Orexin/hypocretin system dysfunction in patients with Takotsubo syndrome : A novel pathophysiological explanation

Takotsubo syndrome (TTS) is an acute heart failure syndrome. Emotional or physical stressors are believed to precipitate TTS, while the pathophysiological mechanism is not yet completely understood. During the coronavirus disease (COVID-19) pandemic, an increased incidence of TTS has been reported in some countries; however, the precise pathophysiological mechanism for developing TTS with acute COVID-19 infection is unknown. Nevertheless, observing the symptoms of COVID-19 might lead to new perspectives in understanding TTS pathophysiology, as some of the symptoms of the COVID-19 infection could be assessed in the context of an orexin/hypocretin-system dysfunction. Orexin/hypocretin is a cardiorespiratory neuromodulator that acts on two orexin receptors widely distributed in the brain and peripheral tissues. In COVID-19 patients, autoantibodies against one of these orexin receptors have been reported. Orexin-system dysfunction affects a variety of systems in an organism. Here, we review the influence of orexin-system dysfunction on the cardiovascular system to propose its connection with TTS. We propose that orexin-system dysfunction is a potential novel explanation for the pathophysiology of TTS due to direct or indirect dynamics of orexin signaling, which could influence cardiac contractility. This is in line with the conceptualization of TTS as a cardiovascular syndrome rather than merely a cardiac abnormality or cardiomyopathy. To the best of our knowledge, this is the first publication to present a plausible connection between TTS and orexin-system dysfunction. We hope that this novel hypothesis will inspire comprehensive studies regarding orexin's role in TTS pathophysiology. Furthermore, confirmation of this plausible pathophysiological mechanism could contribute to the development of orexin-based therapeutics in the treatment and prevention of TTS. Copyright CC BY 4.0© 2022 Knez, Niksic and Omerovic.Correspondence: Rajna Knez, [email protected] study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement, the Swedish Heart-Lung Foundation and the Swedish Scientific Council.</p

Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction

Despite the high prevalence of ischemic heart diseases worldwide, no antibody-based treatment currently exists. Starting from the evidence that a specific isoform of the Bone Morphogenetic Protein 1 (BMP1.3) is particularly elevated in both patients and animal models of myocardial infarction, here we assess whether its inhibition by a specific monoclonal antibody reduces cardiac fibrosis. We find that this treatment reduces collagen deposition and cross-linking, paralleled by enhanced cardiomyocyte survival, both in vivo and in primary cultures of cardiac cells. Mechanistically, we show that the anti-BMP1.3 monoclonal antibody inhibits Transforming Growth Factor β pathway, thus reducing myofibroblast activation and inducing cardioprotection through BMP5. Collectively, these data support the therapeutic use of anti-BMP1.3 antibodies to prevent cardiomyocyte apoptosis, reduce collagen deposition and preserve cardiac function after ischemia

Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in ∼10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1–103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families