Snoring increases the development of coronary artery disease: a systematic review with meta-analysis of observational studies.

PURPOSE: Snoring is one of the cardinal presentations of obstructive sleep apnea (OSA) and is more common than OSA. Abundant evidence has suggested a robust association between OSA and coronary artery disease (CAD). However, whether or not snoring alone is related to a higher risk of CAD is unknown. This study systematically reviewed observational studies with meta-analysis to evaluate the linkage between snoring and CAD. METHODS AND RESULTS: We searched PubMed and Embase and retrieved 13 articles focusing on the relationship between snoring and CAD. These articles included a total of 151,366 participants and 9099 CAD patients. Quantitative analysis indicated that snoring was associated with a 28% (RR: 1.28, 95% CI: 1.13 to 1.45, P < 0.001) increase in the risk of developing CAD. CONCLUSIONS: Snorers are exposed to a 28% increased risk for CAD. Although the association may be partly mediated through OSA, most snorers are not affected by apnea. Given the high prevalence of snoring and the disease burden of CAD in the general population, screening for snoring may be worthwhile for the early prevention of CAD.

The cardioprotective effects of icariin on the isoprenaline-induced takotsubo-like rat model: Involvement of reactive oxygen species and the TLR4/NF-κB signaling pathway.

INTRODUCTION: Takotsubo syndrome (TS) is an acute cardiac syndrome that mimics acute coronary syndrome (ACS) but lacks coronary obstruction and is associated with sudden physical or psychiatric episodes. Several hypotheses have been proposed for the TS mechanism, but the precise cause of this syndrome remains poorly known. Recent studies noted TS patients with acute endogenous catecholamine discharge, which could trigger an oxidative stress response and inflammatory action. METHODS: A single dose of the selective ß-adrenergic agonist isoprenaline (ISO) was used to induce a takotsubo-like (TS-like) model. Different icariin or metoprolol doses were supplied as cardioprotective agents by intragastric administration (IG), and lipopolysaccharides (LPS) were assessed to investigate the possible mechanism of action of icariin. Transthoracic echocardiography was used to study cardiac function and morphology. The amounts of intracellular lipids and myocardial fibrosis, which represent the degree of cardiac impairment, were assessed by histological analysis. Real-time polymerase chain reaction (RT-PCR) was performed to analyze a variety of anti-oxidant elements and inflammatory factors, and Western blotting was conducted to analyze the expression of signaling pathway proteins involved in the development of TS. RESULTS: The TS-like incidence in rats was lowest with icariin precondition at 2-h post-ISO administration, and both the left ventricular ejection fraction (LVEF) and ejection volume per minute were higher than those of the other groups. However, LPS administration increased the incidence of TS and aggravated cardiac impairment. Moreover, ISO significantly increased the levels of both reactive oxygen species (ROS) and TLR4/NF-κB signaling pathway proteins compared to those of the Sha-group, whereas icariin remarkably decreased the ROS levels and increased anti-oxidant element expression while reducing pro-inflammatory factor secretion and suppressing TLR4/NF-κB signaling pathway protein expression. However, the cardioprotective effect of icariin was significantly weakened by combining treatment with LPS. CONCLUSION: Icariin prevented ISO-induced TS-like cardiac dysfunction in rats. The effects were induced mainly through maintenance of the dynamic balance of the ROS system, promotion of anti-oxidant element activity, and suppression of TLR4/NF-κB signaling pathway protein expression. Furthermore, the ability of icariin to increase anti-inflammatory and reduce pro-inflammatory factor secretion may be involved in the protective process.

Mortality in takotsubo syndrome is similar to mortality in myocardial infarction - A report from the SWEDEHEART registry.

BACKGROUND: 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. METHODS: 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. RESULTS: The proportion of the patients diagnosed with takotsubo increased from 0.16% in 2005 to 2.2% in 2012 (P<0.05); 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, P<0.001). 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). CONCLUSIONS: 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.

Atrial fibrillation in patients admitted to coronary care units in western Sweden - focus on obesity and lipotoxicity.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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, P<0.001) and severe obesity (1.6, 95% CI 1.29-1.99, P<0.001) 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, P<0.001). Lipidomic analysis revealed that atrial TAG content was substantially lower in the AF patients (P<0.05). 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 (P<0.05) while no difference was found in saturated DAG. CONCLUSION: 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.

