Publications by authors named "Michael H Criqui"

347 Publications

Lower Extremity Peripheral Artery Disease: Contemporary Epidemiology, Management Gaps, and Future Directions: A Scientific Statement From the American Heart Association.

Circulation 2021 Aug 28;144(9):e171-e191. Epub 2021 Jul 28.

Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.
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http://dx.doi.org/10.1161/CIR.0000000000001005DOI Listing
August 2021

Perceived Versus Objective Change in Walking Ability in Peripheral Artery Disease: Results from 3 Randomized Clinical Trials of Exercise Therapy.

J Am Heart Assoc 2021 Jun 2;10(12):e017609. Epub 2021 Jun 2.

Department of Medicine University of Chicago IL.

Background In people with lower-extremity peripheral artery disease, the effects of exercise on patient-reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6-minute walk and the Walking Impairment Questionnaire distance score (score 0-100, 100=best) at baseline and 6-month follow-up. Compared with the control group, exercise improved 6-minute walk distance by +39.8 m (95% CI, 26.8-52.8, <0.001) and the Walking Impairment Questionnaire distance score by +7.3 (95% CI, 2.4-12.1, =0.003). In all, 2828 individual Walking Impairment Questionnaire distance score questions were completed at baseline and follow-up. Among participants who perceived no change in ability to walk 1 or more distances between baseline and follow-up, 6-minute walk improved in the exercise group and declined in the control group (+26.8 versus -6.5 m, <0.001). Among participants who perceived that their walking ability worsened for 1 or more distances between baseline and follow-up, the 6-minute walk improved in the exercise group and declined in the control group (+18.4 versus -27.3 m, <0.001). Among participants who reported worsening calf symptoms at follow-up, the exercise group improved and the control group declined (+28.9 versus -12.5 m, <0.01). Conclusions In 3 randomized trials, exercise significantly improved the 6-minute walk distance in people with peripheral artery disease, but many participants randomized to exercise reported no change or decline in walking ability. These findings suggest a significant discrepancy in objectively measured walking improvement relative to perceived walking improvement in people with peripheral artery disease. Registration Information clinicaltrials.gov. Identifiers: NCT00106327, NCT01408901.
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http://dx.doi.org/10.1161/JAHA.120.017609DOI Listing
June 2021

Sleep apnea, coronary artery calcium density and cardiovascular events: results from the Multi-Ethnic Study of Atherosclerosis (MESA).

J Clin Sleep Med 2021 May 14. Epub 2021 May 14.

Icahn School of Medicine at Mount Sinai, New York, NY.

Study Objectives: Evaluate the association between obstructive sleep apnea (OSA), coronary artery calcium (CAC) density, and cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods: We analyzed 1041 participants with non-zero CAC scores who had polysomnography and CAC density data from the fifth examination of MESA. OSA was defined as apnea-hypopnea index [AHI] ≥ 15 events/hour. Multivariable linear regression models were used to evaluate the independent association between OSA and CAC density. Additionally, we evaluated the impact of OSA on associations of CAC measures with incident CVD events by testing for interaction in Cox proportional hazard regression models.

Results: Our analytical sample was 45% female with a mean age of 70.6 +/- 9 years. Of this sample, 36.7% (n=383/1041) had OSA (AHI≥15). OSA was inversely and weakly associated with CAC density (β= -0.09, 95% CI -0.17 to -0.02, p=0.014) and remained significantly associated after controlling for traditional cardiovascular risk factors (β= -0.08, 95% CI -0.16 to 0, p=0.043). However, this inverse association was attenuated after controlling for BMI (β=-0.05, 95% CI -0.13 to 0.02, p=0.174). The mean follow-up period for CVD events was 13.3 +/- 2.8 years. Additionally, exploratory analysis demonstrated that CAC density was independently and inversely associated with CVD events only in the non-OSA subgroup (AHI≤15) (HR 0.509 [CI 0.323 - 0.801], p=0.0035).

