Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

Therapeutic Dilemmas Faced When Managing a Life-Threatening Presentation of a Myocardial Bridge.

Background. Myocardial bridges are congenital abnormalities, where a segment of coronary artery travels intramyocardially, rather than the typical epicardial course. The overlying muscle segment is termed "the bridge". Most myocardial bridges are asymptomatic, but some can result in myocardial ischaemia, arrhythmias, and sudden cardiac death. Case Presentation. A 31-year-old male with no past medical history presented to our tertiary cardiac centre following an out-of-hospital ventricular fibrillation arrest. Coronary angiography and computed tomography of the coronary arteries revealed a 2 cm myocardial bridge overlying the left anterior descending (LAD) artery. An exercise echocardiogram demonstrated severe apical ballooning and hypokinesis during peak exercise, with corresponding ST-segment elevation, resolving on rest. Options for medical therapy of a symptomatic myocardial bridge include beta blockers, calcium channel blockers, ivabradine, or a combination thereof. Surgical interventions include deroofing the bridge and revascularisation of the affected region with bypass grafting. However, a lack of trial data comparing medical regimens and surgical interventions makes it difficult to ascertain the most effective management strategy for each patient. There was disagreement between experts at different tertiary centres over the optimal management of this patient. He was treated with multiple regimes of medical therapy with ongoing ischaemia on stress testing, before undergoing a negative stress test on amlodipine, diltiazem, and isosorbide mononitrate. It was felt that no further intervention was necessary at this time given his exercise test was now negative for ischaemia. However, after seeking a second opinion, he underwent surgical intervention with bypass grafting of his left anterior descending artery, followed by implantation of an implantable cardiac defibrillator. Subsequently, an angiogram postsurgery demonstrated concomitant spasm of the LAD and he was resumed on medical therapy with calcium channel blockers and nitrates. Discussion. Without randomised trials, it is impossible to determine the optimal management strategy for each patient. It is possible that some patients with myocardial bridges are not being trialled on optimal medical therapy prior to undergoing invasive and irreversible interventions.

Study protocol: MyoFit46-the cardiac sub-study of the MRC National Survey of Health and Development.

BACKGROUND: The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world's longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46-the cardiac sub-study of the NSHD. METHODS: We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. DISCUSSION: By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR-ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

Long-term Outcomes of Catheter Ablation for Ventricular Arrhythmias in Post-Myocarditis Patients: Insights from a Meta-Analysis of Current Data.

BACKGROUND: In the past decade, catheter ablation (CA) has become a rapidly expanding treatment option for ventricular tachycardia (VT); however it is not commonly utilised for patients with post-myocarditis VT. We aimed to systematically review up-to-date evidence regarding feasibility, effectiveness, and safety of CA, with a specific focus on long-term relapse rate and procedural complications. METHODS: A structured electronic database search (PubMed, Embase, Cochrane) of the scientific literature was performed according to PRISMA guidelines for studies describing outcomes at up to 7.3 years after CA. The primary outcome measured was VT recurrence post-ablation. Procedural success was defined as freedom of ventricular arrhythmias (at the end of follow-up after an ablation procedure). The secondary outcome was significant procedural complications which included procedural death, stroke, cardiac tamponade, acute myocardial infarction, major vascular complications, and major bleeding, assessed on a study-by-study basis. RESULTS: A total of 186 patients were included in analysis with most patients (88%) being male. Over the follow-up period, there was a 18% relapse rate (n = 34) (confidence interval (CI); 0.12-0.24, I 2≈0, p = 0.77) with the majority of patients remaining VT free for the duration of follow-up. The overall procedural complication rate was 3.0% (n = 7) (CI; 0.01-0.07, I 2≈0, p = 0.44), and of note, there were no peri-procedural deaths or heart transplant surgeries reported. However, a single study reported a mortality of 10% (n = 2) during the follow-up period. CONCLUSIONS: CA is an effective and durable long-term therapeutic strategy for post-myocarditis VT patients with limited relapse rate and very low complication rates based on these non-randomised data. Larger randomised-controlled trials with standardised treatment and long follow-up are required to compare CA versus conventional treatment in the post-acute myocardial phase. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42399-022-01137-w.

Effect of tricuspid regurgitation and right ventricular dysfunction on long-term mortality in patients undergoing cardiac devices implantation: >10-year follow-up study.

