Chronic Activation of Tubulin Tyrosination Improves Heart Function.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. OBJECTIVE: In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model (Mybpc3 knock in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs). METHODS AND RESULTS: Adeno-associated virus serotype 9-mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell-derived cardiomyocytes. We show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell-derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs. CONCLUSIONS: This study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.

Home and Community-Based Services: A Systematic Review and Evidence Map.

BACKGROUND: Many adults aged 60 years or older have functional limitations and require home and community-based services (HCBS) to support their independence and delay the transition to an institutionalized setting. This systematic review provides an evidence map of the existing literature on HCBS identifying evidence gaps for policy and research. METHODS: A comprehensive literature search of multiple databases including Medline, Embase, and Scopus was conducted through December 7, 2023. Interviews with various stakeholders were conducted to solicit additional perspectives. Narrative and thematic synthesis was conducted to evaluate HCBS in terms of populations, interventions, outcomes, person-centeredness, and relevant quality measures. RESULTS: We identified 27 primary studies and 29 quality measures. Populations of HCBS studies can be categorized as those with functional disability, cognitive impairment, high-risk/frail conditions, and disease-specific conditions (Parkinson's disease, Alzheimer's disease, and post-stroke). HCBS interventions targeted optimization of person-centered planning, nonpharmacological approaches for dementia care, physical rehabilitation, self-directed home care, geriatric resources for practical support at home, and interdisciplinary care coordination for high-risk conditions. Person-centered planning and self-direction of HCBS services were not explicitly described in many studies and very few studies focused on addressing health-related social needs, whereas the majority reported primary clinical outcomes. Numerous quality measures exist for HCBS, some of which were validated, addressed multiple person-centered domains, and may apply across various conditions and populations. Key challenges in the literature on HCBS include limited number of randomized trials, inadequate descriptions of interventions to determine person-centeredness, limited information on facilitators and barriers, and limited information on workforce challenges in recruiting, retaining, and training personnel delivering HCBS. DISCUSSION: This evidence map describes the current state of HCBS and identifies evidence gaps for future research and policy decisions.

Adult human cardiomyocyte mechanics in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an extracellular matrix disorder characterized by defects in collagen-1 transport or synthesis, resulting in bone abnormalities. Although reduced collagen in OI hearts has been associated with reduced myocardial stiffness and left ventricular remodeling, its impact on cardiomyocyte (CM) function has not been studied. Here, we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI type I. Proteomics and histology confirmed strikingly low expression of collagen 1. Trabecular stretch confirmed low stiffness on the tissue level. However, CMs retained normal viscoelastic properties as revealed by nanoindentation. Interestingly, OI CMs were hypercontractile relative to nonfailing controls after 24 h of culture. In response to 48 h of culture on surfaces with physiological (10 kPa) and pathological (50 kPa) stiffness, OI CMs demonstrated a greater reduction in contractility than nonfailing CMs, suggesting that OI CMs may have an impaired stress response. Levels of detyrosinated α-tubulin, known to be responsive to extracellular stiffness, were reduced in OI CMs. Together these data confirm multiple CM-level adaptations to low stiffness that extend our understanding of OI in the heart and how CMs respond to extracellular stiffness.NEW & NOTEWORTHY In a rare donation of a heart from an individual with osteogenesis imperfecta (OI), we explored cardiomyocyte (CM) adaptations to low stiffness. This represents the first assessment of cardiomyocyte mechanics in OI. The data reveal the hypercontractility of OI CMs with rapid rundown when exposed to acute stiffness challenges, extending our understanding of OI. These data demonstrate that the impact of OI on myocardial mechanics includes cardiomyocyte adaptations beyond known direct effects on the extracellular matrix.

Vasohibin inhibition improves myocardial relaxation in a rat model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with increased myocardial stiffness and cardiac filling abnormalities. Prior studies implicated increased α-tubulin detyrosination, which is catalyzed by the vasohibin enzymes, as a contributor to increased stabilization of the cardiomyocyte microtubule network (MTN) and stiffness in failing human hearts. We explored whether increased MTN detyrosination contributed to impaired diastolic function in the ZSF1 obese rat model of HFpEF and designed a small-molecule vasohibin inhibitor to ablate MTN detyrosination in vivo. Compared with ZSF1 lean and Wistar Kyoto rats, obese rats exhibited increased tubulin detyrosination concomitant with diastolic dysfunction, left atrial enlargement, and cardiac hypertrophy with a preserved left ventricle ejection fraction, consistent with an HFpEF phenotype. Ex vivo myocardial phenotyping assessed cardiomyocyte mechanics and contractility. Vasohibin inhibitor treatment of isolated cardiomyocytes from obese rats resulted in reduced stiffness and faster relaxation. Acute in vivo treatment with vasohibin inhibitor improved diastolic relaxation in ZSF1 obese rats compared with ZSF1 lean and Wistar Kyoto rats. Vasohibin inhibition also improved relaxation in isolated human cardiomyocytes from both failing and nonfailing hearts. Our data suggest the therapeutic potential for vasohibin inhibition to reduce myocardial stiffness and improve relaxation in HFpEF.

A rare and unusual cause of PSA (prostate-specific antigen) elevation: sarcoidosis of the prostate.

