Recurrent myocardial infarction: In-Hospital mortality, cardiovascular complications, and comorbidity profiles.

Role of beta-adrenergic modulation of action potential duration in arrhythmogenesis in Long QT Syndrome Type 1 & 2.

A Real-World Pharmacovigilance Study of Cilostazol Based on the Food and Drug Administration Adverse Event Reporting System: A Cross-Sectional Disproportionality Analysis.

Time trends in ICD recommendations and predictors of device activation hypertrophic cardiomyopathy: a real-world cohort study.

The optimal tidal volume (VT) during Cardio-Pulmonary Resuscitation (CPR) remains unknown. Capnogram could permit to detect ventilation induced harmful effect. The objectives of the present study were to describe the impact of different VT on hemodynamics during CPR; and to evaluate whether capnogram analysis can assess the influence of ventilation on circulation. Eighteen pigs had five minutes of untreated ventricular fibrillation followed by CPR with automated continuous chest compressions and ventilation settings randomly combining VT 6, 10 or 14ml/kg. Capnograms were recorded to determine thoracic distension patterns. After return of spontaneous circulation (ROSC), all surviving animals were ventilated 2h and lungs were withdrawn for histological analysis. VT was associated with differences in the hemodynamic parameters studied. VT at 6 or 14ml/kg graphically showed poorer cerebral and coronary perfusion pressures and mean arterial pressure than a VT at 10ml/kg. The capnogram could distinguish three levels of thoracic distension. Thoracic distension was associated with differences in the hemodynamic parameters studied. Animals with either low or high distension showed poorer cerebral and coronary perfusion pressures and mean arterial pressure than those with moderate distension. ROSC was obtained in 13 (72%) animals. Histology showed that both low and high VT was associated with a trend towards higher lung damage. In this animal study, a U-shaped relationship observed with VT suggests that both small and large VT may impair circulation. Capnogram analysis could contribute to identify ventilation settings associated with hemodynamic compromise.

Early repolarization syndrome (ERS) is diagnosed in survivors of unexplained cardiac arrest (UCA) who exhibit a distinct ECG pattern of early repolarization (ER), defined as J-point elevation ≥0.1 mV in ≥2 contiguous inferolateral leads. UCA survivors without ER or another identifiable cause are classified as idiopathic ventricular fibrillation (IVF). This study evaluated long-term outcomes in ERS compared with IVF. This retrospective cohort study analyzed patients from the CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) who survived UCA and had structurally normal hearts with an Implantable Cardioverter Defibrillator. Of 709 patients, 186 with explanatory diagnoses and no ER pattern were excluded. The remaining 523 were categorized as ERS (n=48), IVF (n=463), or UCA with ER plus an additional diagnosis (Dx+ER, n=12). Patients were followed for the primary outcome of appropriate Implantable Cardioverter Defibrillator therapy, and logistic regression identified predictors of arrhythmia recurrence. Corrected QT interval intervals were significantly shorter in ERS than in IVF (412±25 ms versus 431±41 ms; P<0.01). Over a median follow-up of 5.6 years, appropriate Implantable Cardioverter Defibrillator interventions occurred in 23% of ERS and 13% of IVF patients (P=0.09), with incidence rates of 3.0 and 1.5 per 100 person-years, respectively. Four deaths occurred (0.8%), with no significant difference between groups (P=0.39). In Dx+ER, appropriate Implantable Cardioverter Defibrillator therapies occurred in 42% of patients (IR, 4.5 per 100 person-years). Arrhythmia-free survival was lower in ERS than in IVF (P=0.03). After adjusting for age, sex, and ethnicity, ER was an independent predictor of arrhythmia recurrence (odds ratio, 2.59 [95% CI, 1.33-4.85]; P=0.004). ERS is associated with shorter corrected QT interval intervals and reduced arrhythmia-free survival compared with IVF, with an incidence rate of 3.0 per 100 person-years. These findings underscore the importance of careful ECG review in patients with apparent UCA, to detect ER and undertake individualized risk assessment in affected individuals.

