Detrimental Effects of Alcohol on the Heart: Hypertension and Cardiomyopathy.

Background: Epidemiological evidence suggests a J-shaped association between alcohol consumption and cardiovascular mortality, with higher cardiovascular event rates occurring among abstainers and heavy drinkers compared to moderate consumers. However, this hypothesis has been challenged by more recent studies. Furthermore, ethnicity, gender, type of alcoholic beverage, and pattern of alcohol intake, influence the relationship between alcohol and heart health. Methods: We undertook a review of the relavent literature utilizing PubMed. Results: Heavy alcohol consumption causes resistant hypertension, cardiomyopathy, arrhythmias, hemorrhagic strokes, as well as hepatic cirrhosis and pancreatitis. Excessive drinking is the third most preventable cause of death worldwide behind hypertension and smoking. Conclusions: In this review, we discuss the effects of alcohol abuse on hypertension (a major cause of myocardial infarction and stroke) and alcoholic cardiomyopathy. Another article in this Special Issue "Alcohol and Heart Health" discusses the problem with alcohol and arrhythmias sudden cardiac death.

Alcohol and Cardiovascular Disease: Helpful or Hurtful.

Alcohol has been considered throughout history as both a tonic and a poison. The answer as to which likely depends on one's current health, the amount one consumes, and with what regularity. In examining the relationship of alcohol and cardiovascular health, most, but not all, epidemiological studies suggest that light to moderate alcohol consumption can reduce the incidence of coronary artery disease (CAD), ischemic stroke, and peripheral arterial disease events. Conversely, abuse of alcohol can lead to cardiomyopathy, heart failure, sudden death, and hemorrhagic strokes. In this article, we review the literature studying the effects of alcohol on coronary artery disease and stroke. A recently published study concluded there was no amount of alcohol per day that was heart healthy. Yet more than one hundred previous studies have found that people who drink in moderation have a lower risk of cardiovascular disease events when compared to those who do not drink or drink heavily. Moderate drinking is defined as one to two drinks per day; where one drink is defined as 12 ounces of beer, 5 ounces of wine or 1.5 ounces of hard liquor. In this article we reviewed the data suggesting that consuming alcohol in moderation on a regular basis-as opposed to 7 drinks on Saturday night-could have cardiovascular protective effects.

Renal dysfunction in Takotsubo syndrome-role of segmental left ventricle strain analysis.

BACKGROUND: Takotsubo syndrome (TTS) is a peculiar clinical condition often resembling an acute coronary syndrome and mostly affecting postmenopausal women. We sought to describe the prevalence of acute kidney injury and acute renal failure in TTS patients during index event and assess the usefulness of speckle tracking echocardiography in predicting subjects at risk of developing acute kidney insult. METHODS: We conducted a retrospective descriptive study reviewing study with the discharge diagnosis of TTS between 2003-2016 at our Institution. One hundred and two patients met the Modified Mayo Clinic. Acute kidney injury (AKI) was defined as an increment of serum creatinine 2 times greater than baseline and/or at least 50% reduction in baseline eGFR. Acute renal failure (ARF) was defined as an increment of serum creatinine 3 times greater than baseline and/or at least 75% reduction in baseline eGFR as per RIFLE Classification. RESULTS: AKI/ARF patients had longer length of stay (24 vs 10 days, P = 0.02), had higher mean peak troponin (16.7 ng/mL vs 3.2, P < 0.05) and later peak creatinine day (10 vs 3, P < 0.05). LV Longitudinal strain in the basal segment and apex upon admission was significantly worse in the AKI/ARF group (-4.7 and -6.5, respectively, vs -8.6 and -9.1 in the non-AKI/ARF group, P < 0.05). CONCLUSIONS: One in every 10 TTS patients may develop AKI/ARF during the acute episode. Segmental longitudinal strain by speckle tracking may have important prognostic value in identifying TTS patients at risk of developing AKI/ARF.

Usefulness of left ventricular strain analysis in patients with takotsubo syndrome during acute phase.

