Insights from cardiopulmonary exercise testing in pediatric patients with hypertrophic cardiomyopathy

The usefulness of cardiopulmonary exercise test (CPET) in adult hypertrophic cardiomyopathy (HCM) patients is well-known, whereas its role in pediatric HCM patients has not yet been explored. The present study investigates possible insights from a CPET assessment in a cohort of pediatric HCM outpatients in terms of functional and prognostic assessment. Sixty consecutive pediatric HCM outpatients aged <18 years old were enrolled, each of them undergoing a full clinical assessment including a CPET; a group of 60 healthy subjects served as controls. A unique composite end-point of heart failure (HF) related and sudden cardiac death (SCD) or SCD-equivalent events was also explored. During a median follow-up of 53 months (25th–75th: 13–84 months), a total of 13 HF- and 7 SCD-related first events were collected. Compared to controls, HCM patients showed an impaired functional capacity with most of them showing peak oxygen uptake (pVO2) values of <80% of the predicted, clearly discrepant with functional New York Heart Association class assessment. The composite end-point occurred more frequently in patients with the worst CPETs’ profiles. At the univariate analysis, pVO2% was the variable with the strongest association with adverse events at follow-up (C-index = 0.72, p = 0.025) and a cut-off value equal to 60% was the most accurate in identifying those patients at the highest risk. In a pediatric HCM subset, the CPET assessment allows a true functional capacity estimation and it might be helpful in identifying early those patients at high risk of events.publishedVersio

An overview of molecular mechanisms in fabry disease

Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is alpha-galactosidase A (alpha-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers

PRNP P39L variant is a rare cause of frontotemporal dementia in Iialian population

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%)

Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos

Physiology of living beings show circadian rhythms entrained by a central timekeeper present in the hypothalamic suprachiasmatic nuclei. Nevertheless, virtually all peripheral tissues hold autonomous molecular oscillators constituted essentially by circuits of gene expression that are organized in negative and positive feed-back loops. Accumulating evidence reveals that cell metabolism is rhythmically controlled by cell-intrinsic molecular clocks and the specific pathways involved are being elucidated. Here, we show that in vitro-synchronized cultured cells exhibit BMAL1-dependent oscillation in mitochondrial respiratory activity, which occurs irrespective of the cell type tested, the protocol of synchronization used and the carbon source in the medium. We demonstrate that the rhythmic respiratory activity is associated to oscillation in cellular NAD content and clock-genes-dependent expression of NAMPT and Sirtuins 1/3 and is traceable back to the reversible acetylation of a single subunit of the mitochondrial respiratory chain Complex I. Our findings provide evidence for a new interlocked transcriptional-enzymatic feedback loop controlling the molecular interplay between cellular bioenergetics and the molecular clockwork

589 External validation of the increased wall thickness score for the diagnosis of cardiac amyloidosis

Abstract Aims This study aimed to validate the increased wall thickness (IWT) score, a multiparametric echocardiographic score to facilitate diagnosis of cardiac amyloidosis (CA), in an independent population of patients with increased LV wall thickness suspicious for CA. Methods and results Between January 2019 and December 2020, 152 consecutive patients with increased LV wall thickness suspicious for CA were included. For all patient, the multiparametric echocardiographic score (IWT score) was calculated. To validate the diagnostic accuracy of an IWT score ≥8 to predict the diagnosis of CA, sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy (PA) were calculated. Among the 152 patients included in the study, 50 (33%) were diagnosed as CA, 25 (16%) had severe aortic stenosis, 25 (16%) had hypertensive remodelling, and 52 (34%) had hypertrophic cardiomyopathy. Among the 50 and 102 patients with and without CA, 19 (38%) and 1 (1%) showed an IWT score ≥8, respectively. Overall, the diagnostic accuracy of an IWT score ≥8 for the diagnosis of CA in our population was the following: Se 38% (95% CI: 25–53%); Sp 99% (95% CI: 95–100%); PPV 95% (95% CI: 72–99%); NPV 77% (95% CI: 73–80%); PA 79% (95% CI: 72–85%). Conclusions This study reports the first external validation of the IWT score for the diagnosis of CA in patients with increased LV wall thickness. A score ≥8 showed a high Sp, PPV and PA, suggesting that the IWT score can be used to identify CA patients in those with increased LV wall thickness