While the majority of rodent resuscitation studies prioritize neurologic outcomes, research into the long-term effects of global ischemia and reperfusion on cardiac function is scarce, generally limited to morphologic assessments. Extracorporeal cardiopulmonary resuscitation (ECPR) is a promising strategy for highly selected patients with refractory cardiac arrest (CA). We aimed to investigate the impact of ventricular fibrillation CA (VFCA) and subsequent ECPR on cardiac recovery in rats. Adult male Sprague-Dawley rats were subjected to either 6-8min VFCA, followed by ECPR and compared to sham animals. The primary outcome parameter was cardiac function assessment at 14 days after CA. The hearts of rats surviving for 14 days were isolated and mounted onto an erythrocyte-perfused, isolated working heart (WH) system. Cardiac output (CO), left ventricular systolic pressure (LVSP), and coronary flow were measured. To assess the heart adaptation to hemodynamic stress, the afterload was gradually increased in 10 mmHg increments while CO and LVSP were monitored. Additionally, the hearts from all animals surviving at least 36h were assessed histologically. Of 15 rats that achieved ROSC after 6min of CA, 7 could be evaluated in the WH setup 14 days after CA. In the 8min CA group, 15 animals achieved ROSC, of which 2 were investigated in WH at 14 days after CA. Compared to the hearts of 7 sham animals, no significant differences in cardiac hemodynamics were observed at a set afterload (60mm Hg; baseline) in the 6min CA group. However, the two investigated 8min CA animals exhibited a trend towards reduced CO and LVSP levels. Notably, both CA groups showed impaired hemodynamic performance to hemodynamic stress. Survivors at 14 days consistently showed significant myocardial pathology, with both 6min and 8min CA groups exhibiting fibrosis, inflammation, and edema most pronounced in the interventricular septum and right ventricle of the 8min CA group. Animals that died prematurely displayed time-dependent acute changes, progressing from hypereosinophilic degeneration (36h survivors) to myocardial necrosis, calcification, and the formation of cell-rich granulation tissue (48-108h survivors). VFCA led to impaired left ventricular hemodynamic function in 8min CA rats resuscitated with ECPR at rest and with increasing afterload. The isolated WH system may offer a valuable tool for assessing long-term cardiac function and performance after resuscitation.

Local anesthetics are widely used in medical care. However, their sodium channel blocking properties not only explain their analgesic potency but also their possible cardiotoxic effects. Due to the different pharmacodynamics and pharmacokinetics of different local anesthetics as well as the divergent cellular electrophysiological effects, we aimed to investigate and compare the electrophysiological effects of different local anesthetics in an established Langendorff model of the isolated rabbit heart. 50 hearts of New Zealand White rabbits were retrogradely perfused employing a Langendorff-setup. Eight catheters were placed endo- and epicardially, thereby recording monophasic action potentials. Hearts were paced at seven different cycle lengths (300-900 ms), thus obtaining cycle-length dependent action potential duration at 90% of repolarization (APD90), QT intervals and dispersion of repolarization. In addition, burst pacing was utilized to assess ventricular vulnerability. Thereafter, bradycardic AV-blocked hearts were perfused with a hypokalemic solution to enhance the occurrence of triggered activity. After generating baseline data, the hearts were assigned to four groups: In group 1, hearts were treated with 25 µM, and 50 µM lidocaine. Group 2 was perfused with 25 µM, and 50 µM mepivacaine. Group 3 was perfused with 0.5 µM, and 1 µM bupivacaine. Group 4 was perfused with 5 µM, and 10 µM ropivacaine. As expected, perfusion with all local anesthetics led to a significant prolongation of the effective refractory period as a result of sodium channel blockade. Perfusion with bupivacaine and ropivacaine resulted in pronounced cardiotoxic effects, characterized by electromechanical uncoupling or loss-of-capture phenomena, in the majority of hearts. Perfusion with mepivacaine and ropivacaine resulted in the comparatively most pronounced prolongation of the effective refractory period. Accompanied by a pronounced dispersion of repolarization, the highest incidence of ventricular tachycardia and ventricular fibrillation episodes was observed during perfusion with bupivacaine. Perfusion with the local anesthetics showed pronounced electrophysiological effects, which differed between the various local anesthetics. Bupivacaine showed the most pronounced cardiotoxic effects even at low doses.

