Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098.

Effects of dabigatran versus warfarin on 2-year cognitive outcomes in old patients with atrial fibrillation: results from the GIRAF randomized clinical trial.

BACKGROUND: Observational studies support a role for oral anticoagulation to reduce the risk of dementia in atrial fibrillation patients, but conclusive data are lacking. Since dabigatran offers a more stable anticoagulation, we hypothesized it would reduce cognitive decline when compared to warfarin in old patients with atrial fibrillation. METHODS: The GIRAF trial was a 24-month, randomized, parallel-group, controlled, open-label, hypothesis generating trial. The trial was done in six centers including a geriatric care unit, secondary and tertiary care cardiology hospitals in São Paulo, Brazil. We included patients aged ≥ 70 years and CHA2DS2-VASc score > 1. The primary endpoint was the absolute difference in cognitive performance at 2 years. Patients were assigned 1:1 to take dabigatran (110 or 150 mg twice daily) or warfarin, controlled by INR and followed for 24 months. Patients were evaluated at baseline and at 2 years with a comprehensive and thorough cognitive evaluation protocol of tests for different cognitive domains including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), a composite neuropsychological test battery (NTB), and computer-generated tests (CGNT). RESULTS: Between 2014 and 2019, 5523 participants were screened and 200 were assigned to dabigatran (N = 99) or warfarin (N = 101) treatment. After adjustment for age, log of years of education, and raw baseline score, the difference between the mean change from baseline in the dabigatran group minus warfarin group was - 0.12 for MMSE (95% confidence interval [CI] - 0.88 to 0.63; P = 0.75), 0.05 (95% CI - 0.07 to 0.18; P = 0.40) for NTB, - 0.15 (95% CI - 0.30 to 0.01; P = 0.06) for CGNT, and - 0.96 (95% CI - 1.80 to 0.13; P = 0.02) for MoCA, with higher values suggesting less cognitive decline in the warfarin group. CONCLUSIONS: For elderly patients with atrial fibrillation, and without cognitive compromise at baseline that did not have stroke and were adequately treated with warfarin (TTR of 70%) or dabigatran for 2 years, there was no statistical difference at 5% significance level in any of the cognitive outcomes after adjusting for multiple comparisons. TRIAL REGISTRATION: Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF), NCT01994265 .

Contribution of the vectorcardiogram in the differential diagnosis of Brugada electrocardiographic pattern.

BACKGROUND: The electrocardiogram (ECG) is a powerful tool for differential diagnosis among a group of pathologies with different therapeutic approaches/prognoses, the so-called J-wave syndrome. The vectorcardiogram (VCG) can be used as a complementary method to the ECG in several dubious electrocardiographic alterations. OBJECTIVE: We carried out a VCG analysis after conceiving and measuring a novel parameter (JT-distance) that allows diagnosis of the Brugada ECG pattern. METHODS: A retrospective cohort study selected ninety-six ECGs with J-point elevation in V1/V2, ECG superior leads and VCGs, all performed on the same day. A new VCG measurement by Frank method (JT-distance) was conceived and designed in transverse and right sagittal planes by 3 lines drawn 1) at the final third of the QRS loop, comprehending the J-point; 2) at the initial portion of the T loop; 3) a parallel of the J-point line at the beginning of the T loop. JT measure was determined by the distance between parallels. A validation cohort was established in a new sample of thirty-five patients. RESULTS: JT-distance ≥1.5 mm (tranverse plane) and JT-distance >1.25 mm, in the sagittal plane, differentiated Brugada type-1 from Brugada type-2, early repolarization and others, with 95% sensitivity and 68% specificity. JT-distance <1.5 mm (transverse plane) and JT >1.25 mm (sagittal plane) had 100% sensitivity and 85% specificity for Brugada type-1 diagnosis. A validation cohort showed very similar Cohen's kappa levels (0.65 and 0.77, test and validation cohorts, respectively), with overlapping 95% confidence intervals. CONCLUSIONS: The novel vectorcardiogram measurement (JT-distance) presented a new diagnostic criterion to identify Brugada pattern. Nevertheless, prospective studies should be performed by other centers to confirm these findings.

Patterns and Risk Factors for Rehospitalizations Within the First 90 Days Following Discharge After Heart Transplantation.

