Therapeutic potential of conduction system pacing as a method for improving cardiac output during ventricular tachycardia.

BACKGROUND: Ventricular tachycardia (VT) reduces cardiac output through high heart rates, loss of atrioventricular synchrony, and loss of ventricular synchrony. We studied the contribution of each mechanism and explored the potential therapeutic utility of His bundle pacing to improve cardiac output during VT. METHODS: Study 1 aimed to improve the understanding of mechanisms of harm during VT (using pacing simulated VT). In 23 patients with left ventricular impairment, we recorded continuous ECG and beat-by-beat blood pressure measurements. We assessed the hemodynamic impact of heart rate and restoration of atrial and biventricular synchrony. Study 2 investigated novel pacing interventions during clinical VT by evaluating the hemodynamic effects of His bundle pacing at 5 bpm above the VT rate in 10 patients. RESULTS: In Study 1, at progressively higher rates of simulated VT, systolic blood pressure declined: at rates of 125, 160, and 190 bpm, -22.2%, -42.0%, and -58.7%, respectively (ANOVA p < 0.0001). Restoring atrial synchrony alone had only a modest beneficial effect on systolic blood pressure (+ 3.6% at 160 bpm, p = 0.2117), restoring biventricular synchrony alone had a greater effect (+ 9.1% at 160 bpm, p = 0.242), and simultaneously restoring both significantly increased systolic blood pressure (+ 31.6% at 160 bpm, p = 0.0003). In Study 2, the mean rate of clinical VT was 143 ± 21 bpm. His bundle pacing increased systolic blood pressure by + 14.2% (p = 0.0023). In 6 of 10 patients, VT terminated with His bundle pacing. CONCLUSIONS: Restoring atrial and biventricular synchrony improved hemodynamic function in simulated and clinical VT. Conduction system pacing could improve VT tolerability and treatment.

Catheter Ablation for Ventricular Tachycardia After MI: A Reconstructed Individual Patient Data Meta-analysis of Randomised Controlled Trials.

Background: The prognostic impact of ventricular tachycardia (VT) catheter ablation is an important outstanding research question. We undertook a reconstructed individual patient data meta-analysis of randomised controlled trials comparing ablation to medical therapy in patients developing VT after MI. Methods: We systematically identified all trials comparing catheter ablation to medical therapy in patients with VT and prior MI. The prespecified primary endpoint was reconstructed individual patient assessment of all-cause mortality. Prespecified secondary endpoints included trial-level assessment of all-cause mortality, VT recurrence or defibrillator shocks and all-cause hospitalisations. Prespecified subgroup analysis was performed for ablation approaches involving only substrate modification without VT activation mapping. Sensitivity analyses were performed depending on the proportion of patients with prior MI included. Results: Eight trials, recruiting a total of 874 patients, were included. Of these 874 patients, 430 were randomised to catheter ablation and 444 were randomised to medical therapy. Catheter ablation reduced all-cause mortality compared with medical therapy when synthesising individual patient data (HR 0.63; 95% CI [0.41-0.96]; p=0.03), but not in trial-level analysis (RR 0.91; 95% CI [0.67-1.23]; p=0.53; I2=0%). Catheter ablation significantly reduced VT recurrence, defibrillator shocks and hospitalisations compared with medical therapy. Sensitivity analyses were consistent with the primary analyses. Conclusion: In patients with postinfarct VT, catheter ablation reduces mortality.

Cardiopulmonary exercise testing augments watchful waiting in asymptomatic severe primary mitral regurgitation.

INTRODUCTION: Our aim is to describe the use of cardiopulmonary exercise testing in watchful waiting for asymptomatic severe primary mitral regurgitation. METHODS: Between October 2016 and October 2017, ten patients with asymptomatic severe primary mitral regurgitation underwent watchful waiting in a single centre. Baseline assessment included history, physical examination, transthoracic echocardiogram and cardiopulmonary exercise testing. Patients were re-evaluated every 6 months with history, physical examination and transthoracic echocardiogram; and at 12 months with cardiopulmonary exercise testing. RESULTS: At 1 year follow up, five patients remained asymptomatic with no significant change in left ventricular ejection fraction (p = 0.18). This was associated with no significant change in cardiopulmonary exercise testing parameters. However, five patients developed early new symptoms or changes in echocardiographic parameters with a significant fall in left ventricular ejection fraction (p < 0.01). This was associated with a significant fall in anaerobic threshold (p = 0.04) and four of the five patients having an abnormal percentage predicted peak VO2 at 1 year follow up. CONCLUSIONS: Changes in symptomatic status or echocardiographic parameters during a watchful waiting approach for asymptomatic severe primary mitral regurgitation is associated with a significant reduction in cardiopulmonary exercise testing parameters.

Catheter ablation improves cardiovascular outcomes in patients with atrial fibrillation and heart failure: a meta-analysis of randomized controlled trials.

AIMS: The effect of atrial fibrillation catheter ablation on cardiovascular outcomes in heart failure is an important outstanding research question. We undertook a meta-analysis of randomized controlled trials comparing ablation to medical therapy in patients with AF and heart failure. METHODS AND RESULTS: We systematically identified all trials comparing catheter ablation to medical therapy in patients with heart failure and atrial fibrillation. The pre-specified primary endpoint was all-cause mortality in trials with at least 2 years of follow-up. The secondary endpoint was heart failure hospitalization. Sensitivity analyses were performed for trials with any follow-up and trials deemed at low risk of bias. Eight trials (1390 patients) were included. Seven hundred and seven patients were randomized to catheter ablation and 683 to medical therapy. In the primary analysis (three trials, n = 977), catheter ablation reduced mortality compared with medical therapy [relative risk (RR): 0.61, 95% confidence interval (CI): 0.44 to 0.84, P = 0.003]. Catheter ablation also reduced heart failure hospitalizations compared with medical therapy (RR: 0.60, 95% CI: 0.49-0.74, P < 0.001). The effect on stroke was not statistically significant (RR: 0.62, 95% CI: 0.28-1.37, P = 0.237). There was low heterogeneity between studies. Sensitivity analyses were consistent with the primary analyses. CONCLUSION: In patients with atrial fibrillation and heart failure, catheter ablation reduces mortality and the occurrence of heart failure hospitalizations.

