The role of Sodium Glucose Cotransporter 2 (SGLT2) inhibitors in cardioprotection

Background: Despite the effectiveness of primary coronary angioplasty in reducing myocardial infarct size, ischaemia/reperfusion injury (IRI) accounts for a significant proportion of the final infarct size and there is a need to identify therapies that can mitigate the deleterious effects of myocardial IRI. Sodium glucose cotransporter 2 (SGLT2) inhibitors were initially designed to treat diabetes but recent landmark cardiovascular outcome trials (CVOT) have revealed an unexpected cardiovascular mortality benefit from SGLT2 inhibition in type 2 diabetes mellitus (T2DM) patients. As SGLT2 receptors are predominantly found in the kidneys rather than the heart, it is likely that the cardioprotection conferred by SLGT2 inhibitors occurs in an off-target manner. This research hypothesised that attenuation of myocardial IRI may account for the cardioprotection observed in the trials. Methods and Results: Firstly, two rat models of T2DM were characterised: The high fat diet/streptozotocin (HFD/STZ) and the Zucker Diabetic Fatty (ZDF) rat. For the HFD/STZ rat model, the optimal hyperglycaemic response and survival rates were subsequently established after 5 batches of serial experiments but this model had multiple disadvantages. As the HFD/STZ rat phenotype appeared to be more suggestive of type 1 diabetes mellitus (T1DM), the ZDF rat model, which reflected the obese T2DM phenotype more closely, became the model of choice. Neither subcutaneous nor oral administration of Phlorizin (an SGLT1 and SGLT2 inhibitor) to diabetic rats conferred adequate glycaemic control. In contrast, diabetic rats exposed to oral Canagliflozin (an SGLT2 inhibitor) showed sustained and improved glycaemic profiles without any adverse events. Hence, Canagliflozin became the drug of choice for subsequent experiments. ZDF and non-diabetic Zucker Lean (ZL) rats were then fed either high-fat or standard chow respectively, with or without fortification with Canagliflozin for 4 weeks. As expected, ZDF rats were markedly diabetic with evidence of end-organ renal injury. Canagliflozin improved the blood glucose of ZDF rats and did not cause hypoglycaemia in ZL rats. After 4 weeks, the hearts were harvested, Langendorff- perfused and subjected to 35 minutes regional ischemia and 2 hours reperfusion. Canagliflozin pre-treatment led to robust attenuation of myocardial infarct size in both diabetic ZDF and non-diabetic ZL rat hearts. In contrast, short- term Langendorff-perfusion of non-diabetic (Sprague-Dawley) rat hearts with Canagliflozin had no impact on myocardial infarct size - suggesting that the reduction in myocardial infarct size by SGLT2 inhibitors occurred independent of blood glucose levels and via an in vivo mediated hormone signaling mechanism. Langendorff-perfused hearts of non-diabetic rats pre-treated with oral Canagliflozin for 24 hours also demonstrated a significant reduction in myocardial infarct size compared to that of placebo-treated rats. The cardioprotection occurred independent of blood glucose, insulin, glucagon and ketone levels. Western blot analysis of these protected hearts showed an association between SGLT2 inhibition and increased Akt phosphorylation. Conclusion: The reduction in myocardial size in diabetic rats by SGLT2 inhibition may explain the improved cardiovascular outcomes amongst T2DM patients in the SGLT2 inhibitor CVOTs. Importantly, this is the first demonstration of SGLT2 inhibitor-mediated cardioprotection in non-diabetic animals by mitigation of myocardial IRI. The reduction in myocardial infarct size could be seen within 24 hours and was independent of circulating blood glucose, insulin, glucagon and ketone levels. The association between SGLT2 inhibition and increased Akt phosphorylation suggests that involvement of the anti-apoptotic Reperfusion Injury Salvage Kinase (RISK) pathway of ischaemic conditioning. This thesis therefore provides new insight into the potential cardiovascular benefits of SGLT2 inhibition regardless of diabetes status and strengthens the belief that one day, this novel class of anti-diabetic drugs may be repurposed into highly effective therapies for heart failure, ischaemic heart disease and arrhythmia patients

