Rate of Emergency Lower Extremity Amputations in the United States Among Medicare Beneficiaries.

OBJECTIVE: To determine the rate of emergency versus elective lower extremity amputations in the United States. BACKGROUND: Lower extremity amputation is a common endpoint for patients with poorly controlled diabetes and multilevel peripheral vascular disease. Although the procedure is ideally performed electively, patients with limited access may present later and require an emergency operation. To what extent rates of emergency amputation for lower extremities vary across the United States is unknown. METHODS: Evaluation of Medicare beneficiaries who underwent lower extremity amputation between 2015 and 2020. The rate was determined for each zip code and placed into rank order from lowest to highest rate. We merged each beneficiary's place of residence and location of care with the American Hospital Association Annual Survey using Google Maps Application Programming Interface to determine the travel distance for patients to undergo their procedure. RESULTS: Of 233,084 patients, 66.3% (154,597) were men, 69.8% (162,786) were White. The average age (SD) was 74 years (8). There was wide variation in rates of emergency lower extremity amputation. The lowest quintile of zip codes demonstrated an emergency amputation rate of 3.7%, whereas the highest quintile demonstrated 90%. The median travel distance in the lowest emergency surgery rate quintile was 34.6 miles compared with 10.5 miles in the highest quintile of emergency surgery ( P < 0.001). CONCLUSIONS: There is wide variation in the rate of emergency lower extremity amputations among Medicare beneficiaries, suggesting variable access to essential vascular care. Travel distance and rate of amputation have an inverse relationship, suggesting that barriers other than travel distance are playing a role.

Comparative evaluation of transcutaneous oxygen tension and ankle-brachial index as predictors of reoperation following below-knee amputation.

OBJECTIVE: Decision-making regarding level of lower extremity amputation is sometimes challenging. Selecting an appropriate anatomic level for major amputation requires consideration of tradeoffs between postoperative function and risk of wound complications that may require additional operations, including debridement and/or conversion to above-knee amputation (AKA). We evaluated the utility of common, non-invasive diagnostic tests used in clinical practice to predict the need for reoperations among patients undergoing primary, elective, below knee-amputations (BKAs) by vascular surgeons. METHODS: Patients undergoing elective BKA over a 5-year period were identified using Current Procedural Terminology codes. Medical records were reviewed to characterize demographics, pre-amputation testing transcutaneous oxygen tension (TcPO2), and ankle-brachial index (ABI). The need for ipsilateral post-BKA reoperation (including BKA revision and/or conversion to AKA) regardless of indication was the primary outcome. Associations were evaluated using univariable and multivariable logistic regression models. Cutpoints for TcPO2 values associated with amputation reoperation were evaluated using receiver operating characteristic curves. RESULTS: We identified 175 BKAs, of which 46 (26.3%) required ipsilateral reoperation (18.9% BKA revisions and 14.3% conversions to AKA). The mean age was 63.3 ± 14.8 years. Most patients were male (65.1%) and White (72.0%). Mean pre-amputation calf TcPO2 was 40.0 ± 20.5 mmHg, and mean ABI was 0.64 ± 0.45. In univariable models, post-BKA reoperation was associated with calf TcPO2 (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.94-0.99; P = .013) but not ABI (OR, 0.53; 95% CI, 0.19-1.46; P = .217). Univariable associations with reoperation were also identified for age (OR, 0.97; 95% CI, 0.94-0.990; P = .003) and diabetes (OR, 0.43; 95% CI, 0.21-0.87; P = .019). No associations with amputation revision were identified for gender, race, end-stage renal disease, or preoperative antibiotics. Calf TcPO2 remained associated with post-BKA reoperation in a multivariable model (OR, 0.97; 95% CI, 0.94-0.99; P = .022) adjusted for age (OR, 0.98; 95% CI, 0.94-1.01; P = .222) and diabetes (OR, 0.98; 95% CI, 0.94-1.01; P = .559). Receiver operating characteristic analysis suggested a TcPO2 ≥38 mmHg as an appropriate cut-point for assessing risk for BKA revision (area under the curve = 0.682; negative predictive value, 0.91). CONCLUSIONS: Reoperation after BKA is common, and reoperation risk was associated with pre-amputation TcPO2. For patients undergoing elective BKA, higher risk of reoperation should be discussed with patients with an ipsilateral TcPO2 <38 mmHg.