Recognition of the deteriorating patient.

Following Sir Bruce Keogh's review of 14 NHS Trusts, Buckinghamshire NHS Trust was found to have higher mortality rates than the England average. As part of a series of implementations and investigations to address this, a quality improvement project looking at clinical responses to the deteriorating patients was designed. Buckinghamshire NHS Trust utilises the National Early Warning Score (NEWS) metric for observations and escalation, and this was the standard used for the project. Episodes were eligible for inclusion if the NEWS score was increased to 5 or above. Data was collected by junior doctors from acute wards across the trust using notes and charts available. The initial cycle identified that in 57% of cases the high NEWS was escalated for review. Only half of cases were reviewed by a doctor; only a third were reviewed within an hour. In only 20% of cases were all criteria of the NEWS guidelines met. The first intervention was through education. After this, the project was completed on a monthly basis for 6 months with additional interventions introduced, including increased medical staff availability, grand round presentations, and increased outreach provision. Over this 6 month period, there was an increase to 87% of cases being reviewed by a doctor of appropriate seniority. Whilst this is a surrogate for reducing mortality and improving the clinical care given in the hospital, these results suggest successful interventions for improving clinical response to deteriorating patients across the trust. The project has recruited a new cohort of juniors to continue the quality improvement cycle.

Cellular mechanisms underlying the increased disease severity seen for patients with long QT syndrome caused by compound mutations in KCNQ1.

The KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene encodes the Kv7.1 potassium channel which forms a complex with KCNE1 (potassium voltage-gated channel Isk-related family member 1) in the human heart to produce the repolarizing IKs (slow delayed rectifier potassium current). Mutations in KCNQ1 can perturb IKs function and cause LQT1 (long QT syndrome type 1). In LQT1, compound mutations are relatively common and are associated with increased disease severity. LQT1 compound mutations have been shown to increase channel dysfunction, but whether other disease mechanisms, such as defective channel trafficking, contribute to the increase in arrhythmic risk has not been determined. Using an imaging-based assay we investigated the effects of four compound heterozygous mutations (V310I/R594Q, A341V/P127T, T391I/Q530X and A525T/R518X), one homozygous mutation (W248F) and one novel compound heterozygous mutation (A178T/K422fs39X) (where fs denotes frameshift) on channel trafficking. By analysing the effects in the equivalent of a homozygous, heterozygous and compound heterozygous condition, we identify three different types of behaviour. A341V/P127T and W248F/W248F had no effect, whereas V310I/R594Q had a moderate, but not compound, effect on channel trafficking. In contrast, T391I/Q530X, A525T/R518X and A178T/K422fs39X severely disrupted channel trafficking when expressed in compound form. In conclusion, we have characterized the disease mechanisms for six LQT1 compound mutations and report that, for four of these, defective channel trafficking underlies the severe clinical phenotype.

Readthrough of long-QT syndrome type 1 nonsense mutations rescues function but alters the biophysical properties of the channel.

The nonsense mutations R518X-KCNQ1 and Q530X-KCNQ1 cause LQT1 (long-QT syndrome type 1) and result in a complete loss of I(Ks) channel function. In the present study we attempted to rescue the function of these mutants, in HEK (human embryonic kidney)-293 cells, by promoting readthrough of their PTCs (premature termination codons) using the pharmacological agents G-418, gentamicin and PTC124. Gentamicin and G-418 acted to promote full-length channel protein expression from R518X at 100 µM and from Q530X at 1 mM. In contrast, PTC124 did not, at any dose tested, induce readthrough of either mutant. G-418 (1 mM) treatment also acted to significantly (P<0.05) increase current density and peak-tail current density, at +80 mV for R518X, but not Q530X, to 58±11% and 82±17% of the wild-type level respectively. However, the biophysical properties of the currents produced from R518X, while similar, were not identical with wild-type as the voltage-dependence of activation was significantly (P<0.05) shifted by +25 mV. Overall, these findings indicate that although functional rescue of LQT1 nonsense mutations is possible, it is dependent on the degree of readthrough achieved and the effect on channel function of the amino acid substituted for the PTC. Such considerations will determine the success of future therapies.

Sources of adult mesenchymal stem cells and their applicability for musculoskeletal applications.

There is significant potential for the use of adult mesenchymal stem cells in regenerating musckuloskeletal tissues. The sources of these stem cells discussed in this review are bone marrow, blood, adipose tissue, synovium, periosteum & cartilage. Adult mesenchymal stem cells of bone marrow origin are the cells which are heavily investigated in many studies and have been shown capable of producing a variety of connective tissues especially cartilage and bone. It has recently been suggested that bone marrow derived mesenchymal stem cells originate from microvascular pericytes, and, indeed, many of the tissues from which stem cells have been isolated have good vascularisation and they may give a varied source of cells for future treatments. Clinical trials have shown that these cells are able to be successfully used to regenerate tissues with good clinical outcome. Other sources are showing promise, however, is yet to be brought to the clinical level in humans.