BACKGROUND: Heart transplantation (HT) recipients are at risk for urgent rehospitalizations following discharge. However, data on prevalence, risk factors and clinical outcomes associated with post-HT rehospitalization are limited. METHODS: This study aims to describe patterns of urgent rehospitalizations in HT recipients at a cardiology reference center in Brazil. Rehospitalizations and deaths occurring within the first 90 days following hospital discharge were identified. Regression models were used to identify variables associated with urgent rehospitalizations. RESULTS: A total of 239 patients were included. Of those, 118 (49.4%) presented with a rehospitalization within 90 days following hospital discharge and 5 (2.01%) died. Most patients who were rehospitalized had one new hospital admission (86.0%). The main cause of urgent rehospitalization was infection (55.0%). In the multivariate analysis, elevated C-reactive protein at discharge and the occurrence of intracranial bleeding at index hospitalization were associated with an increased risk of readmission. Longer duration of index hospitalization and use of lower doses of azathioprine were associated with a lower risk of rehospitalization. CONCLUSION: Around half of HT recipients were rehospitalized within the first 90 days after hospital discharge. Understanding factors associated with post-HT rehospitalization may help the implementation of strategies to avoid patient morbidity and hospital costs.

The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms.

The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.

Diagnostic Accuracy of ECG to Detect Left Ventricular Hypertrophy in Patients with Left Bundle Branch Block: A Systematic Review and Meta-analysis.

Background: Electrocardiographic (ECG) criteria to detect left ventricular hypertrophy (LVH) in patients with left bundle branch block (LBBB) remain under debate. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of different ECG criteria for diagnosing LVH in patients with LBBB. Methods: We searched PubMed, Embase, Cochrane, and LILACS for articles evaluating the diagnostic accuracy of ECG criteria for LVH in patients with LBBB published between 1984 and 2023. Echocardiogram, magnetic resonance imaging, or autopsy were used as the reference standard for diagnosis of LVH. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The co-primary outcomes were sensitivity, specificity, the diagnostic odds ratio, and likelihood ratios, estimated using a bivariate generalized linear mixed model for each ECG criterion. The prespecified protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO). Results: We included 12 studies with a total of 1023 patients. We analyzed 10 criteria for LVH on ECG, including the Sokolow-Lyon criterion, the Cornell criterion, the RaVL (R wave in aVL) criterion, the Gubner-Ungerleider criterion, and the Dálfo criterion, among others. The Dalfó criterion was used for 487 patients and had the highest pooled sensitivity of 86% (95% confidence interval [CI] 57%-97%). All the other criteria had poor sensitivities. The Gubner-Ungerleider criterion and the RV5 or RV6 > 25 mm criterion had the highest specificities, with the former being used for 805 patients, obtaining a specificity of 99% (95% CI 80%-100%) and the latter being used for 355 patients, obtaining a specificity of 99% (95% CI 94%-100%). Conclusions: In patients with LBBB, the use of ECG criteria had poor performance for ruling out LVH, mostly due to low sensitivities. None of the criteria analyzed demonstrated a balanced tradeoff between sensitivity and specificity, suggesting that ECG should not be used routinely to screen for LVH.

Contexte: Les critères électrocardiographiques (ECG) visant à détecter une hypertrophie ventriculaire gauche (HVG) chez les patients présentant un bloc de branche gauche (BBG) font encore l'objet de discussions. Nous avons réalisé une synthèse des publications et une méta-analyse afin d'évaluer l'exactitude diagnostique de différents critères ECG pour le diagnostic de l'HVG chez les patients présentant un BBG. Méthodologie: Nous avons effectué une recherche dans les bases de données PubMed, Embase, Cochrane et LILACS afin de recenser les articles publiés entre 1984 et 2023 portant sur l'évaluation de l'exactitude de critères ECG pour le diagnostic d'une HVG chez les patients présentant un BBG. L'échocardiographie, l'imagerie par résonance magnétique et l'autopsie ont servi de normes de référence pour le diagnostic de l'HVG. Le risque de biais a été évalué au moyen de l'outil QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). Les principaux critères d'évaluation étaient la sensibilité, la spécificité, le risque relatif approché diagnostique et les rapports de vraisemblance, estimés au moyen d'un modèle linéaire mixte généralisé à deux variables pour chaque critère ECG. Le protocole défini au préalable a été enregistré dans le registre international de revues systématiques prospectives PROSPERO. Résultats: Nous avons recensé 12 études, comptant au total 1 023 patients. Nous avons analysé 10 critères pour le diagnostic d'HVG à l'ECG, notamment l'indice de Sokolow-Lyon, l'indice de Cornell, l'onde R en aVL, l'indice de Gubner-Ungerleider et l'indice de Dálfo. Ce dernier a été utilisé pour 487 patients et avait la sensibilité regroupée la plus élevée, soit 86 % (intervalle de confiance [IC] à 95 % : 57-97 %). La sensibilité de tous les autres critères était faible. L'indice de Gubner-Ungerleider et le critère de l'onde R en V5 ou V6 > 25 mm étaient associés aux spécificités les plus élevées. Le premier a été utilisé pour 805 patients et présentait une spécificité de 99 % (IC à 95 % : 80-100 %). Le second a été utilisé pour 355 patients et présentait une spécificité de 99 % (IC à 95 % : 94-100 %). Conclusions: Chez les patients présentant un BBG, l'utilisation de critères ECG a été associée à un rendement médiocre pour exclure un diagnostic d'HVG, principalement en raison de la faible sensibilité de ces critères. Aucun des critères analysés n'offrait un compromis équilibré entre la sensibilité et la spécificité, ce qui porte à croire que l'ECG ne devrait pas être utilisée systématiquement pour dépister une HVG.