Low socioeconomic status of a patient's residential area is associated with worse prognosis after acute myocardial infarction in Sweden.

INTRODUCTION: Previous studies have established a relationship between socioeconomic status (SES) and survival in coronary heart disease. Acute cardiac care in Sweden is considered to be excellent and independent of SES. We studied the influence of area-level socioeconomic status on mortality after hospitalization for acute myocardial infarction (AMI) between 1995 and 2013 in the Gothenburg metropolitan area, which has little over 800,000 inhabitants and includes three city hospitals. METHODS: Data were obtained from the SWEDEHEART registry (Swedish Websystem for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) and the Swedish Central Bureau of Statistics for patients hospitalized for ST-elevation myocardial infarction (STEMI) and non-STEMI in the city of Gothenburg in Western Sweden. The groups were compared using Cox proportional hazards regression and logistic regression. RESULTS: 10,895 (36% female) patients were hospitalized due to AMI during the study period. Patients residing in areas with lower SES had higher rates of smoking and diabetes (P<0.001), and were also at increased risk of developing complications, including heart failure and cardiogenic shock (P<0.05). Living in an area with lower SES associated with increased risk of dying after an AMI also in models adjusted for risk factors (P<0.05). CONCLUSION: Also in a country with strong egalitarian traditions, lower SES associates with worse prognosis after AMI, an association that persists after adjustments for differences in traditional cardiovascular risk factors.

Rat models reveal differences in cardiocirculatory profile between Takotsubo syndrome and acute myocardial infarction.

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 < 0.05). CONCLUSION: Takotsubo syndrome and AMI are associated with different cardiocirculatory profiles. Extrapolation of treatment strategies across the syndromes may therefore not be appropriate.

Cardioprotection of the enkephalin analog Eribis peptide 94 in a rat model of ischemia and reperfusion is highly dependent on dosing regimen and timing of administration.

Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40 min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5 µg/kg per dose), whereas single (1 µg/kg) or triple boluses (0.5 µg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0 min before the 30 min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20 min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10 min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia.

Current hypotheses regarding the pathophysiology behind the takotsubo syndrome.

Takotsubo syndrome is an increasingly recognized acute cardiac affliction which is characterized by severe regional left ventricular dysfunction that cannot be explained by one or more occlusive culprit lesions of a coronary artery. A preceding somatic and/or emotional stressor can be identified in a majority of these patients and older women are overrepresented among the afflicted. Catecholamine levels are elevated in patients with takotsubo and exogenous catecholamine administration may cause or exacerbate the condition. Hence, catecholamines appear implicated in the pathogenesis. However, beyond catecholamine the pathogenesis of the takotsubo syndrome is unclear. Five distinct hypotheses have been postulated which attempt to explain why specific regions within the left ventricle are affected in takotsubo. In this manuscript we critically review these hypotheses in light of the available data. We discuss how the different hypotheses may be complementary to each other and to which extent they are contradicting one another.

Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo).

BACKGROUND: Stress-induced cardiomyopathy (SIC) is a common syndrome with substantial morbidity and mortality. SIC is common in intensive care units' patients. No therapeutic intervention for SIC has been evaluated in randomized clinical trial so far. Our aim was to investigate whether isoflurane is cardioprotective in an experimental SIC model. METHODS: We induced SIC-like cardiac dysfunction in rats with intraperitoneal injection of isoprenaline (50 mg/kg) and performed this study in two parts. First, we pre-treated rats with isoflurane (1.5%, n=12), pentobarbital (50 mg/kg, n=12) and ketamine (80 mg/kg, n=12) and compared to controls (n=12). We used glyburide, an ATP-dependent potassium channel blocker (n=6), to test whether isoflurane-protection is mediated through KATPm. In a second set of experiments, we treated rats with two different doses of isoflurane i.e. 0.75% (n=12) and 1.5% (n=12) before induction of SIC and compared to controls. We assessed left ventricular function and morphology in all rats by transthoracic echocardiography. We also measured peak body temperature, blood gases, acid-base homeostasis, blood pressure and heart rate. RESULTS: The extent of apical akinesia was lowest and cardiac function was best in the isoflurane treated rats. The protective effects were not attenuated by glibenclamide. Higher dose of isoflurane was more cardioprotective than the lower dose. This was persistent after the adjustment for changes in hemodynamics and blood biochemistry induced by anesthesia. CONCLUSIONS: Isoflurane prevented SIC-like cardiac dysfunction in rats. This protection was not mediated via KATPm. Our study provides an experimental foundation for future clinical trials in SIC.