BACKGROUND: Takotsubo syndrome (TTS) is peculiar clinical condition often resembling an acute coronary syndrome and mostly affecting postmenopausal women after a stressful trigger. TTS was initially thought to be a relatively benign condition. However, current data have shown it may be associated with considerable inpatient morbidity and carry a small, but important, mortality risk. METHODS: We hypothesized that left ventricular (LV) regional and global longitudinal strain (GLS) assessed with 2D speckle tracking echocardiography could identify early systolic functional impairment and predict in-hospital cardiovascular events. We conducted a retrospective descriptive study reviewing patients with the discharge diagnosis of TCM between 2003 and 2016 at our institution. RESULTS: One hundred patients with TSS met the Modified Mayo Clinic criteria. Using 2D speckle tracking echocardiography, two independent cardiologists assessed the LV GLS as well as the longitudinal strain (LS) of 7 individual segments [basal-septal (BS); mid-septal (MS), apical-septal (AS), apex, basal-lateral (BL), mid-lateral (ML), and apical-lateral (AL)]. The inter-observer variability was <5%. Mean age was 69.1 years, 87% were females, and 53% were African Americans. Mean initial LV EF was 32% ± 9.8%. In univariate analysis, patients with worse BL, ML, and GLS profiles (means: -5.7; -3.3, and -4, respectively) had higher in-hospital mortality (P < .05). Worse BL and ML profiles (means: -8.6 and -7.3, respectively) were associated with higher prevalence of MACE (major adverse cardiovascular outcomes) (P < .05). In a multivariate analysis, mid-lateral strain ≥ -7 and basolateral strain ≥ -10 were independent predictors of in-hospital mortality and MACE + in-hospital heart failure, respectively. CONCLUSIONS: Assessment of LV global and segmental longitudinal strain by speckle tracking has important prognostic value in the acute phase of TTS. Additional large-scale studies will be needed to confirm our findings.

Natural history of severe aortic stenosis: Diastolic wall strain as a novel prognostic marker.

BACKGROUND AND AIM: Diastolic wall strain (DWS) has been proposed as a simple noninvasive measure of left ventricular (LV) stiffness. This study investigated DWS as a possible predictor of mortality in severe aortic stenosis (AS). METHODS: 138 patients with severe AS (indexed aortic valve area [AVA]<0.6 cm2 /m2 ) and normal ejection fraction (>55%) were included. 52 patients (38%) had aortic valve interventions or poor image quality (n=5) and were excluded leaving 86 in the study group (84±8 years, 70% female, 69% African American). DWS was defined as (LVPWs-LVPWd)/LVPWs where LVPWs=left ventricular posterior wall thickness in systole and LVPWd=left ventricular wall thickness in diastole. RESULTS: Follow-up extended 2.0±1.9 years (median 1.6 years). Mean DWS for the group was 0.21±0.11 (normal=0.4±0.07). In patients who died, DWS was significantly lower than in survivors (0.18±0.09 vs 0.24±0.11, P=.02). By contrast, traditional measures of diastolic dysfunction did not predict death. Regression analysis showed DWS predicted death even after adjusting for age, sex, race, indexed AVA, symptoms (angina, shortness of breath, dizziness, syncope), and clinical factors (creatinine, smoking, diabetes, hypertension, hyperlipidemia) (HR 2.5 [95% CI 1.02-5.90], P<.05). The best cutoff value for DWS of 0.25 had a sensitivity of 42% and specificity of 83% for predicting death. CONCLUSIONS: DWS is an independent predictor of all-cause mortality in patients with severe AS, even after accounting for traditional clinical and echocardiographic parameters.

Altered mental status in the emergency department - Can an electrocardiogram show the right way to go?