Natural history of visceral branch artery dissections and the influence of concurrent aortic dissection on overall and intervention-free survival.

OBJECTIVE: Visceral branch artery dissection (VBAD) is uncommon and may occur with or without an associated aortic dissection (AD). We hypothesized that isolated VBAD would have a more benign clinical course than those with concurrent AD and compared survival outcomes stratified based on aortic involvement. METHODS: VBAD over a 5-year period were identified using International Classification of Diseases codes. Data related to patient demographics, comorbid conditions, clinical presentation, management (including procedural interventions), and survival were obtained from medical records. Anatomic imaging studies were reviewed to characterize anatomy, including the presence or absence of concurrent AD. Overall survival and intervention-free survival were evaluated using Kaplan-Meier and Cox proportional hazards models. RESULTS: A total of 299 VBAD were identified, 174 of which were isolated VBAD and 125 were associated with concurrent AD. Seventy-one percent of patients were men, 77% were White, and 85% were non-Hispanic. The mean age was 61.1 ± 14.4 years. The mean follow-up was 53.2 ± 50.0 months. The estimated overall survival was 88.2% and the estimated overall intervention-free survival was 55.6% at 12 months. Isolated VBAD had better overall survival than those with concurrent AD (69.2% vs 32.4%; P < .001). Concurrent AD was also associated with inferior intervention-free survival (57.5% vs 7.3%; P < .001). Acute presentation was associated with decreased intervention-free survival (86.1% vs 13.4%; P < .001). Acute presentation was also associated with decreased overall survival in patients with isolated VBAD (60.8% vs 80.0% at 180 months; P < .001) and inferior intervention-free survival (48.4% vs 69.5% at 180 months; P < .001) in the subgroup of patients with isolated VBAD. Multivariable Cox models identified that age (hazard ratio [HR]: 1.05, standard deviation [SD]: 0.02; P = .001) was associated with inferior survival and renal dissections (HR: 3.08, SD: 0.99; P = .001) or mesenteric and renal dissections (HR: 3.39, SD: 1.44; P = .004) were associated with inferior intervention-free survival. CONCLUSIONS: Isolated VBAD has superior overall and intervention-free survival to those associated with concurrent AD. The absence vs presence of aortic involvement is useful for risk stratification and may support tailored approaches to the frequency of imaging surveillance.

Surgical Care for Racial and Ethnic Minorities and Interventions to Address Inequities: A Narrative Review.

OBJECTIVE: Racial and ethnic inequities in surgical care in the United States are well documented. Less is understood about evidence-based interventions that improve surgical care and reduce or eliminate inequities. In this review, we discuss effective patient, surgeon, community, health care system, policy, and multi-level interventions to reduce inequities and identifying gaps in intervention-based research. BACKGROUND: Evidenced-based interventions to reduce racial and ethnic inequities in surgical care are key to achieving surgical equity. Surgeons, surgical trainees, researchers, and policy makers should be aware of the evidence-based interventions known to reduce racial and ethnic disparities in surgical care for prioritization of resource allocation and implementation. Future research is needed to assess interventions effectiveness in the reduction of disparities and patient-reported measures. METHODS: We searched PubMed database for English-language studies published from January 2012 through June 2022 to assess interventions to reduce or eliminate racial and ethnic disparities in surgical care. A narrative review of existing literature was performed identifying interventions that have been associated with reduction in racial and ethnic disparities in surgical care. RESULTS AND CONCLUSIONS: Achieving surgical equity will require implementing evidenced-based interventions to improve quality for racial and ethnic minorities. Moving beyond description toward elimination of racial and ethnic inequities in surgical care will require prioritizing funding of intervention-based research, utilization of implementation science and community based-participatory research methodology, and principles of learning health systems.

Direct and Indirect Effects of Race and Socioeconomic Deprivation on Outcomes After Lower Extremity Bypass.