P2Y12 inhibitor monotherapy versus dual antiplatelet therapy in patients with acute coronary syndromes undergoing coronary stenting: rationale and design of the NEOMINDSET Trial.

Dual antiplatelet therapy (DAPT) is currently the standard of care after percutaneous coronary intervention (PCI). Recent studies suggest that reducing DAPT to 1-3 months followed by an aspirin-free single antiplatelet therapy (SAPT) strategy with a potent P2Y12 inhibitor is safe and associated with less bleeding. However, to date, no randomised trial has tested the impact of initiating SAPT immediately after PCI, particularly in patients with acute coronary syndromes (ACS). NEOMINDSET is a multicentre, randomised, open-label trial with a blinded outcome assessment designed to compare SAPT versus DAPT in 3,400 ACS patients undergoing PCI with the latest-generation drug-eluting stents (DES). After successful PCI and up to 4 days following hospital admission, patients are randomised to receive SAPT with a potent P2Y12 inhibitor (ticagrelor or prasugrel) or DAPT (aspirin plus a potent P2Y12 inhibitor) for 12 months. Aspirin is discontinued immediately after randomisation in the SAPT group. The choice between ticagrelor and prasugrel is at the investigator's discretion. The primary hypothesis is that SAPT will be non-inferior to DAPT with respect to the composite endpoint of all-cause mortality, stroke, myocardial infarction or urgent target vessel revascularisation, but superior to DAPT on rates of bleeding defined by Bleeding Academic Research Consortium 2, 3 or 5 criteria. NEOMINDSET is the first study that is specifically designed to test SAPT versus DAPT immediately following PCI with DES in ACS patients. This trial will provide important insights on the efficacy and safety of withdrawing aspirin in the early phase of ACS. (ClinicalTrials.gov: NCT04360720).

Unraveling the interplay between dipeptidyl peptidase 4 and the renin-angiotensin system in heart failure.

AIMS: Emerging evidence suggests the existence of a crosstalk between dipeptidyl peptidase 4 (DPP4) and the renin-angiotensin system (RAS). Therefore, combined inhibition of DPP4 and RAS may produce similar pharmacological effects rather than being additive. This study tested the hypothesis that combining an inhibitor of DPP4 with an angiotensin II (Ang II) receptor blocker does not provide additional cardioprotection compared to monotherapy in heart failure (HF) rats. MAIN METHODS: Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were assigned into four groups and received vehicle (water), vildagliptin, valsartan, or both drugs, for four weeks by oral gavage. KEY FINDINGS: Vildagliptin and valsartan in monotherapy reduced LV hypertrophy, alleviated cardiac interstitial fibrosis, and improved systolic and diastolic function in HF rats, with no additional effect of combination treatment. HF rats displayed higher cardiac and serum DPP4 activity and abundance than sham. Surprisingly, not only vildagliptin but also valsartan in monotherapy downregulated the catalytic function and expression levels of systemic and cardiac DPP4. Moreover, vildagliptin and valsartan alone or in combination comparably upregulate the components of the cardiac ACE2/Ang-(1-7)/MasR while downregulating the ACE/Ang II/AT1R axis. SIGNIFICANCE: Vildagliptin or valsartan alone is as effective as combined to treat cardiac dysfunction and remodeling in experimental HF. DPP4 inhibition downregulates classic RAS components, and pharmacological RAS blockade downregulates DPP4 in the heart and serum of HF rats. This interplay between DPP4 and RAS may affect HF progression and pharmacotherapy.