A 38-year-old African American male patient with a past medical history of human immunodeficiency virus and schizophrenia who was noncompliant with medications presented to the emergency department (ED) after activation of the local crisis response center for altered mental status. Upon arrival he was lethargic and uncooperative, unable to provide any significant details apart from pleuritic chest pain. His blood pressure was 133/88 mmHg, heart rate 43 beats per minute and initial body temperature 36.1 °C which prompted an electrocardiogram (EKG). This initial EKG was compared to a prior one obtained six months earlier during an ER visit for an acute psychotic episode. Three hours of being admitted he started shivering. Patient was found to be hypothermic with a rectal temperature of 28.9 °C. He was also hypoglycemic, pancytopenic and had positive urine cultures with >100,000 CFU/ml coagulase-negative Staphylococcus. There was no evidence of medication overdose. His CT scan of the brain did not show evidence of intracranial bleeding and his serum calcium was normal.

Antiplatelet therapy in Takotsubo cardiomyopathy: does it improve cardiovascular outcomes during index event?

Plasma catecholamines may play an important role in Takotsubo cardiomyopathy (TCM) pathophysiology. Patients with disproportionately high catecholamine responses to stressful events are prone to worse clinical outcomes. Catecholamines stimulate platelet activation and, therefore, may determine the clinical presentation and outcomes of TCM. We conducted a retrospective, descriptive study TCM patients admitted between 2003 and 2013 to Einstein Medical Center, Philadelphia, PA, USA and Danbury Hospital, Danbury, CT, USA. A total of 206 patients met Modified Mayo TCM criteria. Using a multiple logistic model, we tested whether aspirin, dual antiplatelet therapy (DAPT) aspirin + clopidogrel, beta blocker, statin, or ACE inhibitor use were independent predictors of major adverse cardiovascular events (MACE) during the index hospitalization. MACE was defined as in-hospital heart failure, in-hospital death, stroke or respiratory failure requiring mechanical ventilation. Incidence of in-hospital heart failure was 26.7 %, in-hospital death was 7.3 %, stroke was 7.3 % and MACE was 42.3 %. In a multiple logistic regression model (adjusted for gender, race, age, physical stressor, hypertension, diabetes, hyperlipidemia, smoking history, body mass index, initial left ventricular ejection fraction, single antiplatelet therapy, DAPT, beta blocker, statin, and ACE inhibitor) aspirin and DAPT at the time of hospitalization were independent predictors of a lower incidence of MACE during the index hospitalization (aspirin: OR 0.4, 95 % CI (0.16-0.9), P = 0.04; DAPT: OR 0.23; 95 % CI (0.1-0.55); P < 0.01. Physical stressor itself was also found to be an independent predictor of worse MACE: OR 5.1; 95 % CI (2.4-11.5); P < 0.01. In our study, aspirin and DAPT were independent predictors of a lower incidence of MACE during hospitalization for TCM. Prospective clinical trials are needed to confirm the findings of this study.

Distinctive Electrocardiographic Features in African Americans Diagnosed with Takotsubo Cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TC) can resemble acute anterior ST-elevation myocardial infarction. Most studies have examined TC in Asians and Caucasians (non-African Americans [AA]), while very few cases have been reported in AA. We aimed to assess the electrocardiographic features of TC in AA patients and compare them to non-AA TC patients. METHODS: We retrospectively compared electrocardiograms of 52 AA and 47 non-AA patients diagnosed with TC. All patients met the modified Mayo Clinic criteria for the diagnosis of TC. Information collected included PR interval, QRS duration and amplitude, QT interval in milliseconds (msec) adjusted for heart rate (QTc), ST-segment deviation at the J point in limb and precordial leads (≥1 mm), ST elevation (≥1 mm), and T-wave inversion (≥0.5 mm). RESULTS: T-wave inversion was more prevalent on presentation among AA patients (82% vs 48% in non-AA; P < 0.01), whereas ST depression was more common among non-AA (21% vs 7% in AA; P = 0.05). T-wave inversions in AA patients were frequent in both limb and precordial leads, whereas T-wave inversions in non-AA were limited to precordial leads. The average QTc upon presentation in AA was longer than non-AA (491 msec in AA vs 456 msec in non-AA; P < 0.01) as was the maximum average QTc during index hospitalization (527 msec in AA vs 497 msec in non-AA, P = 0.03). CONCLUSION: In patients presenting with TC, AA patients more frequently present with diffuse T-wave inversions and a more prolonged QTc, whereas non-AA patients more often present with ST depressions. AA patients also more frequently present with T-wave inversions diffusely, whereas non-AA patients present with T-wave inversions more limited to the precordial leads.