OBJECTIVE: To evaluate the potential pathway, through which race and socioeconomic status, as measured by the social deprivation index (SDI), affect outcomes after lower extremity bypass chronic limb-threatening ischemia (CLTI), a marker for delayed presentation. BACKGROUND: Racial and socioeconomic disparities persist in outcomes after lower extremity bypass; however, limited studies have evaluated the role of disease severity as a mediator to potentially explain these outcomes using clinical registry data. METHODS: We captured patients who underwent lower extremity bypass using a statewide quality registry from 2015 to 2021. We used mediation analysis to assess the direct effects of race and high values of SDI (fifth quintile) on our outcome measures: 30-day major adverse cardiac event defined by new myocardial infarction, transient ischemic attack/stroke, or death, and 30-day and 1-year surgical site infection (SSI), amputation and bypass graft occlusion. RESULTS: A total of 7077 patients underwent a lower extremity bypass procedure. Black patients had a higher prevalence of CLTI (80.63% vs 66.37%, P < 0.001). In mediation analysis, there were significant indirect effects where Black patients were more likely to present with CLTI, and thus had increased odds of 30-day amputation [odds ratio (OR): 1.11, 95% CI: 1.068-1.153], 1-year amputation (OR: 1.083, 95% CI: 1.045-1.123) and SSI (OR: 1.052, 95% CI: 1.016-1.089). There were significant indirect effects where patients in the fifth quintile for SDI were more likely to present with CLTI and thus had increased odds of 30-day amputation (OR: 1.065, 95% CI: 1.034-1.098) and SSI (OR: 1.026, 95% CI: 1.006-1.046), and 1-year amputation (OR: 1.068, 95% CI: 1.036-1.101) and SSI (OR: 1.026, 95% CI: 1.006-1.046). CONCLUSIONS: Black patients and socioeconomically disadvantaged patients tended to present with a more advanced disease, CLTI, which in mediation analysis was associated with increased odds of amputation and other complications after lower extremity bypass compared with White patients and those that were not socioeconomically disadvantaged.

Characterizing patient-reported claudication treatment goals to support patient-centered treatment selection and measurement strategies.

OBJECTIVE: Patient-reported outcomes (PRO) have been increasingly emphasized for peripheral artery disease (PAD). Patient-defined treatment goals and expectations, however, are poorly understood and might not be achievable or aligned with guidelines or clinical outcomes. We evaluated the patient-reported treatment goals among patients with claudication and the associations between patient characteristics, goals, and PAD-specific PRO scores. METHODS: Patients with a diagnosis of claudication were prospectively recruited. Patient-defined treatment goals and outcomes related to walking distance, duration, and speed were quantified using multiple-choice survey items. Free-text items were used to identify activities other than walking distance, duration, or speed associated with symptoms and treatment goals. The peripheral artery disease quality of life and walking impairment questionnaire instruments were included as PRO. The treatment goal categories were compared with the PRO percentile scores using 95% confidence intervals (CIs), categorical tests, and logistic regression models. Associations between the patient characteristics and PRO were evaluated using linear and ordinal logistic regression models. RESULTS: A total of 150 patients meeting the inclusion criteria were included in the present study. Of these 150 patients, 144 (96%) viewed the entire survey. Their mean age was 70.0 ± 11.3 years, and 32.9% were women. Most of the respondents had self-reported their race as White (n = 135), followed by Black (n = 3), Asian (n = 2), Native American (n = 2), and other/unknown (n = 2). Two participants self-reported Hispanic ethnicity. The primary treatment goals were an increased walking distance or duration without stopping (62.0%), the ability to perform a specific activity or task (23.0%), an increased walking speed (8.0%), or other/none of the above (7.0%). The specific activities associated with symptoms or goals included outdoor recreation (38.5%), labor-related tasks (30.7%), sports (26.9%), climbing stairs (23.1%), uphill walking (19.2%), and shopping (6%). Among the patients choosing an increased walking distance and duration as the primary goals, 64% had indicated that a distance of ≥0.5 mile (2640 ft) and 59% had indicated a duration of ≥30 minutes would be a minimum increase consistent with meaningful improvement. Increasing age was associated with lower odds of a distance improvement goal of ≥0.5 mile (odds ratio [OR], 0.68 per 5 years; 95% CI, 0.51-0.92; P = .012) or duration improvement goal of ≥30 minutes (OR, 0.76 per 5 years; 95% CI, 0.58-0.99; P = .047). Patient characteristics associated with PAD Quality of Life percentile scores included age, ankle brachial index, and gender. Ankle brachial index was the only patient characteristic associated with the walking impairment questionnaire percentile scores. CONCLUSIONS: Patients define treatment goals according to their desired activities and expectations, which may influence their goals and perceived outcomes. Patients' expectations of minimum increases in walking distance and duration consistent with meaningful improvement exceeded reported minimum important difference criteria for many patients and would not be captured using common clinic-based walking tests. Patient age was associated with both treatment goals and PRO scores, and the related floor and ceiling effects could influence sensitivity to PRO changes for younger and older patients, respectively. Heterogeneity in treatment goals supports consideration of tailored decision-making and outcomes informed by patient characteristics and perspectives.