Cardiovascular Biomarkers: Lessons of the Past and Prospects for the Future

Cardiovascular diseases (CVDs) are a major healthcare burden on the population worldwide. Early detection of this disease is important in prevention and treatment to minimise morbidity and mortality. Biomarkers are a critical tool to either diagnose, screen, or provide prognostic information for pathological conditions. This review discusses the historical cardiac biomarkers used to detect these conditions, discussing their application and their limitations. Identification of new biomarkers have since replaced these and are now in use in routine clinical practice, but still do not detect all disease. Future cardiac biomarkers are showing promise in early studies, but further studies are required to show their value in improving detection of CVD above the current biomarkers. Additionally, the analytical platforms that would allow them to be adopted in healthcare are yet to be established. There is also the need to identify whether these biomarkers can be used for diagnostic, prognostic, or screening purposes, which will impact their implementation in routine clinical practice

Initial experience of temperature-controlled irrigated radiofrequency ablation for ischaemic cardiomyopathy ventricular tachycardia ablation

Background The DiamondTemp ablation (DTA) catheter system delivers high power, open-irrigated, temperature-controlled radiofrequency (RF) ablation. This novel ablation system has not been previously used for ventricular tachycardia (VT) ablation. Objective Feasibility of using the DTA catheter system for VT ablation in ischaemic cardiomyopathy (ICM) patients. Method Ten ICM patients with optimal anti-arrhythmic drug therapy and implantable cardiac defibrillators (ICD) were recruited. VT inducibility testing was performed at the end of the procedure. ICD data for device detected VT episodes and device treated VT episodes were collected for 6-months pre- and post-ablation. Results Substrate analysis demonstrated reductions in the borderzone area of 4.4 cm2 (p = 0.026) and late potential area of 3.5 cm2 (p = 0.0449) post-ablation, with reductions in the mean bipolar and unipolar voltages of the ablation target areas (0.14 mV (p = 0.0007); 0.59 mV (p = 0.0072) respectively). Complete procedural success was achieved in 9 procedures. Post-ablation VT inducibility testing was not performed in 1 procedure due to a steam pop complication resulting in pericardial tamponade requiring drainage. Mean follow-up of 214 ± 33 days revealed an 88% reduction in total VT episodes (n = 266 median 16 [IQR 3–57] to n = 33 median 0; p = 0.0164) and 77% reduction in ICD therapies (n = 128 median 5 [IQR 2–15] to n = 30 median 0; p = 0.0181). Conclusion The DTA system resulted in adequate lesion characteristics with effective substrate modification, acute procedural success and improved outcomes at intermediate-term follow-up. Randomised controlled trials are required to compare the performance of the DTA system against conventional ablation catheters

Impact of a high-density grid catheter on long-term outcomes for structural heart disease ventricular tachycardia ablation

Substrate mapping has highlighted the importance of targeting diastolic conduction channels and late potentials during ventricular tachycardia (VT) ablation. State-of-the-art multipolar mapping catheters have enhanced mapping capabilities. The purpose of this study was to investigate whether long-term outcomes were improved with the use of a HD Grid mapping catheter combining complementary mapping strategies in patients with structural heart disease VT. Consecutive patients underwent VT ablation assigned to either HD Grid, Pentaray, Duodeca, or point-by-point (PbyP) RF mapping catheters. Clinical endpoints included recurrent anti-tachycardia pacing (ATP), appropriate shock, asymptomatic non-sustained VT, or all-cause death. Seventy-three procedures were performed (33 HD Grid, 22 Pentaray, 12 Duodeca, and 6 PbyP) with no significant difference in baseline characteristics. Substrate mapping was performed in 97% of cases. Activation maps were generated in 82% of HD Grid cases (Pentaray 64%; Duodeca 92%; PbyP 33% (p = 0.025)) with similar trends in entrainment and pace mapping. Elimination of all VTs occurred in 79% of HD Grid cases (Pentaray 55%; Duodeca 83%; PbyP 33% (p = 0.04)). With a mean follow-up of 372 ± 234 days, freedom from recurrent ATP and shock was 97% and 100% respectively in the HD Grid group (Pentaray 64%, 82%; Duodeca 58%, 83%; PbyP 33%, 33% (log rank p = 0.0042, p = 0.0002)). This study highlights a step-wise improvement in survival free from ICD therapies as the density of mapping capability increases. By using a high-density mapping catheter and combining complementary mapping strategies in a strict procedural workflow, long-term clinical outcomes are improved