Dipstick proteinuria is an independent predictor of high on treatment platelet reactivity in patients on clopidogrel, but not aspirin, admitted for major adverse cardiovascular events.

The effectiveness of aspirin and clopidogrel in patients with chronic kidney disease (CKD) suffering from acute cardiovascular events is unclear. High on treatment platelet reactivity (HTPR) has been associated with worse outcomes. Here, we assessed the association of dipstick proteinuria (DP) and renal function on HTPR and clinical outcomes. Retrospective cohort analysis of 261 consecutive, non-dialysis patients admitted for Major Adverse Cardiovascular Events (MACE) that had VerifyNow P2Y12 and VerifyNow Aspirin assays performed. HTPR was defined as P2Y12 reactivity unit (PRU) > 208 for clopidogrel and aspirin reaction units (ARU) > 550 for aspirin. Renal function was classified based on the estimated glomerular filtration rate (eGFR), and dipstick proteinuria was defined as ≥ 30 mg/dl of albumin detected on a spot analysis. All cause mortality, readmissions, and cardiac catheterizations were reviewed over 520 days. In patients on clopidogrel (n = 106), DP was associated with HTPR, independent of eGFR, diabetes mellitus, smoking or use of proton pump inhibitor (AOR = 4.76, p = 0.03). In patients with acute coronary syndromes, HTPR was associated with more cardiac catheterizations (p = 0.009) and readmissions (p = 0.032), but no differences in in-stent thrombosis or re-stenosis were noted in this cohort. In patients on aspirin (n = 155), no associations were seen between DP and HTPR. However, all cause mortality was significantly higher with HTPR in this group (p = 0.038). In this cohort, DP is an independent predictor of HTPR in patients on clopidogrel, but not aspirin, admitted to the hospital for MACE.

Tricuspid Annular Plane Systolic Excursion and Its Association with Mortality in Critically Ill Patients.

BACKGROUND: Transient left ventricular dysfunction can occur under conditions of extreme emotional or physiological stress. There is little data on right ventricular function in such situations. METHODS: One hundred twenty patients admitted to an ICU with a noncardiac illness were studied. Those with documented coronary disease, ejection fraction <40%, sepsis, or intracranial hemorrhage were excluded. Echocardiograms were performed within 24 hours of admission. Tricuspid annular plane systolic excursion (TAPSE) was measured to assess right ventricular systolic function. Plasma catecholamines (norepinephrine, epinephrine, dopamine) were measured on admission. Clinical and demographic data were collected, along with data on ICU length of stay (LOS), hospital LOS, and in-hospital and long-term mortality. TAPSE was tested for correlation with adverse outcomes and length of stay. RESULTS: Mean TAPSE for the group was 2.05 ± 0.66 cm. Based on area under the ROC curve analysis, TAPSE <2.4 cm was the best cutoff for predicting in-hospital and long-term mortality. There were 13 in-hospital deaths, 12 in the group with TAPSE <2.4 cm and one among those with TAPSE ≥2.4 cm. On multivariate analysis, TAPSE <2.4 cm was a significant predictor of in-hospital mortality (χ(2)  = 4.6, P = 0.03). When tested against hospital LOS, an inverse correlation was found (P = 0.04). No association was found between TAPSE and catecholamine levels. CONCLUSIONS: Right ventricular systolic function, as assessed by TAPSE, has important prognostic value in critically ill patients. Mean values were lower in patients who died in-hospital versus those who survived to discharge. In addition, patients with TAPSE <2.4 cm had a longer hospital length of stay.