Conclusions: OSA was associated with lower CAC density, but this association was attenuated by BMI. Further, increased CAC density was associated with a reduced risk of CVD events only in individuals within the non-OSA group in exploratory analysis.
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http://dx.doi.org/10.5664/jcsm.9356DOI Listing
May 2021

Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial.

Vasc Med 2021 Apr 8:1358863X21989430. Epub 2021 Apr 8.

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs.
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http://dx.doi.org/10.1177/1358863X21989430DOI Listing
April 2021

Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial.

JAMA 2021 04;325(13):1266-1276

Wake Forest University, Winston-Salem, North Carolina.

Importance: Supervised high-intensity walking exercise that induces ischemic leg symptoms is the first-line therapy for people with lower-extremity peripheral artery disease (PAD), but adherence is poor.

Objective: To determine whether low-intensity home-based walking exercise at a comfortable pace significantly improves walking ability in people with PAD vs high-intensity home-based walking exercise that induces ischemic leg symptoms and vs a nonexercise control.

Design, Setting, And Participants: Multicenter randomized clinical trial conducted at 4 US centers and including 305 participants. Enrollment occurred between September 25, 2015, and December 11, 2019; final follow-up was October 7, 2020.

Interventions: Participants with PAD were randomized to low-intensity walking exercise (n = 116), high-intensity walking exercise (n = 124), or nonexercise control (n = 65) for 12 months. Both exercise groups were asked to walk for exercise in an unsupervised setting 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. The low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. Accelerometer data were viewable to a coach who telephoned participants weekly for 12 months and helped them adhere to their prescribed exercise. The nonexercise control group received weekly educational telephone calls for 12 months.

Main Outcomes And Measures: The primary outcome was mean change in 6-minute walk distance at 12 months (minimum clinically important difference, 8-20 m).

Results: Among 305 randomized patients (mean age, 69.3 [SD, 9.5] years, 146 [47.9%] women, 181 [59.3%] Black patients), 250 (82%) completed 12-month follow-up. The 6-minute walk distance changed from 332.1 m at baseline to 327.5 m at 12-month follow-up in the low-intensity exercise group (within-group mean change, -6.4 m [95% CI, -21.5 to 8.8 m]; P = .34) and from 338.1 m to 371.2 m in the high-intensity exercise group (within-group mean change, 34.5 m [95% CI, 20.1 to 48.9 m]; P < .001) and the mean change for the between-group comparison was -40.9 m (97.5% CI, -61.7 to -20.0 m; P < .001). The 6-minute walk distance changed from 328.1 m at baseline to 317.5 m at 12-month follow-up in the nonexercise control group (within-group mean change, -15.1 m [95% CI, -35.8 to 5.7 m]; P = .10), which was not significantly different from the change in the low-intensity exercise group (between-group mean change, 8.7 m [97.5% CI, -17.0 to 34.4 m]; P = .44). Of 184 serious adverse events, the event rate per participant was 0.64 in the low-intensity group, 0.65 in the high-intensity group, and 0.46 in the nonexercise control group. One serious adverse event in each exercise group was related to study participation.

Conclusions And Relevance: Among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise and was not significantly different from the nonexercise control for improving 6-minute walk distance. These results do not support the use of low-intensity home-based walking exercise for improving objectively measured walking performance in patients with PAD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02538900.
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http://dx.doi.org/10.1001/jama.2021.2536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025122PMC
April 2021

Distribution of calcium volume, density, number, and type of coronary vessel with calcified plaque in South Asians in the US and other race/ethnic groups: The MASALA and MESA studies.

Atherosclerosis 2021 01 7;317:16-21. Epub 2020 Dec 7.

Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Division of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center and Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Background And Aims: South Asians (SA) experience disproportionately higher rates of atherosclerotic cardiovascular disease (ASCVD) events than non-Hispanic whites (NHW) and several other Asian groups. The coronary artery calcium (CAC) Agatston score may not capture the unique characteristics of coronary plaque in SA. We therefore evaluated the prevalence and patterns of advanced CAC measures (specific coronary vessel involvement, CAC volume and density) in SA versus other race/ethnicities.