Sex differences in the lung ACE/ACE2 balance in hypertensive rats.

The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).

Weighing Coronary Revascularization Options in Patients With Type 2 Diabetes Mellitus.

Patients with diabetes mellitus (DM) are at increased risk for developing coronary artery disease. Choosing the optimal revascularization strategy, such as coronary artery bypass grafting or percutaneous coronary intervention (PCI), may be difficult in this population. A large body of evidence suggests that, for patients with DM and stable multivessel ischemic heart disease, coronary artery bypass grafting is usually superior to PCI, leading to lower rates of all-cause mortality, myocardial infarction and repeat revascularization in the long term. In patients with less complex coronary anatomy (2- or single-vessel disease, especially without involvement of the proximal left anterior descendent artery), PCI may be a viable option. Because these anatomic patterns are less frequent in patients with DM, there is less evidence to guide revascularization in these cases. Patients with DM and left main disease and those in the acute coronary syndrome setting are also underrepresented in randomized trials, and the best revascularization strategy for these patients is not clear. Once the revascularization procedure is performed, patients should be kept engaged in controlling the risk factors for progression of cardiovascular disease. Avoidance of smoking, control of cholesterol, blood pressure and glycemic levels; regular practice of physical activity of at least moderate intensity; and a balanced diet are of key importance in the post-revascularization period. In this study, we review the current literature in the management of patients with DM and coronary artery disease undergoing a revascularization procedure.

Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a public health crisis of major proportions. Advanced age, male gender, and the presence of comorbidities have emerged as risk factors for severe illness or death from COVID-19 in observation studies. Hypertension is one of the most common comorbidities in patients with COVID-19. Indeed, hypertension has been shown to be associated with increased risk for mortality, acute respiratory distress syndrome, need for intensive care unit admission, and disease progression in COVID-19 patients. However, up to the present time, the precise mechanisms of how hypertension may lead to the more severe manifestations of disease in patients with COVID-19 remains unknown. This review aims to present the biological plausibility linking hypertension and higher risk for COVID-19 severity. Emphasis is given to the role of the renin-angiotensin system and its inhibitors, given the crucial role that this system plays in both viral transmissibility and the pathophysiology of arterial hypertension. We also describe the importance of the immune system, which is dysregulated in hypertension and SARS-CoV-2 infection, and the potential involvement of the multifunctional enzyme dipeptidyl peptidase 4 (DPP4), that, in addition to the angiotensin-converting enzyme 2 (ACE2), may contribute to the SARS-CoV-2 entrance into target cells. The role of hemodynamic changes in hypertension that might aggravate myocardial injury in the setting of COVID-19, including endothelial dysfunction, arterial stiffness, and left ventricle hypertrophy, are also discussed.

P2Y12 inhibitor monotherapy versus dual antiplatelet therapy in patients with acute coronary syndromes undergoing coronary stenting: rationale and design of the NEOMINDSET Trial

Dual antiplatelet therapy (DAPT) is currently the standard of care after percutaneous coronary intervention (PCI). Recent studies suggest that reducing DAPT to 1-3 months followed by an aspirin-free single antiplatelet therapy (SAPT) strategy with a potent P2Y12 inhibitor is safe and associated with less bleeding. However, to date, no randomised trial has tested the impact of initiating SAPT immediately after PCI, particularly in patients with acute coronary syndromes (ACS). NEOMINDSET is a multicentre, randomised, open-label trial with a blinded outcome assessment designed to compare SAPT versus DAPT in 3,400 ACS patients undergoing PCI with the latest-generation drug-eluting stents (DES). After successful PCI and up to 4 days following hospital admission, patients are randomised to receive SAPT with a potent P2Y12 inhibitor (ticagrelor or prasugrel) or DAPT (aspirin plus a potent P2Y12 inhibitor) for 12 months. Aspirin is discontinued immediately after randomisation in the SAPT group. The choice between ticagrelor and prasugrel is at the investigator's discretion. The primary hypothesis is that SAPT will be non-inferior to DAPT with respect to the composite endpoint of all-cause mortality, stroke, myocardial infarction or urgent target vessel revascularisation, but superior to DAPT on rates of bleeding defined by Bleeding Academic Research Consortium 2, 3 or 5 criteria. NEOMINDSET is the first study that is specifically designed to test SAPT versus DAPT immediately following PCI with DES in ACS patients. This trial will provide important insights on the efficacy and safety of withdrawing aspirin in the early phase of ACS.