BACKGROUND: The long-term effect of tricuspid regurgitation (TR) after device implantation on long-term mortality remains unknown. In the present study, we sought to examine whether patients undergoing an implantable cardiac device procedure (pacemaker, cardiac defibrillator or cardiac resynchronisation therapy) have an increased risk of TR and to determine the effect of this on long-term survival. METHODS: A total of 304 patients who underwent device implant and had pre- and post-implant transthoracic echocardiogram were included in the analysis. All-cause mortality was the study endpoint over a follow-up period of median 11.6 years. RESULTS: New ≥ moderate tricuspid regurgitation post-device implantation developed in 66/304 (21.7%) patients. New right ventricular dysfunction post-device implantation occurred in 59/304 (19.4%) patients. Independent predictors of new RV dysfunction were ischaemic heart disease (OR 4.23, 95% CI 1.58 - 11.33, p = 0.004), left ventricular impairment (OR 2.74, 95% CI 5.41 - 30.00, p < 0.0001) and new ≥ moderate TR (OR 7.72, 95% CI 3.27 - 18.23, p < 0.001). Independent predictors of mortality were new ≥ moderate TR [HR: 3.14 (95% CI 1.29 - 7.63) p = 0.01] and new RV impairment [HR: 2.82 (95% CI 1.33 - 5.98) p = 0.01. CONCLUSIONS: Worsening TR and RV dysfunction post-device implantation is common. New post-implant ≥ moderate TR is associated with increased risk of new RV impairment and poor long term (>10 years) survival.

Predictive Role of BNP/NT-proBNP in Non-Heart Failure Patients Undergoing Catheter Ablation for Atrial Fibrillation: An Updated Systematic Review.

Atrial Fibrillation (AF) is a growing public health issue, associated with significant morbidity and mortality. In addition to pharmacological therapy, catheter ablation is an effective strategy in restoring and maintaining sinus rhythm. However, ablation is not without risk, and AF recurs in a significant proportion of patients. Non-invasive, easily accessible markers or indices that could stratify patients depending on the likelihood of a successful outcome following ablation would allow us to select the most appropriate patients for the procedure, reducing the AF recurrence rate and exposure to potentially life-threatening risks. There has been much attention paid to Brain Natriuretic Peptide (BNP) and N-Terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) as possible predictive markers of successful ablation. Several studies have demonstrated an association between higher pre-ablation levels of these peptides, and a greater likelihood of AF recurrence. Therefore, there may be a role for measuring brain natriuretic peptides levels when selecting patients for catheter ablation.

Full blood count as potential predictor of outcomes in patients undergoing cardiac resynchronization therapy.

Almost a third of patients fulfilling current guidelines criteria have suboptimal responses following cardiac resynchronization therapy (CRT). Circulating biomarkers may help identify these patients. We aimed to assess the predictive role of full blood count (FBC) parameters in prognosis of heart failure (HF) patients undergoing CRT device implantation. We enrolled 612 consecutive CRT patients and FBC was measured within 24 hours prior to implantation. The follow-up period was a median of 1652 days (IQR: 837-2612). The study endpoints were i) composite of all-cause mortality or transplant, and ii) reverse left ventricular (LV) remodeling. On multivariate analysis [hazard ratio (HR), 95% confidence interval (CI)] only red cell count (RCC) (p = 0.004), red cell distribution width (RDW) (p < 0.001), percentage of lymphocytes (p = 0.03) and platelet count (p < 0.001) predicted all-cause mortality. Interestingly, RDW (p = 0.004) and platelet count (p = 0.008) were independent predictors of reverse LV remodeling. This is the first powered single-centre study to demonstrate that RDW and platelet count are independent predictors of long-term all-cause mortality and/or heart transplant in CRT patients. Further studies, on the role of these parameters in enhancing patient selection for CRT implantation should be conducted to confirm our findings.

Biomarkers Associated with Stroke Risk in Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of cardioembolic stroke. The risk of cardioembolism is not adequately reduced with the administration of oral anticoagulants, since a number of patients continue to experience thromboembolic events despite receiving treatment. Therefore, identification of a circulating biomarker to identify these high-risk patients would be clinically beneficial. OBJECTIVE: In the present article, we aim to review the available data regarding use of biomarkers to predict cardioembolic stroke in patients with AF. METHODS: We performed a thorough search of the literature in order to analyze the biomarkers identified thus far and critically evaluate their clinical significance. RESULTS: A number of biomarkers have been proposed to predict cardioembolic stroke in patients with AF. Some of them are already used in the clinical practice, such as d-dimers, troponins and brain natriuretic peptide. Novel biomarkers, such as the inflammatory growth differentiation factor-15, appear to be promising, while the role of micro-RNAs and genetics appear to be useful as well. Even though these biomarkers are associated with an increased risk for thromboembolism, they cannot accurately predict future events. In light of this, the use of a scoring system, that would incorporate both circulating biomarkers and clinical factors, might be more useful. CONCLUSIONS: Recent research has disclosed several biomarkers as potential predictors of cardioembolic stroke in patients with AF. However, further research is required to establish a multifactorial scoring system that will identify patients at high-risk of thromboembolism, who would benefit from more intensive treatment and monitoring.