ABSTRACT OBJECTIVES The Double Sequential External Defibrillation for Refractory Ventricular Fibrillation (DOSE VF) trial demonstrated improved outcomes for patients randomized to double sequential external defibrillation (DSED) in comparison to standard defibrillation, yet large-scale data on prehospital DSED use remain limited. We evaluated prehospital DSED use before and after publication of DOSE VF. METHODS We conducted a retrospective analysis of adult (>18 years of age) non-traumatic out-of-hospital cardiac arrest (OHCA) patients who had an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia and at least 4 successive defibrillation attempts in the ESO Data Collaborative from 2018-2024. We excluded patients with return of spontaneous circulation prior to the fourth defibrillation, resuscitation-limiting advanced directives, or OHCA due to drowning or overdose. To minimize the influence of agencies joining the Collaborative during the study period, we excluded agencies that did not contribute data during the first study year. We identified DSED using three methods: 1.) documentation of “Dual Sequence Defibrillation (DSD)”, 2.) defibrillation at a 400J or 720J energy setting, or 3.) two defibrillations within 5 seconds. The DOSE VF trial was published in November 2022, and Q4 2022 was used as a washout period. We classified patients as treated pre-DOSE VF if treated before Q4 2022, and post-DOSE VF if treated after Q4 2022. We compared pre- and post-DOSE VF use of DSED using Pearson’s 𝜒2 test and an interrupted time-series analysis using segmented Poisson regression with 3-month non-overlapping segments. RESULTS We identified 16,450 DSED-eligible patients treated by 906 emergency medical services agencies. Estimates of DSED use varied by ascertainment method (Method 1: 3.7%, Method 2: 1.8%, Method 3: 4.4%, any method: 7.6%). The use of DSED detected by any method increased post-DOSE VF (pre vs. post: 822/11,228 (7.3%) vs. 381/4,625 (8.2%), p = 0.048). Segmented Poisson regression suggested an increase in the rate of DSED use (slope change) after DOSE VF (RR: 1.09 (1.04, 1.14) per quarter). CONCLUSIONS Our findings suggest an increasing rate of DSED use after publication of DOSE VF, but the proportion of eligible patients receiving DSED remains low. Limitations include the potential for patient misclassification by our DSED ascertainment methods.

Different modes of onset of ventricular arrhythmias (VA), preceded by characteristic electrocardiogram patterns, have been observed in patients with J-wave syndromes (JWS), including Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. However, the underlying mechanisms remain unclear. The goal of this study is to use computational modeling to elucidate the mechanisms for spontaneous initiation of VA in JWS, particularly the characteristic modes of onset shown in clinical settings. Phase-2 reentry (P2R) was induced by transient outward potassium currents (Ito) or loss of function sodium channel (INa) mutations in heterogeneous tissue. The computational models replicated the characteristic electrocardiogram patterns and modes of VA onset observed in human patients, including: 1) fast heart rate-dependent or "short-long-normal-short" sequence to VA; 2) pause-dependent or "short-long-short" sequence to VA; and 3) sudden onset of VA. Fast heart rate-dependent arrhythmogenesis was driven by either fast Ito or INa mutations induced P2R with the rate dependence caused by delayed rectifier potassium current recovery. Pause-dependent arrhythmogenesis was driven by slow Ito or by fast Ito combined with calcium transient restitution. P2Rs could manifest as short-coupled premature ventricular complexes or degenerate into reentrant arrhythmias, depending on the size of the all-or-none repolarization region caused by the spike-and-dome action potential morphology. In conclusion, VA in JWS can be initiated via P2R following a "short-long-normal-short" sequence, a "short-long-short" sequence, or suddenly. P2R and its rate-dependence via the recovery of slow Ito, delayed rectifier potassium current, or calcium transient underlie different modes of onset of VA.

Mitral valve prolapse (MVP) is a common valvular disorder associated with ventricular arrhythmias (VAs) in a subgroup of patients, known as arrhythmic MVP (AMVP). AMVP patients with malignant VAs typically receive an implantable cardioverter-defibrillator (ICD) for secondary prevention. However, data regarding the incidence of appropriate ICD therapy and the type of arrhythmia recurrence in this population remain scarce. This study aimed to evaluate the incidence of appropriate ICD therapies and type of arrythmia recurrence in AMVP patients with an ICD implanted for secondary prevention. A systematic literature search was conducted in PubMed/MEDLINE and EMBASE databases until January 2025. Studies reporting the incidence of appropriate ICD therapy in AMVP patients were included. A total of 9 studies met the inclusion criteria, resulting in 166 AMVP patients with ICDs for secondary prevention. The mean age was 41.8 years, with 55.8% of patients being female. Over a weighted mean follow-up of 4.9±3.1 years, 34.9% (95%CI: 28.1-42.5) of the patients experienced recurrence of VA. The pooled incidence of appropriate ICD therapies during follow-up was 8.1 per 100 person-year (95% CI: 5.6-10.5, I2: 11.7%). Regarding the type of arrhythmic recurrence, the majority of arrhythmias (53.8%, 95% CI: 44.3%-63.0%) were in the form of ventricular fibrillation or polymorphic ventricular tachycardia (VT), while the remaining arrhythmias were reported as monomorphic VT. Among 67 ventricular arrhythmic episodes reported in 7 studies with available data, 65 required shock therapy, corresponding to a shock proportion of 97.0% (95% CI: 89.6-99.6%). AMVP patients with ICDs for secondary prevention exhibit a high risk of recurrent arrhythmias, with recurrences in the form of polymorphic VA occurring in more than half of the cases.