Underutilization of medical management of peripheral artery disease among patients with claudication undergoing lower extremity bypass.

OBJECTIVE: First-line treatment of peripheral artery disease (PAD) involves medical therapy and lifestyle modification. Multiple professional organizations such as the Society for Vascular Surgery and the American Heart Association/American College of Cardiology make Class I recommendations for medical management including antiplatelet, statin, antihypertensive, and cilostazol medications, as well as lifestyle therapy including exercise and smoking cessation. Although evidence supports up-front medical and lifestyle management prior to surgical intervention, it is unclear how well this occurs in contemporary clinical practice. It is also unclear whether variability in first-line treatment prior to revascularization is associated with postoperative outcomes. This study examined the proportion of patients with claudication actively receiving evidence-based therapy prior to surgery in a statewide surgical registry. METHODS: We conducted a retrospective cohort study of adult patients undergoing elective open lower extremity bypass for claudication from 2012 to 2021 within a statewide surgical quality registry. The primary exposure was optimal medical therapy, defined as an antiplatelet agent, a statin, and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (if the patient had hypertension) on the patient's home medication list on admission for surgery, all of which are Class I recommendations. Despite also being Class I recommendations, cilostazol was not included in the primary exposure due to its highly selective use and our inability to capture intolerance and/or contraindications that are common, and lifestyle therapies were not included as they were only recorded at the time of discharge rather than preoperatively. The primary outcomes were mortality, hospital readmission, amputation, wound complication, myocardial infarction (MI), non-patent bypass, and non-independent ambulatory status at 30 days and 1 year after surgery. Multivariable logistic regression was performed to estimate the association of receiving optimal vs non-optimal medical therapy. RESULTS: A total of 3829 patients with claudication underwent bypass surgery during the study period, with a mean age of 64.8 years (standard deviation, 9.8 years); 2690 (70.3%) were males, and 1873 (48.9%) were current smokers. Of the patients, 1822 (47.6%) were on optimal medical therapy prior to surgery. Additionally, at discharge, 66.5% of smokers received referral to smoking cessation therapy, and 54.1% of patients received referral to exercise therapy. In a multivariable logistic regression, compared with patients not on optimal medical therapy, patients on optimal medical therapy prior to surgery had lower 30-day odds of mortality (adjusted odds ratio [aOR], 0.45; 95% confidence interval [CI], 0.26-0.78) and MI (aOR, 0.46; 95% CI, 0.28-0.76), lower 1-year odds of mortality (aOR, 0.57; 95% CI, 0.39-0.82), MI (aOR, 0.48; 95% CI, 0.32-0.74), and lower readmission (aOR, 0.79; 95% CI, 0.64-0.96). CONCLUSIONS: Although medical and lifestyle management is recommended as first-line treatment for patients with PAD, only one-half of patients were on optimal medical therapy prior to surgery. Patients receiving optimal therapy had a lower risk of postoperative mortality, MI, and readmission. This suggests that not only are there significant opportunities to improve clinical utilization of evidence-based treatment of PAD, but that doing so can benefit patients postoperatively.

Direct visualization of the arterial wall water permeability barrier using CARS microscopy.

The artery wall is equipped with a water permeation barrier that allows blood to flow at high pressure without significant water leak. The precise location of this barrier is unknown despite its importance in vascular function and its contribution to many vascular complications when it is compromised. Herein we map the water permeability in intact arteries, using coherent anti-Stokes Raman scattering (CARS) microscopy and isotopic perfusion experiments. Generation of the CARS signal is optimized for water imaging with broadband excitation. We identify the water permeation barrier as the endothelial basolateral membrane and show that the apical membrane is highly permeable. This is confirmed by the distribution of the AQP1 water channel within endothelial membranes. These results indicate that arterial pressure equilibrates within the endothelium and is transmitted to the supporting basement membrane and internal elastic lamina macromolecules with minimal deformation of the sensitive endothelial cell. Disruption of this pressure transmission could contribute to endothelial cell dysfunction in various pathologies.

No longer failing to treat heart failure: A guideline update review.