Sarcoidosis and prostate cancer are 2 separate conditions that are more prevalent among the African American population. However, sarcoidosis of the prostate is a very rare clinical entity. Its association with prostate cancer is described in clinical case series. The use of PSA (prostate specific antigen) test for screening prostate cancer may be associated with false-positive results in this patient population. We report a patient who had an elevated PSA but had a biopsy proven to be sarcoidosis of the prostate gland.

Improving Value of Care for Older Adults With Advanced Medical Illness and Functional Decline: Cost Analyses of a Home-Based Palliative Care Program.

CONTEXT: Identifying high-value health care delivery for patients with clinically complex and high-cost conditions is important for future reimbursement models. OBJECTIVES: The objective of this study was to assess the Medicare reimbursement savings of an established palliative care homebound program. METHODS: This is a retrospective cohort study involving 50 participants enrolled in a palliative care homebound program and 95 propensity-matched control patients at Mayo Clinic in Rochester, Minnesota, between September 1, 2012, and March 31, 2013. Total Medicare reimbursement was compared in the year before enrollment with the year after enrollment for participants and controls. RESULTS: No significant differences were observed in demographic characteristics or prognostic indices between the two groups. Total Medicare reimbursement per program participant the year before program enrollment was $16,429 compared with $14,427 per control patient, resulting in $2004 higher charges per program patient. In 12 months after program enrollment, mean annual payment was $5783 per patient among participants and $22,031 per patient among the matched controls. In the second year, the intervention group had a decrease of $10,646 per patient; the control group had an increase of $7604 per patient. The difference between the participant group and control group was statistically significant (P < 0.001) and favored the palliative care homebound program enrollees by $18,251 (95% CI, $11,268-$25,234). CONCLUSION: The Mayo Clinic Palliative Care Homebound Program reduced annual Medicare expenditures by $18,251 per program participant compared with matched control patients. This supports the role of home-based palliative medicine in delivering high-value care to high-risk older adults.

Complementary and integrative medicine in the management of headache.

Headaches, including primary headaches such as migraine and tension-type headache, are a common clinical problem. Complementary and integrative medicine (CIM), formerly known as complementary and alternative medicine (CAM), uses evidence informed modalities to assist in the health and healing of patients. CIM commonly includes the use of nutrition, movement practices, manual therapy, traditional Chinese medicine, and mind-body strategies. This review summarizes the literature on the use of CIM for primary headache and is based on five meta-analyses, seven systematic reviews, and 34 randomized controlled trials (RCTs). The overall quality of the evidence for CIM in headache management is generally low and occasionally moderate. Available evidence suggests that traditional Chinese medicine including acupuncture, massage, yoga, biofeedback, and meditation have a positive effect on migraine and tension headaches. Spinal manipulation, chiropractic care, some supplements and botanicals, diet alteration, and hydrotherapy may also be beneficial in migraine headache. CIM has not been studied or it is not effective for cluster headache. Further research is needed to determine the most effective role for CIM in patients with headache.

Health care outcomes and advance care planning in older adults who receive home-based palliative care: a pilot cohort study.

BACKGROUND: Approximately 20% of seniors live with five or more chronic medical illnesses. Terminal stages of their lives are often characterized by repeated burdensome hospitalizations and advance care directives are insufficiently addressed. This study reports on the preliminary results of a Palliative Care Homebound Program (PCHP) at the Mayo Clinic in Rochester, Minnesota to service these vulnerable populations. OBJECTIVE: The study objective was to evaluate inpatient hospital utilization and the adequacy of advance care planning in patients who receive home-based palliative care. METHODS: This is a retrospective pilot cohort study of patients enrolled in the PCHP between September 2012 and March 2013. Two control patients were matched to each intervention patient by propensity scoring methods that factor in risk and prognosis. Primary outcomes were six-month hospital utilization including ER visits. Secondary outcomes evaluated advance care directive completion and overall mortality. RESULTS: Patients enrolled in the PCHP group (n = 54) were matched to 108 controls with an average age of 87 years. Ninety-two percent of controls and 33% of PCHP patients were admitted to the hospital at least once. The average number of hospital admissions was 1.36 per patient for controls versus 0.35 in the PCHP (p < 0.001). Total hospital days were reduced by 5.13 days. There was no difference between rates of ER visits. Advanced care directive were completed more often in the intervention group (98%) as compared to controls (31%), with p < 0.001. Goals of care discussions were held at least once for all patients in the PCHP group, compared to 41% in the controls.

Common curbsides and conundrums in geriatric medicine.

Within the next 15 years, the population of adults 65 years and older in the United States will double to approximately 70 million. Physicians must be well prepared to care for this rapidly growing population. Senior adults comprise a large proportion of most primary care practices in the United States, and the unique needs of this population cannot be overstated. Although traditional preventive screening modalities and disease-specific care models are of great utility, these processes may not be appropriate or consistent with the health goals of many older patients with multiple chronic conditions and reduced functional capacity. This Concise Review highlights commonly encountered clinical scenarios important to the care of these older patients. The topics include diagnosis and management of mild cognitive impairment, assessment of the cognitively impaired driver, cancer screening in the older patient, and sarcopenia.