The incidence of congestive heart failure was studied in the Beta Blocker Heart Attack Trial in which postmyocardial infarction patients between the ages of 30 and 69 years, with no contraindication to propranolol, were randomly assigned to receive placebo (n = 1921) or propranolol 180 or 240 mg daily (n = 1916) 5 to 21 days after admission to the hospital for the event. Survivors of acute myocardial infarction with compensated or mild congestive heart failure, including those on digitalis and diuretics, were included in the study. A history of congestive heart failure before randomization characterized 710 (18.5%) patients: 345 (18.0%) in the propranolol group and 365 (19.0%) in the placebo group. The incidence of definite congestive heart failure after randomization and during the study was 6.7% in both groups. In patients with a history of congestive heart failure before randomization, 51 of 345 (14.8%) in the propranolol group and 46 of 365 (12.6%) in the placebo group developed congestive heart failure during an average 25 month follow-up. In the patients with no history of congestive heart failure, 5% in the propranolol group developed congestive heart failure and 5.3% in the placebo group developed congestive heart failure. Baseline characteristics predictive of the occurrence of congestive heart failure by multivariate analyses included an increased cardiothoracic ratio, diabetes, increased heart rate, low baseline weight, prior myocardial infarction, age, and more than 10 ventricular premature beats per hour. Patients with congestive heart failure in the propranolol group experienced a similar decrease in the total mortality (27%) compared with those without congestive heart failure (25%), whereas propranolol decreased the occurrence of sudden death by 47% in the patients with prior heart failure compared with 13% without congestive heart failure. Circulation 73, No. 3, 503-510, 1986. THE USE OF ,3-adrenergic blocking agents in survivors of acute myocardial infarction with evidence of congestive heart failure poses a therapeutic paradox for the clinician. A number of 3-adrenergic blocking agents have been shown to decrease the mortality rate in postmyocardial infarction patients when administered between 1 and 3 weeks after the event. 1-' Patients with evidence of severe heart failure were usually but not always excluded from enrollment in these studies. These reports have been supplemented by both prospective and retrospective studies suggesting that a relatively greater benefit, including a significant reduction in sudden death, may be realized in the group of patients at the highest risk of future events. The Beta Blocker Heart Attack Trial (BHAT) offers an opportunity to evaluate the effect of long-term therapy with propranolol in patients after an acute myocardial infarction with congestive heart failure. As part of the design and safety features, patients with shock or overt heart failure were excluded from enrollment in BHAT until these conditions were ameliorated. In this analysis we wi...

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.

The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K+ channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K+ channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them.

Graphical abstract

Graphical abstract

While the increased arrhythmic tendency during acute COVID-19 infection is recognised, the long-term cardiac electrophysiological complications are less well known. There are a high number of patients reporting ongoing symptoms post-infection, termed long COVID. A recent hypothesis is that long COVID symptoms could be attributed to dysautonomia, defined as malfunction of the autonomic nervous system (ANS). The most prevalent cardiovascular dysautonomia amongst young people is postural orthostatic tachycardia syndrome (POTS). Numerous reports have described the development of POTS as part of long COVID. Possible underlying mechanisms, although not mutually exclusive or exhaustive, include hypovolaemia, neurotropism, inflammation and autoimmunity. Treatment options for POTS and other long COVID symptoms are currently limited. Future research studies should aim to elucidate the underlying mechanisms of dysautonomia to enable the development of targeted therapies. Furthermore, it is important to educate healthcare professionals to recognise complications and conditions arising from COVID-19, such as POTS, to allow prompt diagnosis and access to early treatment.

Summary Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon‐like peptide‐1 (GLP‐1) agonists in T2DM, pre‐diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP‐1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre‐diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre‐diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP‐1 agonist therapy. Compared with controls, GLP‐1 agonist therapy reduced HbA1c by −0.30% (95% confidence interval [CI] −0.57, −0.04) with a larger effect in children with (pre‐)diabetes (−0.72%; 95% CI −1.17, −0.28; three studies) than in children with obesity (−0.08%; 95% CI −0.13, −0.02; four studies). Conversely, GLP‐1 agonist therapy reduced body weight more in children with obesity (−2.74 kg; 95% CI −3.77, −1.70; six studies) than in children with T2DM (−0.97 kg; 95% CI −2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP‐1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.

CONTEXT: Preterm brain injuries are common; neurodevelopmental outcomes following contemporary neonatal care are continually evolving. OBJECTIVE: To systematically review and meta-analyze neurodevelopmental outcomes among preterm infants after intraventricular hemorrhage (IVH) and white matter injury (WMI). DATA SOURCES: Published and gray literature were searched across 10 databases between 2000 and 2021. STUDY SELECTION: Observational studies reporting 3-year neurodevelopmental outcomes for preterm infants with IVH or WMI compared with preterm infants without injury. DATA EXTRACTION: Study characteristics, population characteristics, and outcome data were extracted. RESULTS: Thirty eight studies were included. There was an increased adjusted risk of moderate-severe neurodevelopmental impairment after IVH grade 1 to 2 (adjusted odds ratio 1.35 [95% confidence interval 1.05–1.75]) and IVH grade 3 to 4 (adjusted odds ratio 4.26 [3.25–5.59]). Children with IVH grade 1 to 2 had higher risks of cerebral palsy (odds ratio [OR] 1.76 [1.39–2.24]), cognitive (OR 1.79 [1.09–2.95]), hearing (OR 1.83 [1.03–3.24]), and visual impairment (OR 1.77 [1.08–2.9]). Children with IVH grade 3 to 4 had markedly higher risks of cerebral palsy (OR 4.98 [4.13–6.00]), motor (OR 2.7 [1.52–4.8]), cognitive (OR 2.3 [1.67–3.15]), hearing (OR 2.44 [1.42–4.2]), and visual impairment (OR 5.42 [2.77–10.58]). Children with WMI had much higher risks of cerebral palsy (OR 14.91 [7.3–30.46]), motor (OR 5.3 [3–9.36]), and cognitive impairment (OR 3.48 [2.18–5.53]). LIMITATIONS: Heterogeneity of outcome data. CONCLUSIONS: Mild IVH, severe IVH, and WMI are associated with adverse neurodevelopmental outcomes. Utilization of core outcome sets and availability of open-access study data would improve our understanding of the nuances of these outcomes.