Decrementing evoked-potential propagation map defines the ventricular rachycardia isthmus

We present a 65-year-old man with ischemic cardiomyopathy, prior myocardial infarction with mid-left anterior descending coronary artery occlusion, and an implantable cardioverter-defibrillator (ICD) who presented in December 2019 with ventricular tachycardia (VT) storm, receiving several ICD shocks. He was commenced on oral amiodarone; however, in February 2020, he presented with further VT and appropriate shocks. He underwent VT ablation under conscious sedation with antegrade mapping of the left ventricle (LV) using the Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ combined with the steerable Agilis™ sheath. The sinus rhythm LV substrate map confirmed extensive septal and apical scar as shown in Figure 1A. Within the dense scar region (< 0.5 mV), a low-voltage conduction channel (CC) at the highlighted high-density grid position was identified (white arrow in Figure 1A). Sinus rhythm low-amplitude ventricular activities were identified at the anterior border zone (BZ) of the CC; however, as shown in Figure 1C, they were buried within the QRS complex

Impact of sodium-glucose co-transporter inhibitors on cardiac autonomic function and mortality:no time to die

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes not only in patients with diabetes but also in those with heart failure, irrespective of diabetic status. However, the mechanisms underlying the cardioprotective effects of these newer anti-diabetic drugs remain to be fully elucidated. One exciting avenue that has been recently explored in both preclinical and clinical studies is the modulation of the cardiovascular autonomic nervous system. A reduction in sympathetic nervous system activity by SGLT2 inhibitors may potentially translate into a reduction in arrhythmic risk and sudden arrhythmic death, which may explain, at least partly, the cardioprotection shown in the cardiovascular outcome trials with different SGLT2 inhibitors. Although some of the data from the preclinical and clinical studies are promising, overall the findings can be contradictory. This highlights the need for more studies to address gaps in our knowledge of these novel drugs. The present review offers an in depth overview of the existing literature regarding the role of SGLT2 inhibitors in modulating cardiovascular autonomic function as one of the possible pathways of their cardioprotective effects

Obstructive Sleep Apnoea and Cardiac Arrhythmias (OSCA) trial : a nested cohort study using injectable loop recorders and Holter monitoring in patients with obstructive sleep apnoea

Introduction Obstructive sleep apnoea (OSA) is associated with increased cardiovascular mortality despite continuous positive airways pressure (CPAP) therapy. This excess risk may be related to increased arrhythmia risk, especially atrial fibrillation (AF). The true incidence of arrhythmia in patients with OSA is unknown. Implantable loop recorders (ILR) are powerful tools for detecting arrhythmias long-term. Cardiac autonomic function may be important in arrhythmogenesis in these patients but needs further study. We aim to identify the true incidence of arrhythmias (especially AF) using ILRs, assess cardiac autonomic function using Holter monitors in patients with OSA and explore cardiovascular outcomes. Methods and analysis A two-centre (University Hospital Coventry and St. Cross Hospital, Rugby) nested cohort study using Reveal LINQ (Medtronic, UK) ILR to identify precise arrhythmia (atrial/ventricular) incidence in patients with moderate–severe OSA. 200 patients will be randomised 1:1 to standard care alone or standard care+ILR (+Holter monitor at baseline and 12 months). The primary objective is to compare arrhythmia detection over 3 years between the two groups. Cardiac autonomic function will be assessed in the ILR-arm at baseline and 12 months post CPAP. Secondary objectives will explore the mechanisms linking OSA and arrhythmia using cardiac autonomic function parameters based on Holter recordings and circulating biomarkers (high sensitivity Troponin-T, N-terminal pro B-type natriuretic peptide, matrix metalloproteinase-9, fibroblast growth factor 23, high sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-α) before and after CPAP initiation in the ILR-arm. Ethics and dissemination This study has been approved by the Health Research Authority after examination by the Solihull Research and Ethics Committee. The main ethical considerations was the minimally invasive nature of ILR insertion outside of usual care. Patient advisory groups were consulted with a positive outcome for this type of research. We plan on publishing papers in peer-reviewed journals based on the primary objective and any interesting findings from secondary objectives. We will endeavour to publish all relevant data. Trial registration number NCT03866148