Heart failure is a leading cause of hospital admissions and death in the United States and worldwide. In 2016, the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America released a joint focused guideline update for the management of patients with Stage C heart failure with reduced ejection fraction. An additional update released in 2017 reinforces the 2016 update's strong recommendation for substituting angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with an angiotensin receptor-neprilysin inhibitor to reduce morbidity and mortality in selected patients. The 2017 and 2016 updates also support adding a sinoatrial node modulator to further reduce heart rates in patients already maximized on beta-blocker therapy. These innovative therapies can significantly improve patients' quality of life and reduce the healthcare costs associated with managing heart failure.

Regional variation in racial disparities among patients with peripheral artery disease.

OBJECTIVE: Prior studies identified significant racial disparities as well as regional variation in outcomes of patients with peripheral artery disease (PAD). We aimed to determine whether regional variation contributes to these racial disparities. METHODS: We identified all white or black patients who underwent infrainguinal revascularization or amputation in 15 deidentified regions of the Vascular Quality Initiative between 2003 and 2017. We excluded three regions with <100 procedures. We used multivariable linear regression, allowing clustering at the hospital level to calculate the marginal effects of race and region on adjusted 30-day mortality, major adverse limb events (MALEs), and amputation. We compared long-term outcomes between black and white patients within each region and within patients of each race treated in different regions using multivariable Cox regression. RESULTS: We identified 90,418 patients, 15,527 (17%) of whom were black. Patients underwent 31,263 bypasses, 52,462 endovascular interventions, and 6693 amputations. Black patients were younger and less likely to smoke, to have coronary artery disease, or to have chronic obstructive pulmonary disease, but they were more likely to have diabetes, limb-threatening ischemia, dialysis dependence, and hypertension and to be self-insured or on Medicaid (all P < .05). Adjusted 30-day mortality ranged from 1.2% to 2.1% across regions for white patients and 0% to 3.0% for black patients; adjusted 30-day MALE varied from 4.0% to 8.3% for white patients and 2.4% to 8.1% for black patients; and adjusted 30-day amputation rates varied from 0.3% to 1.2% for white patients and 0% to 2.1% for black patients. Black patients experienced significantly different (both higher and lower) adjusted rates of 30-day mortality and amputation than white patients did in several regions (P < .05) but not MALEs. In addition, within each racial group, we found significant variation in the adjusted rates of all outcomes between regions (all P < .01). In adjusted analyses, compared with white patients, black patients experienced consistently lower long-term mortality (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.73-0.88; P < .001) and higher rates of MALEs (HR, 1.15; 95% CI, 1.06-1.25; P < .001) and amputation (HR, 1.33; 95% CI, 1.18-1.51; P < .001), with no statistically significant variation across the regions. However, rates of all long-term outcomes varied within both racial groups across regions. CONCLUSIONS: Significant racial disparities exist in outcomes after lower extremity procedures in patients with PAD, with regional variation contributing to perioperative but not long-term outcome disparities. Underperforming regions should use these data to generate quality improvement projects, as understanding the etiology of these disparities is critical to improving the care of all patients with PAD.

PML-IRIS in an HIV-2-infected patient presenting as Bell's palsy.

We present the case of an HIV-2-infected patient who developed progressive multifocal leukoencephalopathy (PML) in the setting of immune reconstitution inflammatory syndrome (IRIS) presenting as Bell's palsy. The brain MRI showed a single lesion in the facial colliculus considered initially to be ischemic in nature. This case report should alert clinicians that PML can occur in the setting of HIV-2 infection. It also illustrates the difficulty of establishing the diagnosis of PML.

Community-engaged research in vascular surgery: An approach to decrease amputation disparities and effect population-level change.

Community-engaged research (CEnR) is a powerful tool to create sustainable and effective change in health outcomes. CEnR engages community members as equal partners, amplifying their voices and priorities by including them throughout the research process. Such engagement increases the relevance and meaning of research, improves the translation of research findings into sustainable health policy and practice, and ultimately enhances mutual trust among academic, clinical, and community partners for ongoing research partnership. There are a number of key principles that must be considered in the planning, design, and implementation of CEnR. These principles are focused on inclusive representation and participation, community empowerment, building community capacity, and protecting community self-determination. Although vascular surgeons may not be equipped to address these issues from the ground up by themselves, they should work with a team who can help them incorporate these elements into their CEnR project designs and proposals. This may be best accomplished by collaborating with researchers and community-based organizations who already have this expertise and have established social capital within the community. This article describes the theory and principles of CEnR, its relevance to vascular surgeons, researchers, and patients, and how using CEnR principles in vascular surgery practice, research, and outreach can benefit our patient population, with a specific focus on reducing disparities related to amputation.

