Clinical considerations and pathophysiological associations among obesity, weight loss, heart failure, and hypertension.

PURPOSE OF REVIEW: To describe the relationship between three pandemics: hypertension, obesity, and heart failure. From pathophysiology to treatment, understanding how these disease entities are linked can lead to breakthroughs in their prevention and treatment. The relevance of this review lies in its discussion of novel pharmacological and surgical treatment strategies for obesity and hypertension, and their role in the prevention and treatment of heart failure. RECENT FINDINGS: Novel medications such as GLP-1 agonists have demonstrated sustained weight loss in patients with obesity, and concurrent improvements in their cardiometabolic profile, and possibly also reductions in hypertension-related comorbidities including heart failure. Surgical therapies including laparoscopic bariatric surgery represent an important treatment strategy in obese patients, and recent studies describe their use even in patients with advanced heart failure, including those with ventricular assist devices. SUMMARY: These developments have deep implications on our efforts to understand, mitigate, and ultimately prevent the three pandemics, and offer promising improvements to quality of life, survival, and the cost burden of these diseases.

U-shaped relationship between apolipoprotein A1 levels and mortality risk in men and women.

BACKGROUND: Apolipoprotein A1 (ApoA1) is the principal protein component of high-density lipoprotein (HDL). Although low HDL cholesterol (HDL-C) levels are known to be associated with greater cardiovascular risk, recent studies have also shown heightened mortality risk at very high HDL-C levels. AIMS: To investigate the sex-specific association between elevated ApoA1 levels and adverse outcomes, and their genetic basis. METHODS: A prospective cohort study of United Kingdom Biobank participants without coronary artery disease at enrollment was performed. The primary exposure was serum ApoA1 levels. The primary and secondary outcome measures were cardiovascular and all-cause death, respectively. RESULTS: In 402 783 participants followed for a median of 12.1 years, there was a U-shaped relationship between ApoA1 levels and both cardiovascular as well as all-cause mortality, after adjustment for traditional cardiovascular risk factors. Individuals in the highest decile of ApoA1 levels (1.91-2.50 g/L) demonstrated higher cardiovascular (HR 1.21, 95% CI 1.07-1.37, P < 0.0022) and all-cause mortality (HR 1.14, 95% CI 1.07-1.21, P < 0.0001) compared with those within the lowest risk eighth decile (1.67-1.75 g/L). The U-shaped relationship was present in both sexes, though more pronounced in men. Sensitivity analyses showed that cardiovascular mortality rates were higher in those with greater alcohol intake (P < 0.004). Adjustment for polygenic variation associated with higher ApoA1 levels did not attenuate the effect of very high ApoA1 levels on mortality. In the sub-group with very elevated HDL-C levels (> 80 mg/dL in men, > 100 mg/dL in women), there was no association between ApoA1 levels and mortality. CONCLUSION: Both very low and very elevated ApoA1 levels are associated with higher cardiovascular and all-cause mortality.

Pre-existing Systolic Dysfunction is the Most Powerful Predictor of Failed Arteriovenous Fistula Maturation.

BACKGROUND: Patients requiring hemodialysis access creation often have significant comorbid conditions, which may impact access maturation. Underlying cardiac dysfunction likely plays an important role in the maturation of arteriovenous fistulae (AVF). The effect of specific parameters of cardiac function on successful AVF creation has not previously been explored. METHODS: A retrospective chart analysis of patients undergoing first-time AVF creation at a single center from 2011 to 2018 was performed. Patients with a transthoracic echocardiogram within the 12 months prior to surgery were included. Standard demographic and perioperative variables were collected, in addition to echocardiographic and vascular mapping data. The primary outcome was access maturation, defined as the use of the access site for hemodialysis at 3, 6, and 12 months after surgery. RESULTS: A total of 121 patients met inclusion criteria with a cumulative AVF maturation rate of 57% (69/121) in this select population. Patients with pre-existing systolic cardiac dysfunction were more than 5 times less likely to see their AVF mature by one year postsurgery (OR = 0.17, P = 0.018). Preoperative venous diameter, access site location, and the type of fistula did not differ significantly between patients with and without systolic dysfunction. Selection of the cephalic vein as the venous anastomosis and diastolic dysfunction (≥ Grade 2) were also associated with lower rates of access maturation, although these associations were less robust. CONCLUSIONS: Systolic cardiac dysfunction is the most important nonmodifiable variable associated with failed AVF maturation. Patients requiring hemodialysis with significant pre-existing cardiac dysfunction may not be appropriate for permanent access creation, and long-term catheter use should be seriously considered as an alternative.

Actin at stereocilia tips is regulated by mechanotransduction and ADF/cofilin.

Stereocilia on auditory sensory cells are actin-based protrusions that mechanotransduce sound into an electrical signal. These stereocilia are arranged into a bundle with three rows of increasing length to form a staircase-like morphology that is required for hearing. Stereocilia in the shorter rows, but not the tallest row, are mechanotransducing because they have force-sensitive channels localized at their tips. The onset of mechanotransduction during mouse postnatal development refines stereocilia length and width. However, it is unclear how actin is differentially regulated between stereocilia in the tallest row of the bundle and the shorter, mechanotransducing rows. Here, we show actin turnover is increased at the tips of mechanotransducing stereocilia during bundle maturation. Correspondingly, from birth to postnatal day 6, these stereocilia had increasing amounts of available actin barbed ends, where monomers can be added or lost readily, as compared with the non-mechanotransducing stereocilia in the tallest row. The increase in available barbed ends depended on both mechanotransduction and MYO15 or EPS8, which are required for the normal specification and elongation of the tallest row of stereocilia. We also found that loss of the F-actin-severing proteins ADF and cofilin-1 decreased barbed end availability at stereocilia tips. These proteins enriched at mechanotransducing stereocilia tips, and their localization was perturbed by the loss of mechanotransduction, MYO15, or EPS8. Finally, stereocilia lengths and widths were dysregulated in Adf and Cfl1 mutants. Together, these data show that actin is remodeled, likely by a severing mechanism, in response to mechanotransduction.