Exploring the Therapeutic Potential of Gene Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy.

Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents a promising avenue for targeted therapeutic interventions, potentially revolutionising treatment approaches for ARVC patients. Encouraging results from preclinical studies have sparked optimism about the possibility of curing specific subtypes of ARVC in the near future. This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages, and providing updates on forthcoming trials. Additionally, it examines the hurdles and complexities impeding the successful translation of ARVC genetic therapies into clinical practice. Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases.

Adeno-associated virus-mediated gene therapy for cardiac tachyarrhythmia: A systematic review and meta-analysis.

Cardiac tachyarrhythmia presents a significant health care challenge, causing notable morbidity and mortality. Conventional treatments have limitations and potential risks, resulting in an elevated disease burden. Adeno-associated virus (AAV)-mediated gene therapy holds promise as a potential future treatment option. Therefore, we aimed to provide a measured overview of the latest developments in this rapidly growing field. PubMed and Embase databases were searched up to January 2024. Studies that employed AAV as a vector for delivery of therapeutic agents to treat cardiac tachyarrhythmia were included. Of the 26 studies included, 20 published in the last 5 years. There were 22 novel molecular targets identified. More than 80% of the included studies employed small-animal models or used AAV9. In atrial fibrillation preclinical studies, AAV-mediated gene therapy reduced atrial fibrillation inducibility by 81% (odds ratio, 0.19 [0.08-0.45]; P < .01). Similarly, for acquired and inherited ventricular arrhythmia, animal models receiving gene therapy had less inducible ventricular arrhythmia (odds ratio, 0.06 [0.03-0.11]; P < .01). This review highlights the rapid progress of AAV-mediated gene therapy for cardiac tachyarrhythmia. Although these investigations are currently in the early stages of clinical application, they present promising prospects for gene therapy. (PROSPERO registry: CRD42023479448).

Gene Therapy in Cardiology: Is a Cure for Hypertrophic Cardiomyopathy on the Horizon?

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy worldwide, affecting approximately 1 in 500 individuals. Current therapeutic interventions include lifestyle optimisation, medications, septal reduction therapies, and, rarely, cardiac transplantation. Advances in our understanding of disease-causing genetic variants in HCM and their associated molecular mechanisms have led to the potential for targeted therapeutics and implementation of precision and personalised medicine. Results from preclinical research are promising and raise the question of whether cure of some subtypes of HCM may be possible in the future. This review provides an overview of current genetic therapy platforms, including 1) genome editing, 2) gene replacement, 3) allelic-specific silencing, and 4) signalling pathway modulation. The current applicability of each of these platforms within the paradigm of HCM is examined, with updates on current and emerging trials in each domain. Barriers and limitations within the current landscape are also highlighted. Despite recent advances, translation of genetic therapy for HCM to clinical practice is still in early development. In realising the promises of genetic HCM therapies, ethical and equitable access to safe gene therapy must be prioritised.

Prevalence and Prognostic Implication of Atrial Fibrillation in Heart Failure Subtypes: Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) portends a poor outcome. The HF universal definition has incorporated Heart Failure with mildly reduced Ejection Fraction (HFmrEF). We sought to evaluate the relationship between AF and different HF subtypes, with emphasis on HFmrEF. METHODS: PubMed and Embase databases were searched up to July 2022. Studies that classified HF with EF≥50% as Heart Failure with Preserved Ejection Fraction (HFpEF); EF 40%-49% as HFmrEF; and EF <40% as Heart Failure with Reduced Ejection Fraction (HFrEF) were included. RESULTS: Fifty (50) eligible studies, with 126,720 acute HF and 109,683 chronic HF patients, were included. Ten percent (10%) and 12% of patients constituted HFmrEF subtype in patients with acute and chronic HF, respectively. The AF prevalence was 38% (95%CI [33, 44], I2=96.9%) in HFmrEF, as compared to 43% (95%CI [39, 47], I2=97.9%) in HFpEF, and 32% (95%CI [29, 35], I2=98.6%) in HFrEF in acute HF patients. Meta-regression showed HFmrEF shared age as a determinant for AF prevalence with HFrEF and HFpEF. Similar AF prevalence also was observed in chronic HF. Compared to sinus rhythm, AF was associated with an increased risk of all-cause mortality in all HF subtypes: HFmrEF (n=6; HR 1.28, 95%CI [1.08, 1.51], I2=71%), HFpEF (n=10; HR 1.14, 95%CI [1.06, 1.23], I2=55%) and HFrEF (n=9; HR 1.11, 95%CI [1.02, 1.21], I2=78%). CONCLUSION: The prevalence of AF was intermediate for HFmrEF in between HFpEF and HFrEF, with determinants shared with either HF subtype. The co-existence of AF and HF predicts an increased all-cause mortality across all categories of HF. (PROSPERO registry: CRD42021189411).

Vascular Responses Among Adults Four Years Post Exposure to 6 Weeks of Smoke from the Hazelwood Coal Mine Fire.