Methods: We combined data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts. We used multivariable-adjusted linear regression models to compare advanced CAC measures between SA and other ethnicities.

Results: Our analyses included 7,625 individuals (810 SA, 2,622 whites, 1,893 African Americans, 1,496 Hispanics, 803 Chinese Americans) with mean (SD) age 62 (10) years and 48% men. In adjusted analyses, compared to NHW, SA had lower overall CAC volume [beta coefficient (95% CI)] [-0.46 (-0.62,-0.29)] but higher overall CAC density [0.14 (0.11,0.18)]. These trends were similar when SA were compared to non-whites (Hispanics, Chinese Americans, and African Americans). SA had higher overall [0.07 (0.03,0.12)] and right coronary artery [0.09 (0.03,0.16)] CAC density compared to non-whites, while CAC volume was not significantly different between these two groups.

Conclusions: SA have lower CAC volume compared to NHW but similar compared to non-whites. Overall CAC density is higher among SA compared to NHW and non-whites. Future longitudinal studies of ASCVD events are required to confirm the prognostic significance of these findings among SA.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790973PMC
January 2021

Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study.

JAMA Neurol 2021 Feb;78(2):165-176

Department of Systems, Populations, and Leadership, University of Michigan, Ann Arbor.

Importance: Accurate and up-to-date estimates on incidence, prevalence, mortality, and disability-adjusted life-years (burden) of neurological disorders are the backbone of evidence-based health care planning and resource allocation for these disorders. It appears that no such estimates have been reported at the state level for the US.

Objective: To present burden estimates of major neurological disorders in the US states by age and sex from 1990 to 2017.

Design, Setting, And Participants: This is a systematic analysis of the Global Burden of Disease (GBD) 2017 study. Data on incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of major neurological disorders were derived from the GBD 2017 study of the 48 contiguous US states, Alaska, and Hawaii. Fourteen major neurological disorders were analyzed: stroke, Alzheimer disease and other dementias, Parkinson disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.

Exposures: Any of the 14 listed neurological diseases.

Main Outcome And Measure: Absolute numbers in detail by age and sex and age-standardized rates (with 95% uncertainty intervals) were calculated.

Results: The 3 most burdensome neurological disorders in the US in terms of absolute number of DALYs were stroke (3.58 [95% uncertainty interval [UI], 3.25-3.92] million DALYs), Alzheimer disease and other dementias (2.55 [95% UI, 2.43-2.68] million DALYs), and migraine (2.40 [95% UI, 1.53-3.44] million DALYs). The burden of almost all neurological disorders (in terms of absolute number of incident, prevalent, and fatal cases, as well as DALYs) increased from 1990 to 2017, largely because of the aging of the population. Exceptions for this trend included traumatic brain injury incidence (-29.1% [95% UI, -32.4% to -25.8%]); spinal cord injury prevalence (-38.5% [95% UI, -43.1% to -34.0%]); meningitis prevalence (-44.8% [95% UI, -47.3% to -42.3%]), deaths (-64.4% [95% UI, -67.7% to -50.3%]), and DALYs (-66.9% [95% UI, -70.1% to -55.9%]); and encephalitis DALYs (-25.8% [95% UI, -30.7% to -5.8%]). The different metrics of age-standardized rates varied between the US states from a 1.2-fold difference for tension-type headache to 7.5-fold for tetanus; southeastern states and Arkansas had a relatively higher burden for stroke, while northern states had a relatively higher burden of multiple sclerosis and eastern states had higher rates of Parkinson disease, idiopathic epilepsy, migraine and tension-type headache, and meningitis, encephalitis, and tetanus.