Multimodality Imaging in Cardiomyopathies with Hypertrophic Phenotypes

Multimodality imaging is a comprehensive strategy to investigate left ventricular hypertrophy (LVH), providing morphologic, functional, and often clinical information to clinicians. Hypertrophic cardiomyopathy (HCM) is defined by an increased LV wall thickness not only explainable by abnormal loading conditions. In the context of HCM, multimodality imaging, by different imaging techniques, such as echocardiography, cardiac magnetic resonance, cardiac computer tomography, and cardiac nuclear imaging, provides essential information for diagnosis, sudden cardiac death stratification, and management. Furthermore, it is essential to uncover the specific cause of HCM, such as Fabry disease and cardiac amyloidosis, which can benefit of specific treatments. This review aims to elucidate the current role of multimodality imaging in adult patients with HCM

pathogenesis of takotsubo syndrome

Takotsubo syndrome (TTS) is an enigmatic disease with a multifactorial and still unresolved pathogenesis. Postulated mechanisms include catecholamine excess, coronary artery spasm, and microvascular dysfunction, however catecholamines seem to play a central role in the pathophysiology of TTS. In facts catecholamines have relevant effects on the vasculature and myocardium. Toxic direct effects of catecholamine on myocardium are mediated by multiple pathway including functional hypoxia, metabolic changes and changes in membrane permeability leading to various electrolytic imbalances. Recently report of familial cases has suggested a genetic component. Further research is required to help clarify the proposed hypotheses and to increase our understanding of the cardiovascular responses to acute stress and the pathophysiology underpinning TTS

Changes in disease burden in Poland between 1990-2017 in comparison with other Central European countries : a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND:Systematic collection of mortality/morbidity data over time is crucial for monitoring trends in population health, developing health policies, assessing the impact of health programs. In Poland, a comprehensive analysis describing trends in disease burden for major conditions has never been published. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides data on the burden of over 300 diseases in 195 countries since 1990. We used the GBD database to undertake an assessment of disease burden in Poland, evaluate changes in population health between 1990-2017, and compare Poland with other Central European (CE) countries. METHODS:The results of GBD 2017 for 1990 and 2017 for Poland and CE were used to assess rates and trends in years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life years (DALYs). Data came from cause-of-death registration systems, population health surveys, disease registries, hospitalization databases, and the scientific literature. Analytical approaches have been used to adjust for missing data, errors in cause-of-death certification, and differences in data collection methodology. Main estimation strategies were ensemble modelling for mortality and Bayesian meta-regression for disability. RESULTS:Between 1990-2017, age-standardized YLL rates for all causes declined in Poland by 46.0% (95% UI: 43.7-48.2), YLD rates declined by 4.0% (4.2-4.9), DALY rates by 31.7% (29.2-34.4). For both YLLs and YLDs, greater relative declines were observed for females. There was a large decrease in communicable, maternal, neonatal, and nutritional disease DALYs (48.2%; 46.3-50.4). DALYs due to non-communicable diseases (NCDs) decreased slightly (2.0%; 0.1-4.6). In 2017, Poland performed better than CE as a whole (ranked fourth for YLLs, sixth for YLDs, and fifth for DALYs) and achieved greater reductions in YLLs and DALYs than most CE countries. In 2017 and 1990, the leading cause of YLLs and DALYs in Poland and CE was ischaemic heart disease (IHD), and the leading cause of YLDs was low back pain. In 2017, the top 20 causes of YLLs and YLDs in Poland and CE were the same, although in different order. In Poland, age-standardized DALYs from neonatal causes, other cardiovascular and circulatory diseases, and road injuries declined substantially between 1990-2017, while alcohol use disorders and chronic liver diseases increased. The highest observed-to-expected ratios were seen for alcohol use disorders for YLLs, neonatal sepsis for YLDs, and falls for DALYs (3.21, 2.65, and 2.03, respectively). CONCLUSIONS:There was relatively little geographical variation in premature death and disability in CE in 2017, although some between-country differences existed. Health in Poland has been improving since 1990; in 2017 Poland outperformed CE as a whole for YLLs, YLDs, and DALYs. While the health gap between Poland and Western Europe has diminished, it remains substantial. The shift to NCDs and chronic disability, together with marked between-gender health inequalities, poses a challenge for the Polish health-care system. IHD is still the leading cause of disease burden in Poland, but DALYs from IHD are declining. To further reduce disease burden, an integrated response focused on NCDs and population groups with disproportionally high burden is needed