Nitric oxide donors for peripheral artery disease.

Current management of peripheral arterial disease involves risk factor modification and revascularisation, but many patients are still left with debilitating symptoms. Therefore, new treatment strategies are needed. The importance of nitric oxide, and its role in regulating endothelial function, is well-established. Altering the nitric oxide pathway has been extensively studied as a means of treating vascular disease, including peripheral arterial disease. Statins and ACE inhibitors have been shown to enhance endogenous nitric oxide and improve intermittent claudication symptoms. Studies using l-arginine have produced differing results, for reasons for yet fully understood. A greater understanding of the nitric oxide pathway, and its enzymatic control, has generated more potential therapeutic targets to alter NO levels.

Biological therapies targeting arrhythmias: are cells and genes the answer?

INTRODUCTION: Arrhythmias can cause symptoms ranging from simple dizziness to life-threatening circulatory collapse. Current management includes medical therapy and procedures such as catheter ablation or device implantation. However, these strategies still pose a risk of serious side effects, and some patients remain symptomatic. Advancement in our understanding of how arrhythmias develop on the cellular level has made more targeted approaches possible. In addition, contemporary studies have found that several genes are involved in the pathogenesis of arrhythmias. AREAS COVERED: In the present review, the authors explore the cellular and genetic mechanisms leading to arrhythmias as well as the progress that has been made in using both gene and cell therapy to treat tachy- and bradyarrhythmias. They also consider why gene and cell therapy has resulted into a few clinical trials with promising results, however still not applicable in routine clinical practice. EXPERT OPINION: The question currently is whether such biological therapies could replace current established approaches. The contemporary evidence suggests that despite recent advances in this field, it will need more work in experimental models before this is applied into clinical practice. Gene and cell studies targeting conduction and repolarization are promising, but still not ready for use in the clinical setting.

Impact of an Age-Adjusted Co-morbidity Index on Survival of Patients With Heart Failure Implanted With Cardiac Resynchronization Therapy Devices.

Age is an adverse prognostic factor in patients with heart failure. We aimed to assess the impact of age and noncardiac co-morbidities in the outcome of patients undergoing cardiac resynchronization therapy (CRT), and determine which of these two factors is the most important predictor of survival. The study involved a single-center retrospective assessment of 697 consecutive CRT implants during a 12-year period. Patient co-morbidity profile was assessed using the Charlson Co-morbidity Index (CCI) and the Charlson Age-Co-morbidity Index (CACI). Predictors of survival free from heart transplantation were assessed. CRT-related complications and cause of death analysis were assessed within tertiles of the CACI. During a mean follow-up of 1,813 ± 1,177 days, 347 patients (49.9%) died and 37 (5.3%) underwent heart transplantation. On multivariate Cox regression, female gender (HR = 0.78, 95% confidence interval [CI] 0.62 to 0.99, p = 0.041), estimated glomerular filtration rate (HR per ml/min = 0.99, 95% CI 0.98 to 0.99, p < 0.001), left ventricular ejection fraction (HR per % = 0.99, 95% CI 0.98 to 1.00, p = 0.022), New York Heart Association class (HR = 1.83, 95% CI 1.53 to 2.20, p < 0.001), presence of left bundle branch block (HR = 0.70, 95% CI 0.56 to 0.87, p = 0.001), and CACI tertile (HR = 1.37, 95% CI 1.18 to 1.59, p < 0.001) were independent predictors of all-cause mortality or heart transplantation. Compared with age and the CCI, the CACI was the best discriminator of all-cause mortality. Inappropriate therapies occurred less frequently in higher co-morbidity tertiles. In conclusion, patient co-morbidity profile adjusted to age impacts on mortality after CRT implantation. Use of the CACI may help refine guideline criteria to identify patients more likely to benefit from CRT.

Dual-site right ventricular pacing in patients undergoing cardiac resynchronization therapy: Results of a multicenter propensity-matched analysis.

BACKGROUND: Dual-site right ventricular pacing (Dual RV) has been proposed as an alternative for patients with heart failure undergoing cardiac resynchronization therapy (CRT) with a failure to deliver a coronary sinus (CS) lead. Only short-term hemodynamic and echocardiographic results of Dual RV are available. We aimed to assess the long-term results of Dual RV and its impact on survival. METHODS: Multicenter retrospective assessment of all CRT implants during a 12-year period. Patients with failed CS lead implantation, treated with Dual RV, were followed and assessed for the primary endpoint of all-cause mortality and/or heart transplant. A control group was obtained from contemporary patients using propensity matching for all available baseline variables. RESULTS: Ninety-three patients were implanted with Dual RV devices and compared with 93 matched controls. During a median of 1,273 days (interquartile range 557-2,218), intention-to-treat analysis showed that all-cause mortality and/or heart transplant was higher in the Dual RV group (adjusted hazard ratio [HR] = 1.66, 95% confidence interval [CI] 1.12-2.47, P = 0.012). As-treated analysis yielded similar results (HR = 1.97, 95% CI 1.31-2.96, P = 0.001). Cardiac device-related infections occurred seven times more frequently in the Dual RV site group (HR = 7.60, 95% CI 1.51-38.33, P = 0.014). Among Dual RV nonresponders, four had their apical leads switched off, five required an epicardial LV lead insertion, a transseptal LV lead was implanted in two, and in nine patients, after reviewing the CS venogram, a new CS lead insertion was successfully attempted. CONCLUSION: Dual RV pacing is associated with worse clinical outcomes and higher complication rates than conventional CRT.

Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy.

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development.

Factors affecting successful outcome from ICSI in men following previous vasectomy.

There are conflicting reports as to whether the interval between vasectomy and surgical sperm retrieval (SSR) for intra-cytoplasmic sperm injection (ICSI) is related to clinical pregnancy (CPR), and live birth (LBR), rates. This study aimed to evaluate factors that may influence the outcome of ICSI in males with secondary azoospermia due to previous vasectomy. We analysed the medical records of 198 azoospermic males following vasectomy who underwent percutaneous epididymal sperm aspiration (PESA) and/or testicular sperm extraction (TeSE), between 1997 and 2005 by a single urologist, and whose sperm was subsequently frozen for use in an IVF treatment programme on their partner's behalf. Hundred and forty-four (73%) males had a positive PESA, and the remaining 54 (27%) had a positive TeSE. Forty-four percent of males with no clinical evidence of epididymal distension still had epididymal sperm retrieved successfully. Hundred and twenty-eight patients proceeded with ICSI, and a total of 237 cycles were performed. The CPR and LBR overall were 29 and 27%, respectively. Using logistic regression there was no association between time since vasectomy and CPR (P = 0.17) or LBR (P = 0.31). A history of an attempted reversal of vasectomy did not negatively affect retrieval rates or CPR and LBR. The success of SSR and the outcome of ICSI, using frozen sperm, are independent of male age and time since vasectomy. Epididymal sperm may be retrieved in over 40% of men in whom there is no clinical evidence of epididymal distension.

Sperm retrieval rates in subgroups of primary azoospermic males.

OBJECTIVES: Men presenting with primary infertility and azoospermia may be offered surgical sperm retrieval (SSR) as a prelude to intracytoplasmic sperm injection (ICSI). We evaluated sperm retrieval rates in subgroups of men with azoospermia, based on obstructive aetiology, testicular volume and FSH. METHODS: 106 patients with primary infertility underwent clinical evaluation and SSR with percuataneous epididymal aspiration (PESA) and/or testicular sperm extraction (TeSE) by a single urologist over a five year period. Ten percent of this group (11 patients) had a clear cause of obstruction, congenital absence of the vas deferens (CBAVD), labelled group A. Ninety percent (95 patients) had no definite cause of obstruction, labelled group B. RESULTS: All eleven patients in group A had adequate sperm retrieved, compared with 56% of 95 men in group B. Clinical pregnancy and live birth rates were 47% and 44% for group A respectively compared with 21% and 20% for group B. Twenty-one men had testes <4 cm and FSH>10; a significantly lower sperm retrieval rate was seen in this subgroup (29%) compared to men with normal testicular volume and FSH (77%), p=0.0001, which corresponded to a LBR of 28% and 14% respectively. CONCLUSIONS: In the absence of testicular histology prior to SSR clinical parameters can be used to aid in counselling. Azoospermic males with normal sized testes and normal FSH can expect acceptable numbers of sperm to be retrieved by SSR for ICSI. Less than one third of men with raised FSH and small testes will have successful SSR.

Waiting for in vitro fertilization treatment: spontaneous and ART live births.

This study analysed the live birth rates in 760 couples referred in 1994 to St Mary's Hospital, Manchester, a non-fee-paying National Health Service (NHS) centre, who had waited for up to 4 years for IVF treatment. These live birth rates were compared with those of 199 couples referred at a similar time to Manchester Fertility Services, a fee-paying unit, where they received IVF treatment shortly after referral. The waiting time was advantageous in that 17.8% (135 of 760) of the couples referred to St Mary's Hospital conceived without IVF treatment, 60% within one year of referral. However, the waiting time was detrimental to women aged 30-34 in whom treatment was delayed by 3-4 years. Only 26.8% (204 of 760) of couples originally referred eventually received NHS-funded IVF treatment at St Mary's. A waiting time not exceeding 18 months would allow most spontaneous conceptions and reduce the adverse effect of prolonged waiting on the take-up rate for treatment and on the chance of success in the older women.