Pre-ordering lunch at work. Results of the what to eat for lunch study.

The objective of this study was to evaluate an intervention that combined mindful eating and online pre-ordering to promote healthier lunch purchases at work. The study took place at an urban hospital with 26 employees who were overweight or obese. The design included a contemporaneous comparison with delayed-treatment control and a three-phase prospective study. A minimum 4-week baseline period preceded a 4-week full-intervention, in which participants received mindful eating training, pre-ordered their lunches, and received price discounts toward lunch purchases. In a 4-week reduced intervention phase, participants pre-ordered lunches without price discounts. Participant lunch purchases were tracked electronically at the point of purchase. The primary outcome measures were the amounts of kilocalories and fat grams in purchased lunches. In contemporaneous comparisons, the treatment group purchased lunches with an average of 144.6 fewer kilocalories (p = 0.01) and 8.9 fewer grams of fat (p = 0.005) compared to controls. In multivariable longitudinal analyses, participants decreased the average number of calories in their meals by 114.6 kcal per lunch and the average grams of fat by 5.4 per lunch during the partial-intervention compared to the baseline (p < 0.001). At the end of the study, a moderate increase was observed in participants' overall mindful eating behaviors as compared to the beginning of the study (p < 0.001). The majority of participants (92%) said they would use the pre-ordering system if offered in the future. Combined mindful eating training and online pre-ordering appears a feasible and useful worksite intervention to improve food choices by employees.

Global T-wave inversion on electrocardiogram: what is the differential?

Global T-wave inversion as seen on electrocardiogram is associated with a variety of pathophysiologic states, including cardiac, pulmonary, and cerebrovascular disease, and acute electrolyte disorders. Although some of these are chronic conditions, others are acute emergencies, necessitating early diagnosis and treatment. This article reviews and provides examples of possible etiologies of global T-wave inversion on electrocardiogram.

HDL cholesterol: all hope is not lost after the torcetrapib setback--emerging therapeutic strategies on the horizon.

Lowering low-density lipoprotein cholesterol (LDL) has been definitely shown to reduce cardiovascular events and improve clinical outcomes in the literature. As a result, LDL lowering has become the cornerstone of therapeutic approaches to cardiovascular disease prevention. Recently, there has been a focus on targeting other lipid fractions to improve the clinical risk profile of patients. Raising high-density lipoprotein (HDL) has received considerable attention. Low HDL levels are often seen in combination with elevated triglyceride levels. New therapeutic modalities are being developed to increase HDL levels. Recent failure of agents such as cholesteryl ester transferase protein inhibitor torcetrapib has highlighted the importance of measuring functionality of HDL particles and not just focus quantitatively on HDL-C levels. The heterogeneity of HDL within the systemic circulation results from constant remodeling of particles in response to several factors. Established dyslipidemia therapies such as stains, fibrates, and niacin have already been well known in the literature to have a substantial benefit. Lifestyle changes such as smoking cessation and moderate alcohol consumption have also shown to have some benefit. Several novel HDL therapies are currently being developed, but only the cholesteryl ester transferase protein inhibitors have received considerable attention. Although torcetrapib has received some negative attention due to adverse effects, this overall class of therapeutic agents still holds a lot of promise. Newer agents without the concerned toxicities are currently being developed. ApoA-1-related peptides, peroxisome proliferator-activated receptor agonists, endothelial lipase inhibitors, and liver X receptor agonists are some of the other novel agents currently in various stages of development.

Prognostic value of prolonged QTc interval in patients with acute pulmonary embolism.

