Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy.

BACKGROUND: Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer's disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies 'beyond the brain'. This study aims to establish tau's putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). METHODS AND RESULTS: A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. CONCLUSION: The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.

Heart and Brain: Complex Relationships for Left Ventricular Dysfunction.

PURPOSE OF REVIEW: This review summarizes the evidence for the established vascular/hypoperfusion model and explores the new hypothesis that configures the heart/brain axis as an organ system where similar pathogenic mechanisms exploit physiological and pathological changes. RECENT FINDINGS: Although associated by common risk factors, similar epidemiological stratification and common triggers (including inflammation, oxidative stress, and hypoxia), heart failure and Alzheimer's disease have been, for long time, viewed as pathogenically separate illnesses. The silos began to be broken down with the awareness that vascular dysfunction, and loss of cardiac perfusion pump power, trigger biochemical changes, contributing to the typical hallmark of Alzheimer's disease (AD)-the accumulation of Aß plaques and hyperphosphorylated Tau tangles. Compromised blood flow to the brain becomes the paradigm for the "heart-to-head" connection. Compelling evidence of common genetic variants, biochemical characteristics, and the accumulation of Aß outside the brain suggests a common pathogenesis for heart failure (HF) and AD. These new findings represent just the beginning of the understanding the complex connection between AD and HF requiring further studies and interdisciplinary approaches. Altogether, the current evidence briefly summarized in this review, highlight a closer and complex relationship between heart failure and Alzheimer's that goes beyond the vascular/perfusion hypothesis. Genetic and biochemical evidence begin to suggest common pathogenic mechanisms between the two diseases involving a systemic defect in the folding of protein or a seeding at distance of the misfolded proteins from one organ to the other.

Rapid weight gain in professional boxing and correlation with fight decisions: analysis from 71 title fights.

OBJECTIVES: Boxing is a sport where athletes compete in several weight categories. Professional boxers typically dehydrate to cut their weight for the weigh-in (24 h before the contest) and then rehydrate before the fight. The International Boxing Federation (IBF) mandates a second weigh-in 12 h before the fight. Our objectives were: 1) To quantify the weight gain (WG) from the 1st to the 2nd weigh-in; 2) to investigate whether rapid WG affects boxing performance (win/loss rate) and 3) whether weight discrepancy (WD) 15 between boxers exposes them to increased health risks (rate of fights ended before time limit). METHODS: From official weigh-in reports of 71 IBF fights (142 fighters) the following data were gathered/calculated for each boxer: age, weight division, 1st weight, 2nd weight, WG between weigh-ins (kg and %), WD between opponents, and fight decision. RESULTS: Between the weigh-ins, the average WG was 2.52 ± 1.37 kg (range -0.3/6.4 kg) and 3.8 ± 2.2% of the initial body weight (range -0.4/9.3%) and the average WD 1.94 ± 1.50 kg (maximum 7.10 kg). Both WG and WD did not affect match outcomes. We observed tendencies for higher loss rate among boxers gaining more weight, and for higher victory rate in boxers with larger WD, however without reaching significance. A significant negative correlation was found between the 1st weight and the WG, both in absolute (r = -0.278, p = 0.001) and relative value (r = -0.497, p < 0.0001). CONCLUSIONS: Although correlations between WG, WD and boxing performance were not found, single cases with an alarming high WG and WD were noted.

Amateur boxing in the last 59 years. Impact of rules changes on the type of verdicts recorded and implications on boxers' health.

BACKGROUND/AIM: Several changes have occurred in Olympic boxing (OB) in the last few decades, influencing the results in official competitions. The aim of this study was to assess how the evolution of rules changed the rate of the results that can influence boxers' health. METHODS: From a web-research, the results of OB tournaments from 1952 to 2011 were reviewed (29,357 bouts). For each event, rate of knockout (KO), referee-stop contest (RSC), RSC-Head (RSCH), RSC-Injury (RSCI), RSC-Outclassed (RSCO), abandon, disqualification and points decisions were recorded. In our analysis we investigated the changes that occurred after the introduction of the standing-count rule (1964), mandatory head guard (1984), computerised scoring system (1992), RSCO (2000-2009) and modification of bout formula 3×3 min rounds (3×3, until 1997, 5×2 min rounds (5×2) until 1999, 4×2 min rounds (4×2) until 2008, 3×3 from 2009). RESULTS: The most important results were: (1) an RSCI rate increase (0.72-2.42%, p<0.03) after the standing-count rule; (2) a lower RSCI (0.60%, p<0.001) and higher RSCH (1.31-4.92%, p<0.001) and RSC (9.71-13.05%, p<0.03) rate with mandatory head guard; (3) a KO rate reduction (6.44-2.09%, p<0.001) with the computerised scoring system; (4) an RSC (13.15-5.91%, p<0.05) and RSCH (4.23-1.41%, p<0.001) rate reduction comparing 5×2-4×2 bouts. CONCLUSIONS: In the last six decades, along with rule changes in OB, a clear reduction of health challenging results was observed. In the near future, older rules will be adopted (no head guard and a manual scoring system). Continued medical surveillance is important to ensure that new rule changes do not result in poor medical outcomes for the boxers.