High-Sensitivity Cardiac Troponin I for Enhanced Risk Stratification in Primary Prevention for Sudden Cardiac Death in Hypertrophic Cardiomyopathy.

Patient: Male, 48-year-oldFinal Diagnosis: Diabetic ketoacidosisSymptoms: ConfusionClinical Procedure: —Specialty: Critical Care MedicineObjective: Unusual clinical courseBackgroundInsulin deficiency can cause hypothermia by preventing glucose uptake into cells, and acidosis can impair metabolic rate. Diabetic ketoacidosis (DKA) and a body temperature <35°C (hypothermia) is a combination with a high mortality rate due to refractory cardiocirculatory collapse and requires emergency management. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a rescue therapy to restore perfusion, rewarming, and manage cardiac arrest. This report describes the case of a 48-year-old man with DKA, hypothermia, and cardiac arrest managed with VA-ECMO.Case ReportA 48-year-old man with impaired glucose tolerance presented with unconsciousness and severe hypothermia (body surface temperature: <30°C), DKA (glucose concentration: 58.8 mmol/L, pH: 6.853, HbA1c: 11.1%), and subsequent ventricular fibrillation requiring cardiopulmonary resuscitation. Despite return of spontaneous circulation and conventional therapy, including insulin, fluid resuscitation, and vasopressor support, refractory cardiogenic shock unresponsive to maximal medical therapy required VA-ECMO. His temperature was maintained at 32°C for 24 h for neuroprotection, followed by controlled rewarming. Intensive metabolic management with continuous insulin therapy achieved rapid correction of hyperglycemia (52.2 to 12.1 mmol/L) and hyperosmolality (392 to 327 mmol/kg) within 72 h. Acidosis resolved rapidly, with progressive recovery of renal function, which allowed weaning from VA-ECMO on day 4 and extubation on day 8. Despite concerns for cerebral injury, brain magnetic resonance imaging (MRI) showed no major hypoxic-ischemic damage. The patient achieved good functional recovery.ConclusionsVA-ECMO provides essential dual functionality as circulatory support and precise temperature control in complex metabolic emergencies, enabling successful management of diabetic ketoacidosis-associated hypothermia and cardiac arrest.

Cardiac toxicity from QT-prolonging drugs can precipitate malignant ventricular arrhythmias in susceptible individuals, and family screening may clarify inherited risk. We report a 33-year-old woman with a history of postpartum cardiac arrest treated with a secondary-prevention implantable cardioverter-defibrillator (ICD) who developed an electrical storm after self-administration of a single low dose of amitriptyline (12.5mg). ICD interrogation documented 176 episodes of ventricular fibrillation requiring repeated shocks, followed by complete battery depletion, hemodynamic collapse, and the need for venoarterial extracorporeal membrane oxygenation and continuous renal replacement therapy. The admission electrocardiogram showed marked QT prolongation (QTc 651 ms), with previously documented prolonged baseline QTc values. Targeted next-generation sequencing identified a novel SCN5A missense variant (NM_000335.5:c.5738G > A) and a rare pathogenic KCNQ1 splice variant (NM_000218.3:c.1032G > C), cascade testing across the family demonstrated variable expressivity among carriers. Given a suspected contribution of late sodium current, a mechanism-based strategy was implemented with mexiletine added to propranolol and overdrive pacing (90bpm). This case underscores the risk of malignant ventricular arrhythmias after exposure to QT-prolonging agents even at low doses, and supports genotype-informed, mechanism-based therapy to mitigate arrhythmic risk in patients with marked QT prolongation.