Treatment and contemporary outcomes associated with adjunct tourniquet use during phlebectomy of complex, voluminous truncular varicosities.

OBJECTIVE: Phlebectomy of large voluminous varicose veins comes with a risk of substantial blood loss. The purpose of the present study was to investigate the outcomes associated with the use of an adjunct tourniquet during varicose vein surgery of complex and large truncular varicosities. METHODS: The prospectively collected registry data included anatomic and outcomes details for patients who presented with complex and large truncular varicosities with a CEAP clinical class of C2, or higher (indicating more serious venous disease) from December 2014 to December 2021. Of all patients, those treated with an adjunct tourniquet for large complex varicosities (largest diameter varicosity ≥1 cm by visual inspection) were selected for analysis. The venous clinical severity scores (VCSSs) and patient-reported outcomes (PROs) were obtained. Additional parameters, including operative time, tourniquet time, and blood loss, were obtained retrospectively via a review of the medical records. Univariate descriptive statistics of the demographic and procedural data were performed pre- and postoperatively, with comparisons performed using the Student two-tailed t test. RESULTS: The data from 19 patients (22 limbs; 7 women and 12 men) were analyzed. Of the 22 limbs, 11 (50%) had advanced venous disease of C4 or higher preoperatively. A review of the preoperative duplex ultrasound scans confirmed the presence of large varicosities (average, 1.0 ± 0.54 cm; n = 18). All the limbs were treated using radiofrequency ablation of axial reflux and phlebectomy (a combination of powered and stab) under tourniquet control (82%) or phlebectomy under tourniquet control alone (18%). The average tourniquet time was 40 ± 12 minutes, with a median blood loss of 50 mL (interquartile range, 30-100 mL). The average follow-up was 332 ± 422 days after 19 procedures for 16 patients (2 patients moved out of state during the immediate postoperative period and 1 patient was lost to follow-up). Of the patients who completed >3 months of follow-up, 14 limbs experienced improvement in the CEAP class, 5 limbs had no change, and 3 were limbs of patients who moved or were lost to follow-up. The VCSSs significantly improved (8.8 ± 2.8 vs 3.9 ± 1.9; P < .0001). The PROs also improved significantly (16.1 ± 5.0 vs 2.2 ± 2.3; P < .0001). CONCLUSIONS: Tourniquet use in the treatment of varicosities has only been described in the setting of high ligation and stripping. Our data suggest that in the modern era of minimally invasive endovenous treatment of axial reflux and phlebectomy, adjunct tourniquet use during the treatment of large complex varicosities can result in significant improvements in the VCSSs and PROs, with minimal blood loss.

Human coronary microvascular contractile dysfunction associates with viable synthetic smooth muscle cells.

AIMS: Coronary microvascular smooth muscle cells (SMCs) respond to luminal pressure by developing myogenic tone (MT), a process integral to the regulation of microvascular perfusion. The cellular mechanisms underlying poor myogenic reactivity in patients with heart valve disease are unknown and form the focus of this study. METHODS AND RESULTS: Intramyocardial coronary micro-arteries (IMCAs) isolated from human and pig right atrial (RA) appendage and left ventricular (LV) biopsies were studied using pressure myography combined with confocal microscopy. All RA- and LV-IMCAs from organ donors and pigs developed circa 25% MT. In contrast, 44% of human RA-IMCAs from 88 patients with heart valve disease had poor (<10%) MT yet retained cell viability and an ability to raise cytoplasmic Ca2+ in response to vasoconstrictor agents. Comparing across human heart chambers and species, we found that based on patient medical history and six tests, the strongest predictor of poor MT in IMCAs was increased expression of the synthetic marker caldesmon relative to the contractile marker SM-myosin heavy chain. In addition, high resolution imaging revealed a distinct layer of longitudinally aligned SMCs between ECs and radial SMCs, and we show poor MT was associated with disruptions in these cellular alignments. CONCLUSION: These data demonstrate the first use of atrial and ventricular biopsies from patients and pigs to reveal that impaired coronary MT reflects a switch of viable SMCs towards a synthetic phenotype, rather than a loss of SMC viability. These arteries represent a model for further studies of coronary microvascular contractile dysfunction.

Caenorhabditis elegans body mechanics are regulated by body wall muscle tone.