Ranolazine injection into coronary or femoral arteries exerts marked, transient regional vasodilation without systemic hypotension in an intact porcine model.

BACKGROUND: We examined whether intracoronary or intrafemoral administration of ranolazine produces local vasodilation. METHODS AND RESULTS: Effects of intra-arterial ranolazine on coronary and femoral artery vasodilation and systemic hemodynamic function were studied in anesthetized pigs (n=27). Ranolazine, nitroglycerin, or saline (control) was injected into the left anterior descending (LAD) coronary artery or femoral artery (2-mL bolus in 10 seconds). Pretreatment with prazosin (300 µg/kg IV) allowed determination of α(1)-adrenergic receptor involvement (n=8). Rapid intracoronary administration of ranolazine (0.048 mg/kg) to achieve high local concentrations resulted in 91±11% increase in LAD coronary artery flow and 39±7% reduction in coronary vascular resistance (both, P<0.0001). This effect lasted 2-3 minutes without change in heart rate or rate-pressure product. Mean arterial pressure decreased marginally (by 2±1 mm Hg, P=0.01). Maximum systemic plasma concentration (0.93±0.29 µmol/L) remained in subtherapeutic range. Pretreatment with prazosin abolished these effects. Intracoronary nitroglycerin (100 µg) increased LAD coronary artery flow by 112±25% (P=0.02), but the effect lasted <2 minutes; mean arterial pressure decreased by 4±1 mm Hg (P=0.01). Intrafemoral injection of ranolazine (0.24 mg/kg, ie, one-tenth of the systemic bolus) resulted in a 70±19% increase in femoral artery flow (P=0.05) and 26±5% reduction in femoral artery resistance (P=0.004). At 2 minutes after the injection, the femoral flow remained 16±9% above the baseline and dilatory effects occurred without tolerance to repeated injections. CONCLUSIONS: Intracoronary or intrafemoral ranolazine bolus exerts a marked, 2- to 3-minute dilatory effect that is comparable to nitroglycerin in magnitude but more persistent, attributable primarily to α(1)-adrenergic blockade.

Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model.

BACKGROUND: Clinical evidence suggests that the antianginal agent ranolazine has antiarrhythmic properties, but its effects on vulnerability to ventricular fibrillation (VF) and T-wave alternans (TWA) during coronary artery stenosis have not been measured. OBJECTIVE: We investigated whether the antiarrhythmic effect of ranolazine during acute coronary stenosis could be quantified by measuring VF threshold and TWA magnitude. METHODS: Electrode catheters placed in the left ventricular apex were used to determine VF threshold during ventricular pacing at 130 beats/min, and TWA was quantified from epicardial electrograms using modified moving average method (N = 18). Left anterior descending coronary flow was reduced with a balloon occluder by 75% for 10 minutes. The I(Kr) blocker E-4031 was used to distinguish effects of late I(Na) and I(Kr) inhibition by ranolazine. RESULTS: Before stenosis, ranolazine and E-4031 increased VF threshold from 32 ± 4 mA to 46 ± 4 mA (mean ± SEM), P = .02, and from 33 ± 5 mA to 40 ± 9 mA, P = .02, respectively. During stenosis, ranolazine increased VF threshold from 19 ± 2 mA to 33 ± 3 mA (P = .02), whereas E-4031 decreased VF threshold from 21 ± 3 mA to 15 ± 3 mA (P = .02). The ischemia-induced increase in TWA was suppressed by ranolazine but not by E-4031, consistent with effects of these agents on VF threshold. CONCLUSION: Ranolazine exerts significant antifibrillatory effects during coronary stenosis through direct effects on cardiac electrical properties independent of coronary flow. Ranolazine's antifibrillatory action during myocardial ischemia does not appear to be mediated by blockade of I(Kr) but rather by inhibition of late I(Na). TWA changes paralleled vulnerability to VF as indicated by VF threshold testing.