BACKGROUND/OBJECTIVES: Acute pulmonary embolism (PE) can be a life-threatening condition. Right ventricular function evaluated by echocardiography, brain natriuretic peptide levels and several patterns on the electrocardiogram have been utilized to guide treatment and prognosis. Case reports described heart rate corrected QT (QTc) prolongation as an ECG finding associated with PE. However, the prognostic value of QTc prolongation has not been studied. METHODS: Retrospective chart review of 300 consecutive patients (mean age 60.3 ± 17.6 years; 40.7% men) diagnosed with acute PE by computed tomography pulmonary angiography or ventilation perfusion scan were studied. Patients were divided into two groups: a prolonged QTc group with QTc >460 milliseconds (n=178) and a control group (n=122). We retrospectively reviewed medical records, electrocardiography, echocardiography and radiography results. Statistical analyses included unpaired t-test and Fisher's exact test using Stata version12. RESULTS: The prolonged QTc group demonstrated significantly increased right ventricular dilatation and systolic dysfunction. Additionally, the duration of hospitalization and intensive care unit stay were longer in the prolonged QTc group. Further, the prolonged QTc group had more hypotensive episodes and received thrombolytic treatment more frequently. There was no statistical difference in in-patient mortality rates (4.5% for the study group and 4.2% for the control group, P=1). CONCLUSIONS: Prolonged QTc may prove a novel predictor for evaluating prognosis in acute PE. Larger studies will need to confirm this finding.

Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury.

PURPOSE: Necroptosis has been proposed as a mode of cell death that is a caspase-independent programmed necrosis. We investigated whether necroptosis is involved in myocardial ischemia-reperfusion injury in isolated guinea pig hearts and, if so, whether simultaneous inhibition of necroptosis and apoptosis confers enhanced cardioprotection. METHODS: Isolated perfused guinea pig hearts were subjected to 30 min ischemia and 4 h reperfusion (control = CTL, n = 8). Necrostatin-1 (necroptosis inhibitor, 10 µM), Z-VAD (apoptosis inhibitor, 0.1 µM) and both inhibitors were administered starting 5 min before ischemia and during the initial 30 min of reperfusion (Nec, Z-VAD, Nec + Z-VAD; n = 8 each). Contractile recovery was monitored by left ventricular developed (LVDP) and end-diastolic (LVEDP) pressure. Infarct size was determined by triphenyltetrazolium chloride staining. Tissue samples were obtained after 4 h reperfusion to determine expression of receptor-interacting protein 1 (RIP1) and activated caspase 3 by Western blot analysis. RESULTS: After reperfusion, Nec + Z-VAD had higher LVDP and lower LVEDP compared with CTL. Infarct size was reduced in Nec and Z-VAD compared with CTL. Combination of necroptosis and apoptosis inhibition further reduced infarct size. Expression of activated caspase 3 was not increased in Z-VAD and Nec + Z-VAD compared with Nec and CTL. Expression of RIP1 was preserved in Z-VAD and Nec + Z-VAD compared with CTL, suggesting RIP1-mediated necrosis is involved in myocardial ischemia-reperfusion injury. CONCLUSION: Necroptosis is involved in myocardial ischemia-reperfusion injury, and simultaneous inhibition of necroptosis and apoptosis enhances the cardioprotective effect. These findings may provide a novel, additive strategy for cardioprotection in acute myocardial infarction.

Sevoflurane induces cardioprotection through reactive oxygen species-mediated upregulation of autophagy in isolated guinea pig hearts.

PURPOSE: Sevoflurane increases reactive oxygen species (ROS), which mediate cardioprotection against myocardial ischemia-reperfusion injury. Emerging evidence suggests that autophagy is involved in cardioprotection. We examined whether reactive oxygen species mediate sevoflurane preconditioning through autophagy. METHODS: Isolated guinea pigs hearts were subjected to 30 min ischemia followed by 120 min reperfusion (control). Anesthetic preconditioning was elicited with 2 % sevoflurane for 10 min before ischemia (SEVO). The ROS-scavenger, N-(2-mercaptopropionyl) glycine (MPG, 1 mmol/l), was administered starting 30 min before ischemia to sevoflurane-treated (SEVO + MPG) or non-sevoflurane-treated (MPG) hearts. Infarct size was determined by triphenyltetrazolium chloride stain. Tissue samples were obtained after reperfusion to determine autophagy-related protein (microtubule-associated protein light chain I and II: LC3-I, -II) and 5' AMP-activated protein kinase (AMPK) expression using Western blot analysis. Electron microscopy was used to detect autophagosomes. RESULTS: Infarct size was significantly reduced and there were more abundant autophagosomes in SEVO compared with control. Western blot analysis revealed that the ratio of LC3-II/I and phosphorylation of AMPK were significantly increased in SEVO. These effects were abolished by MPG. CONCLUSIONS: Sevoflurane induces cardioprotection through ROS-mediated upregulation of autophagy.