Background and Aims: Mega-wild fires are exposing large communities to weeks or months of high concentration smoke-related fine particulate air pollution (PM). However, little research has examined the long-term vascular responses from exposure to PM of this concentration and duration. We investigated whether level of exposure to 6 weeks of PM from the 2014 Hazelwood coal mine fire was associated with abnormal vascular responses approximately four years later. Methods: A cross-sectional analysis was undertaken of 387 participants (225 exposed, 162 unexposed) aged 55-89 years, 3.5-4 years after the mine fire. The primary outcome was flow-mediated dilatation (FMD), with time to reach peak diameter as the secondary outcome. Other secondary markers included high-sensitivity C-reactive protein (hsCRP) and ischaemic Electrocardiogram (ECG) changes. Results: There was no evidence of a difference in FMD between participants with high, medium, low or no mine-fire related PM2.5 exposure (4.09% vs 4.06% vs 4.02% vs 3.98%, respectively, p=0.99). Likewise, there was no difference in hsCRP or ischaemic ECG changes. In contrast, there was evidence of a difference in time to peak diameter (p=0.002) with more unexposed participants reaching peak diameter within 30 seconds (36%) compared to those who had high, medium, or low exposure (23%, 22%, 13%, respectively). Multivariate ordinal logistic regression analysis suggested that township, Morwell (exposed) vs Sale (unexposed), but not level of PM2.5 exposure, was associated with delayed time to peak diameter (OR 2.71; 95% CI 1.56, 4.69). Smokers also had delayed time to peak diameter. Conclusion: There was no association between level of exposure to PM2.5 from the 6-week Hazelwood coal mine fire smoke event and reduced FMD, elevated hsCRP or ischaemic ECG four years later. Evidence of delayed time to peak diameter observed in adults from the exposed town, compared to an unexposed town, requires further investigation.

A Single-Center Experience of the Optimal Initial Immunosuppressive Strategy for Preventing Early Acute Cellular Rejection in Orthotopic Heart Transplantation Associated With Renal Dysfunction.

BACKGROUND: Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain. METHODS: We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant. RESULTS: Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy (P < .05, log rank test). In patients treated with basiliximab, early administration (<24 hours) was associated with a higher freedom from acute rejection compared to ≥24 hours, (72% vs 29%, P < .05). CONCLUSIONS: The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy; however, it was only effective when administered within 24 hours.

Trends and Clinical Outcomes in Patients Undergoing Primary Percutaneous Revascularisation for ST-Elevation Myocardial Infarction: A Single Centre Experience.

BACKGROUND: Primary percutaneous coronary intervention (PPCI) is the preferred therapy for patients presenting with ST-elevation myocardial infarction (STEMI). We reviewed patients undergoing PCI for STEMI over a 6-year period to evaluate changes in procedural characteristics and clinical outcomes given recent changes to STEMI guidelines. METHODS: All patients presenting to the Alfred Hospital, a tertiary referral hospital, between 1 January 2010 and 31 December 2015 undergoing PCI for STEMI were identified. Detailed review of their procedure reports was performed and 30-day and 12-month clinical outcomes were recorded including major adverse cardiac events (MACE). RESULTS: There was a total of 445 patients aged 60.6±12.4 years with 369 (82.9%) male. There was a significant increase in radial access use over the 6-year period 0/49 (0%) in 2010 vs 56/113 (49.6%) in 2015 (p<0.01). There was a significant reduction in the use of IIb/IIIa receptor antagonists during the period 29/49 (59%) in 2010 vs 24/113 (21%) in 2015 (p<0.01) and use of aspiration thrombectomy 15/49 (31%) in 2010 vs 19/113 (17%) in 2015 (p<0.01). There was no significant reduction in major bleeding over this period with 2/49 (4%) in 2010 vs 5/108 (5%) in 2015 (p=0.32). Thirty-day and 12-month mortality was also unchanged. CONCLUSION: Between 2010 and 2015 there has been a significant increase in the use of radial access and a reduction in the use of glycoprotein IIb/IIIa antagonists and aspiration thrombectomy in patients undergoing PPCI. This was not associated with changes in major bleeding or 30-day or 12-month mortality.

Interactions between inflammatory activation and endothelial dysfunction selectively modulate valve disease progression in patients with bicuspid aortic valve.

OBJECTIVES: Bicuspid aortic valve (BAV) is associated with increased risk of valvular degeneration and ascending aortic aneurysm formation and rupture. We sought to evaluate the roles of endothelial dysfunction and inflammatory activation in modulating these processes. METHODS: We performed a case-control study of patients with BAV together with a multivariate analysis within the BAV group to identify factors associated with: development of significant valvular disease; dilatation of the ascending aorta; differential valve relative to aortic disease. Endothelial function of patients and controls was evaluated via flow-mediated dilatation (FMD) and plasma concentrations of asymmetric dimethylarginine (ADMA). Correlations with inflammatory markers and endothelial progenitor cell counts were also examined. Morphological and physiological assessment of the valve and ascending aorta was performed with transthoracic echocardiography and MRI. RESULTS: Patients with BAV (n=43) and controls (n=25) were matched for age and gender. FMD was significantly lower in patients than controls (7.85±3.48% vs 11.58±3.98%, p=0.001), and these differences were age-independent. Within the BAV cohort, multivariate correlates of peak aortic valve velocity were plasma concentrations of ADMA and myeloperoxidase (MPO) (both p<0.01), while increasing age was an independent correlate of ascending aortic diameter (p<0.05). Furthermore, both low FMD and inflammatory activation were multivariate correlates of selectivity for valvular disease. CONCLUSIONS: BAV is associated with endothelial dysfunction. The extent of inflammatory activation (specifically MPO release) and that of endothelial dysfunction impact primarily on integrity of the valve rather than aortic structure.