly to moderately elevated in SIC and extreme values are rare. SIC is typically preceded by an emotional or somatic stressor and although the pathophysiology of SIC is poorly understood, there exist strong evidence for an important role of catecholamine overstimulation [5]. Among the evidence indicating catecholamines in the pathogenesis of SIC are the observations that plasma levels of epinephrine and norepinephrine are severely elevated in SIC patients, also compared to AMI patients, and several reports where iatrogenously administered beta-adrenergic agonists have triggered SIC or worsened the patients' condition [5,6]. Furthermore, we have shown that i.p. administration of isoprenaline, a nonselective β-adrenoreceptor agonist, induces SIC-like left ventricular apical akinesia in rats [7]. We believe that there is reason to believe that SIC may be particularly prevalent among patients admitted because of severe non-cardiac disease, conditions associated with internal somatic stress and a strong adrenergic drive. A recent report showed that N20% of patients admitted to an intensive care unit (ICU) displayed SIC-like left ventricular apical ballooning. Development of SIC-like cardiac dysfunction was particularly likely in sepsis, a condition associated with a profound endogenous stress response [1]. Considering the liberal use of inotropic support in ICU patients, including catecholamine, detection of SIC patients in this setting may be of particular importance and may merit re-evaluation of treatment strategies [6,8]. Cardiac output is often inadequate in ICUpatients despite optimization of filling pressures and afterload. These patients therefore require additional support tomaintain adequate tissue perfusion. Typical regimens include positive inotropes and/or vasopressor substances, manyofwhich are catecholamines.Webelieve that further stimulation of adrenergic signaling pathways may exacerbate cardiac dysfunction in somepatients andmay lead toparadoxical deterioration of these patients condition (Fig.1). In patients suffering from severe heart failure inotropic support by the β-adrenoreceptor agonist dobutamine was associated with a near statistically significantly increased mortality compared to placebo [8]. We believe that suspicion of stress-induced cardiac dysfunction should deter the anesthesiologist towards switching to non-catecholamine vasopressors. Similarly, non-catecholamine vasopressors may also be preferable in these patients. We propose that many so-called AMIs detected in the ICU may in fact be SIC and in many cases these SICs may have been caused or exacerbated by iatrogenously administered inotropic agents, especially β-adrenoreceptor agonist. Non-catecholamine inotropes and/or vasopressors or mechanical assist may be preferable in patients at risk of developing SIC. Until SIC is better understood and these patients can be identified we argue for judicious use of catecholamine inotropes and liberal use of mechanical assist, particularly in patients displaying signs of cardiac dysfunction or injury.