Body mechanics in the nematode Caenorhabditis elegans are central to both mechanosensation and locomotion. Previous work revealed that the mechanics of the outer shell, rather than internal hydrostatic pressure, dominates stiffness. This shell is comprised of the cuticle and the body wall muscles, either of which could contribute to the body mechanics. Here, we tested the hypothesis that the muscles are an important contributor by modulating muscle tone using optogenetic and pharmacological tools, and measuring animal stiffness using piezoresistive microcantilevers. As a proxy for muscle tone, we measured changes in animal length under the same treatments. We found that treatments that induce muscle contraction generally resulted in body shortening and stiffening. Conversely, methods to relax the muscles more modestly increased length and decreased stiffness. The results support the idea that body wall muscle activation contributes significantly to and can modulate C. elegans body mechanics. Modulation of body stiffness would enable nematodes to tune locomotion or swimming gaits and may have implications in touch sensation.

Maternal experiences of racial discrimination and offspring sleep in the first 2 years of life: Project Viva cohort, Massachusetts, USA (1999-2002).

OBJECTIVE: To examine the association of maternal lifetime experiences of racial discrimination with infant sleep duration over the first 2 years of life. DESIGN: Prebirth cohort study. SETTING: Massachusetts, USA (baseline: 1999-2002). PARTICIPANTS: 552 mother-infant dyads in Project Viva, for whom the mother self-identified as being a woman of color. MEASUREMENTS: During pregnancy, mothers completed the Experiences of Discrimination survey that measured lifetime experiences of racial discrimination in eight domains. The main outcome was a weighted average of their infants' 24-hour sleep duration from 6 months to 2 years. RESULTS: 30% reported 0 domains of racial discrimination, 35% 1-2 domains, and 34% ≥3 domains. Any racial discrimination (≥1 vs. 0 domains) was higher among black (80%) versus Hispanic (58%) or Asian (53%) mothers and the United States versus foreign-born mothers (79% vs. 58%) and was associated with higher mean prepregnancy BMI (26.8 vs. 24.5 kg/m2). Children whose mothers reported ≥3 domains versus 0 domains had shorter sleep duration from 6 months to 2 years in unadjusted analysis (ß -18.6 min/d; 95% CI -37.3, 0.0), which was attenuated after adjusting for maternal race/ethnicity and nativity (-13.6 min/d; -33.7, 6.5). We found stronger associations of racial discrimination with offspring sleep at 6 months (-49.3 min/d; -85.3, -13.2) than for sleep at 1 year (-13.5 min/d; -47.2, 20.3) or 2 years (4.2 min/d; -21.5, 29.9). CONCLUSIONS: Maternal lifetime experiences of racial discrimination was associated with shorter offspring sleep duration at 6 months, but not with infant's sleep at 1 and 2 years of age.

Voltage-dependent Ca2+ entry into smooth muscle during contraction promotes endothelium-mediated feedback vasodilation in arterioles.

Vascular smooth muscle contraction is suppressed by feedback dilation mediated by the endothelium. In skeletal muscle arterioles, this feedback can be activated by Ca2+ signals passing from smooth muscle through gap junctions to endothelial cells, which protrude through holes in the internal elastic lamina to make contact with vascular smooth muscle cells. Although hypothetically either Ca2+ or inositol trisphosphate (IP3) may provide the intercellular signal, it is generally thought that IP3 diffusion is responsible. We provide evidence that Ca2+ entry through L-type voltage-dependent Ca2+ channels (VDCCs) in vascular smooth muscle can pass to the endothelium through positions aligned with holes in the internal elastic lamina in amounts sufficient to activate endothelial cell Ca2+ signaling. In endothelial cells in which IP3 receptors (IP3Rs) were blocked, VDCC-driven Ca2+ events were transient and localized to the endothelium that protrudes through the internal elastic lamina to contact vascular smooth muscle cells. In endothelial cells in which IP3Rs were not blocked, VDCC-driven Ca2+ events in endothelial cells were amplified to form propagating waves. These waves activated voltage-insensitive, intermediate-conductance, Ca2+-activated K+ (IKCa) channels, thereby providing feedback that effectively suppressed vasoconstriction and enabled cycles of constriction and dilation called vasomotion. Thus, agonists that stimulate vascular smooth muscle depolarization provide Ca2+ to endothelial cells to activate a feedback circuit that protects tissue blood flow.