Predicting sudden death … and other research

Predicting sudden death

My dad died of a sudden cardiac arrest when he was 48 years old. His death, like many similar cases, was never really explained. One recently discovered cause of sudden death is a genetic arrhythmia syndrome called calcium release deficiency syndrome (CRDS). Could a new test identify CRDS before it presents as a sudden death?

This multicentre case-control study found a unique repolarisation response on electrocardiography (T wave amplitude) to brief tachycardia and a pause in 10 patients with CRDS compared with controls, which could form the basis of a predictive test. The human findings were replicated in genetic mouse models and were caused by abnormally high release of calcium from the sarcoplasmic reticulum during systole. This was a small preliminary report from an ongoing DIAGNOSE CRDS study that will take years to complete. It offers the prospect of a clinical diagnostic test for CRDS in families who have been devastated by multiple and early sudden deaths.

JAMA doi:10.1001/jama.2024.8599

No smoke without fire

What works best if you want to quit smoking; electronic cigarettes containing nicotine or varenicline?

In this Finnish randomised, placebo controlled trial of 458 adults with moderate to heavy dependence on nicotine who were motivated to quit smoking traditional cigarettes, 12 weeks of nicotine-containing electronic cigarettes and varenicline were both effective in helping people to stop smoking for up to six months compared with placebo (40.4% v 43.8% v 19.7%) with no serious side effects.

Given that electronic cigarettes and varenicline are equally effective, it may be better to recommend varenicline over electronic cigarettes because it weans people off the habit of smoking and doesn’t contain nicotine.

JAMA Intern Med doi:10.1001/jamainternmed.2024.1822

Shedding light on dementia

In the department of Antioquia in north west Colombia there is a large family of 6000 blood relatives that include more than 1000 carriers of the autosomal dominant E280A variant of the PSEN1 gene (encoding the protein presenilin 1). Almost 100% of these carriers develop Alzheimer’s disease with mild cognitive impairment starting in their mid-40s and dementia by the time they’re 50 years old.

This study found 27 of the family members carrying the E280A variant who were also heterozygous for the APOE3^Ch gene variant (encoding apolipoprotein E) and who had later onset of symptoms than 1050 family E280A carriers who didn’t have the APOE3^Ch variant (onset of cognitive decline 5 years later and dementia 4 years later) as well as a different pattern on brain imaging (positron emission tomography).

The hypothesis is that the variant prevents the accumulation of tau tangles and associated cell death, and researchers are working on treatments for Alzheimer’s disease that could replicate its apparent protective effects.

N Engl J Med doi:10.1056/NEJMoa2308583

Safety of metformin in early pregnancy

Is metformin safe to use in early pregnancy? This US observational cohort study of over 12 000 pregnant women with pregestational type 2 diabetes who were taking metformin monotherapy before their last menstrual period (LMP) compared insulin monotherapy (discontinue metformin treatment and initiate insulin monotherapy within 90 days of LMP) with insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP).

Taking metformin in addition to insulin was as safe as insulin alone (risk ratio estimated non-live births and congenital malformation 1.02 and 0.72 respectively). There was some risk of confounding based on glycaemic control and body mass index, but results were reassuring and warrant further study.

Ann Intern Med doi:10.7326/M23-2038

But what about the dads?

Metformin has known antiandrogenic and epigenetic modifying effects. So, if men take metformin during the period of spermatogenesis before conception, does it increase the risk of genomic changes and major congenital malformations in the newborn?

This nationally representative cohort study from Israel of nearly 400 000 live births (1999-2020) found that paternal use of metformin monotherapy did not increase the risk of major congenital malformations. However, paternal use of metformin in polytherapy was associated with an increased risk of major congenital malformations (adjusted odds ratio 1.36), which was possibly because these men had more poorly controlled diabetes and worse cardiometabolic health. One limitation of the study was that results for haemoglobin A_1c weren’t available in all subsets.

Taking these two studies together, metformin for men and women trying to conceive a child seems to be safe.

Ann Intern Med doi:10.7326/M23-1405