Takotsubo triggered by acute myocardial infarction: a common but overlooked syndrome?

Takotsubo cardiomyopathy (TCM) is an acute cardiac syndrome characterized by extensive, but potentially reversible, left ventricular dysfunction in the absence of an explanatory coronary obstruction. Thus, TCM is distinct from coronary artery disease (CAD) and acute myocardial infarction (AMI). However, substantial evidence for co-existing CAD in some TCM patients exist. Herein, we take this association one step further and present a case in which the patient simultaneously suffered from AMI and TCM, and in which we believe that a primary coronary event triggered TCM. An 88-year-old female presented with chest pain. Echocardiography revealed apical akinesia with hypercontractile bases. An occluded diagonal branch with suspected acute plaque rupture was identified on the angiogram, but could not explain the extent of akinesia. Cardiac function recovered completely. Thus, this patient adhered to current diagnostic criteria for TCM. TCM is a well-known complication for other conditions associated with somatic stress. It is therefore intuitive to assume that AMI, which also associates with somatic stress and elevated catecholamine, can cause TCM. Our case illustrates that TCM and AMI may occur simultaneously. Although causality cannot be conclusively inferred from this association, the somatic stress associated with AMI may have caused TCM in this patient.

Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner.

BACKGROUND: Takotsubo cardiomyopathy (TCM) is characterized by regional left ventricular dysfunction that cannot be explained by an occlusive lesion in a coronary artery. Catecholamines are implicated in the pathogenesis of TCM but the mechanisms involved are unknown. Because the endogenous and the most commonly used exogenous catecholamines have well defined adrenoceptor subtype affinities, inferences can be made about the importance of each adrenoceptor subtype based on the ability of different catecholamines to induce TCM. We therefore studied which of five well-known catecholamines, that differ in receptor subtype affinity, are able to induce TCM-like cardiac dysfunction in the rat. METHODS: 255 rats received intraperitoneally isoprenaline (ß1/ß2-adrenoceptor agonist), epinephrine (ß1/ß2/α-adrenoceptor agonist), norepinephrine (ß1/α-adrenoceptor agonist), dopamine (α/ß1/ß2-adrenoceptor agonist) or phenylephrine (α-adrenoceptor agonist). Each catecholamine was given in five different doses. We measured blood pressure through a catheter inserted in the right carotid artery and studied cardiac morphology and function by echocardiography. RESULTS: All catecholamines induced takotsubo-like cardiac dysfunction. Isoprenaline induced low blood pressure and predominantly apical dysfunction whereas the other catecholamines induced high blood pressure and basal dysfunction. In another set of experiments, we continuously infused hydralazine or nitroprusside to rats that received epinephrine or norepinephrine to maintain systolic blood pressure < 120 mm Hg. These rats developed akinesia of the apex instead of the base. Infusion of phenylephrine to maintain blood pressure > 120 mm Hg after isoprenaline administration prevented apical TCM-like dysfunction. CONCLUSIONS: Catecholamine-induced takotsubo-like cardiac dysfunction appears to be afterload dependent rather than depend on stimulation of a specific adrenergic receptor subtype.

Lipid metabolites and their differential pro-arrhythmic profiles: of importance in the development of a new anti-arrhythmic pharmacology.

Arrhythmias have been treated for a long time with drugs that mainly target the ionic pumps and channels. These anti-arrhythmic regimens per se introduce new arrhythmias, which can be detrimental to patients. Advances in development of novel pharmacology without introduction of iatrogenic arrhythmias are thus favorable for an effective treatment of arrhythmias. Electrophysiological stability of the heart has been shown to be closely associated with cardiac metabolism. The present effective anti-arrhythmic drugs such as beta-blockers and amiodarone have profound beneficial effects in regulating myocardial metabolism. Aiming at decreasing production of toxic metabolites or preventing accumulation of arrhythmogenic lipids perhaps is a good strategy to effectively control arrhythmias. Therefore, a better understanding of the pro-arrhythmic profiles of cardiac metabolites helps to explore a new generation of metabolically oriented anti-arrhythmic medications. In this review, we present several lipid metabolites and summarize their arrhythmogenic characteristics.