Objectives Large language models (LLMs) using a retrieval-augmented generation (RAG) approach have the ability to respond to user queries with answers grounded in specific sources. We conducted an exploratory evaluation of the accuracy of a RAG-based LLM to provide care recommendations for prehospital scenarios based on the emergency medical services (EMS) policies and treatment protocols (TPs). Methods We conducted a non-human, simulation-based experimental study by uploading all text-based policies/TPs from a single large EMS system into Google’s NotebookLM platform, which uses a RAG-based LLM (Gemini 2.5 Flash) framework to generate grounded responses. We developed six clinical scenario prompts, including adult patient scenarios (i.e., ventricular fibrillation out-of-hospital cardiac arrest [OHCA], blunt head trauma, stroke, hazardous materials exposure mass-casualty incident) and pediatric patient scenarios (i.e., pulseless electrical activity OHCA, traumatic penetrating extremity hemorrhagic shock). For each scenario, we used all relevant policies/TPs to create a specific set of expected patient care actions. We categorized actions as procedures/interventions, medications, and destination guidance. Medication grading included dose/route for all patients and weight-based dosing for pediatrics. After providing the LLM with the prompts, two investigators independently graded the LLM responses and evaluated for LLM “hallucinations.” Missing actions were categorized by investigators based on applicability to the case and potential safety risk (e.g., “non-applicable,” “minor miss,” “major miss”). The primary outcome was model recommendation accuracy, defined as the percentage of all actions correctly provided in the model’s response. We reported descriptive statistics. Results The LLM recommended 127 (75%) of 169 patient care actions across all cases. There were 42 missed actions. Nine of the 169 actions (5%) were categorized as “major misses,” 13 (8%) as “minor misses,” and 20 (12%) as non-applicable to the specific case. Five of nine major misses occurred during the pediatric OHCA case; the majority of these resulted from failure to prompt for evaluation of secondary treatable causes. We identified 12 hallucinations; none were judged to endanger patient safety. Conclusion We found that a RAG-based LLM demonstrated 75% accuracy across various prehospital scenarios when providing responses grounded in the policies/TPs of a single large EMS agency.

This report describes the case of a 44-year-old woman without structural heart disease who developed ventricular fibrillation (VF) during preoperative management of multiple pancreatic neuroendocrine tumors (NETs) associated with multiple endocrine neoplasia type 1. She had an insulinoma in the uncinate process and a non-functioning NET in the pancreatic tail. Immediately after intravenous glucose administration for recurrent hypoglycemia, VF occurred. An electrocardiogram obtained immediately before VF onset showed repolarization abnormalities with marked QTc prolongation, terminal T-wave bulging, and U waves. Laboratory testing revealed concomitant mild hypokalemia. No coronary artery disease was detected. The severe repolarization abnormalities improved after resection of the insulinoma. The presumed mechanism was that mild hypokalemia and recurrent hypoglycemia, together with hypoglycemia-induced epinephrine surge and extracellular-to-intracellular potassium shift, synergistically prolonged the action potential duration and induced early afterdepolarizations, which progressed from torsades de pointes to VF. This case highlights that unstable glycemic control in insulinoma can precipitate life-threatening arrhythmias, even in the absence of structural heart disease. Particularly when surgery is delayed, maintaining serum potassium as 4.5-5.0 mmol/L and preventing recurrent hypoglycemia are crucially important. Early recognition and intervention might help reduce arrhythmic risk in such patients.

Polymorphic ventricular tachycardia deteriorating into ventricular fibrillation during radiofrequency-facilitated left bundle branch pacing lead implantation in complete atrioventricular block.