Distribution of dyssynchrony in subjects with no known cardiac disease and comparison of velocity vector imaging to color-coded tissue Doppler imaging.

Data on the distribution of dyssynchrony in subjects with normal ejection fraction (EF) and normal QRS are scarce. We studied 100 subjects with no known cardiac disease (52% male, mean age 60 ± 17 years) using velocity vector imaging (VVI). Seventeen percent had septal to lateral (S-L) wall longitudinal delay >75 msec, 63% of subjects had S-L wall radial delay >75 msec, and 25% had a circumferential opposing wall delay >100 msec. Those with circumferential opposing wall delay of >100 msec had a lower EF (57 ± 5% vs. 62 ± 5%, P < 0.05). In an additional group of 33 patients, we compared the longitudinal dyssynchrony parameters as assessed by VVI and tissue Doppler imaging (TDI) and found them to be comparable. In conclusion, we find significant variation in time to peak velocities in subjects with no known cardiac disease, who had a normal left ventricular ejection fraction and QRS duration. VVI is comparable to TDI.

Sevoflurane confers additive cardioprotection to ethanol preconditioning associated with enhanced phosphorylation of glycogen synthase kinase-3ß and inhibition of mitochondrial permeability transition pore opening.

OBJECTIVE: The purposes of this study were to investigate whether sevoflurane (SEVO) enhances moderate-dose ethanol (EtOH) preconditioning and whether this additional cardioprotection is associated with glycogen synthase kinase-3ß (GSK-3ß), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 70-kDa ribosomal s6 kinase-1 (p70s6K), and/or mitochondrial permeability transition pore (MPTP) opening. DESIGN: In vitro study using an isolated heart Langendorff preparation. SETTING: University research laboratory. PARTICIPANTS: Male guinea pigs (n = 170). INTERVENTIONS: Isolated perfused guinea pig hearts underwent 30-minute ischemia and 120-minute reperfusion (control). The EtOH group received 5% EtOH in the drinking water for 8 weeks. Anesthetic preconditioning was elicited by a 10-minute exposure to 2% SEVO in EtOH (EtOH + SEVO group) or non-EtOH (SEVO group) hearts. The inhibition of GSK-3ß phosphorylation and mTOR was achieved with LY294002 and rapamycin, respectively. GSK-3ß, Akt, mTOR, and p70s6K expressions were determined by western blot. Calcium-induced MPTP opening was assessed in isolated calcein-loaded mitochondria. MEASUREMENTS AND MAIN RESULTS: After ischemia-reperfusion, the EtOH, SEVO, and EtOH + SEVO groups had higher left ventricular developed pressure recovery and lower end-diastolic pressure versus the control group. Infarct size was smaller in the EtOH and SEVO groups versus control and even smaller in the EtOH + SEVO group. Phosphorylation of GSK-3ß and Akt, but not mTOR and p70s6K, was increased in the EtOH and SEVO groups. Phosphorylation of GSK-3ß, but not mTOR and p70s6K, was further increased in the EtOH + SEVO group. The EtOH and SEVO groups exhibited a smaller calcium-induced MPTP opening, and the EtOH + SEVO presented an even smaller MPTP opening. CONCLUSIONS: SEVO and chronic EtOH preconditioning offer additive cardioprotection. This effect is associated with an increased GSK-3ß phosphorylation and an inhibition of MPTP opening.