Mechanistic cardiac simulations are increasingly used in research, pharmaceutical development, and regulatory science, yet most existing human cardiomyocyte models lack the generality required for predictive translation across scales. Our recently developed T-World model overcomes this barrier by reproducing all major cellular arrhythmia mechanisms and showing comprehensive agreement with experimental and clinical data. Here, we aimed to demonstrate the utility of T-World for organ-level and translational research, from ionic mechanisms of arrhythmogenesis to emergent whole-heart physiology. T-World was embedded into anatomically realistic models of biventricular electrophysiology and electromechanics derived from clinical imaging for organ-scale simulations. Drug safety was assessed using populations-of-single-cell models exposed to 60 compounds with updated CredibleMeds annotations. Mechanistic drug-efficacy studies on mexiletine were conducted using long QT syndrome type 2 model variants. Disease applications included arrhythmia mechanisms in human type 2 diabetes and the proarrhythmic potential of NaV1.8, a neuronal sodium channel ectopically expressed in cardiac disease. T-World reproduced human-like ECG morphology and ventricular mechanics (ejection fraction of 61%) and generated ventricular fibrillation under physiologically relevant ischemic conditions without parameter tuning. In the drug safety assessment of torsadogenic risk, T-World achieved 87% accuracy and 100% specificity, and exposed incomplete pharmacological descriptions based on in vitro measurements for lidocaine and cilostazol. Mexiletine simulations revealed that both INaL and ICaL inhibition underlie its antiarrhythmic benefit in long QT syndrome type 2. Cellular simulations of type 2 diabetes remodeling explained heightened vulnerability to early afterdepolarizations and increased risk of alternans associated with diastolic dysfunction, mechanistically linked to SERCA (sarco/endoplasmic reticulum Ca2+ ATPase) reduction. Finally, even minor expression of NaV1.8 can directly trigger early afterdepolarizations through uniquely right-shifted activation and inactivation properties. T-World provides a unified, human-specific open-source platform bridging cellular mechanisms with organ-level dynamics and translational outcomes. Its predictive performance across arrhythmia, contraction, drug safety/mechanisms, and disease physiology makes it a powerful tool for multiscale cardiac research, therapeutic discovery, and next-generation cardiac digital twins.

Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastric cancer that enables the en bloc resection of large lesions. However, it is associated with a significant risk of delayed bleeding, particularly in patients receiving antithrombotic therapy. Delayed bleeding after ESD causes anemia and serious systemic complications, including cardiovascular events. Here, we report a rare case of Takotsubo syndrome triggered by delayed bleeding after gastric ESD that culminated in cardiac arrest. A man in his 70s who underwent gastric ESD experienced delayed bleeding six days after the treatment, requiring emergency endoscopic hemostasis. The following day, the patient developed sudden ventricular fibrillation without prior chest symptoms. After resuscitation with electrical defibrillation, left ventriculography revealed apical ballooning consistent with Takotsubo syndrome. With intensive care, cardiac function recovered, and the patient was discharged ambulatory. Takotsubo syndrome is typically induced by stress, and often triggers psychological and physical stimuli. Although most patients present with chest pain or discomfort, our patient showed no preceding symptoms and developed sudden arrhythmia and cardiac arrest. This case highlights the need for aggressive bleeding prevention and enhanced post-ESD cardiac surveillance to mitigate rare but potentially fatal complications.

Ventricular fibrillation (VF) in coronary heart disease accounts for up to 70% of sudden cardiac death. We examined whether diltiazem N-oxide (DNO) has ischaemia-selective antiarrhythmic activity. Randomised and blinded experiments were performed in rat isolated hearts and in anaesthetised rats to determine antiarrhythmic effectiveness, adverse drug reaction (ADR) profile and mechanism of action of DNO, using diltiazem as a positive control. The ratio of the lowest concentration with antiarrhythmic activity to the highest concentration without ADRs was defined as the translational therapeutic index (TTI). In Langendorff-perfused hearts, diltiazem (100 nM-6 µM) and DNO (1 µM-6 µM) reduced ischaemia-induced VF occurrence. Diltiazem caused vasodilation (≥100 nM), atrioventricular (AV) block (≥3 µM), and negative inotropy (≥3 µM) with a TTI ≤ 1 while DNO had no adverse effects (TTI > 6). Ultra-high performance liquid chromatography with tandem mass spectrometry analysis of hearts perfused with 1-μM DNO detected almost complete conversion of DNO to diltiazem in ischaemia, but not in normoxia. 31P nuclear magnetic resonance spectroscopy (NMR) revealed ischaemia-induced intracellular acidosis, decreased β-ATP and phosphocreatine, all unaffected by either 1-μM diltiazem or 1-μM DNO. Diltiazem (2 mg·kg-1 + 0.2 mg·kg-1·min-1) and DNO (6.5 mg·kg-1 + 0.65 mg·kg-1·min-1) prevented ischaemia-induced VF in anaesthetised rats, with diltiazem causing AV block and bradycardia and DNO causing no ADRs. DNO was converted to diltiazem selectively in ischaemic cardiac tissue where it mimicked diltiazem's effect on VF, but without its associated ADRs. Neither drug affected cardiac energetics.