Conclusions And Relevance: There is a large and increasing burden of noncommunicable neurological disorders in the US, with up to a 5-fold variation in the burden of and trends in particular neurological disorders across the US states. The information reported in this article can be used by health care professionals and policy makers at the national and state levels to advance their health care planning and resource allocation to prevent and reduce the burden of neurological disorders.
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http://dx.doi.org/10.1001/jamaneurol.2020.4152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607495PMC
February 2021

Relation of Statin Use Prior to Admission to Severity and Recovery Among COVID-19 Inpatients.

Am J Cardiol 2020 12 16;136:149-155. Epub 2020 Sep 16.

University of California San Diego Health Moores Cancer Center, University of California San Diego, La Jolla, California; Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California.

The impact of statins, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) on coronavirus disease 2019 (COVID-19) severity and recovery is important given their high prevalence of use among individuals at risk for severe COVID-19. We studied the association between use of statin/angiotensin-converting enzyme inhibitors/ARB in the month before hospital admission, with risk of severe outcome, and with time to severe outcome or disease recovery, among patients hospitalized for COVID-19. We performed a retrospective single-center study of all patients hospitalized at University of California San Diego Health between February 10, 2020 and June 17, 2020 (n = 170 hospitalized for COVID-19, n = 5,281 COVID-negative controls). Logistic regression and competing risks analyses were used to investigate progression to severe disease (death or intensive care unit admission), and time to discharge without severe disease. Severe disease occurred in 53% of COVID-positive inpatients. Median time from hospitalization to severe disease was 2 days; median time to recovery was 7 days. Statin use prior to admission was associated with reduced risk of severe COVID-19 (adjusted OR 0.29, 95%CI 0.11 to 0.71, p < 0.01) and faster time to recovery among those without severe disease (adjusted HR for recovery 2.69, 95%CI 1.36 to 5.33, p < 0.01). The association between statin use and severe disease was smaller in the COVID-negative cohort (p for interaction = 0.07). There was potential evidence of faster time to recovery with ARB use (adjusted HR 1.92, 95%CI 0.81 to 4.56). In conclusion, statin use during the 30 days prior to admission for COVID-19 was associated with a lower risk of developing severe COVID-19, and a faster time to recovery among patients without severe disease.
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http://dx.doi.org/10.1016/j.amjcard.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492151PMC
December 2020

Associations of Poly (ADP-Ribose) Polymerase1 abundance in calf skeletal muscle with walking performance in peripheral artery disease.

Exp Gerontol 2020 10 2;140:111048. Epub 2020 Aug 2.

Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL, United States of America; Northwestern University Feinberg School of Medicine, Department of Medicine, Chicago, IL, United States of America. Electronic address:

Objective: This study investigated associations of markers of oxidative stress and mitochondrial function in calf muscle biopsies with walking performance in people with and without lower extremity peripheral artery disease (PAD).

Methods: Participants with PAD (ankle-brachial index (ABI) <0.90) and without PAD (ABI: 0.90-1.50) underwent calf muscle biopsy and measurement of 6-min walk and four-meter walking velocity. PARP1 (Poly (ADP-Ribose) Polymerase 1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), silent information regulator 1 (SIRT1) and 4-hydroxynonenal (4HNE) expression were measured in calf muscle using western blot.

Results: Among 15 participants with PAD mean age: 66.8 years (standard deviation (SD): 6.4) and six without PAD (age: 64.4 years, SD: 5.9), mean PARP1-abundance in calf muscle was 1.16 ± 0.92 AU and 0.96 ± 0.38 AU, respectively (P = 0.61). Among participants with PAD after adjustment with ABI, a greater abundance of PARP1 was associated with poorer 6-min walking distance (r = -0.65, P = 0.01), usual-paced 4-m walking velocity (r = -0.73, P = 0.003) and slower fast-paced four-meter walking velocity (r = -0.51, P = 0.07). Among participants with PAD, ABI was not associated with PARP1 abundance in calf muscle (r = 0.02, P = 0.93). Among participants without PAD, skeletal muscle PARP1 abundance was not significantly associated with 6-min walk distance (r = -0.58; P = 0.22), usual-paced walking velocity (r = -0.26; P = 0.62), or fast-paced walking velocity (r = -0.21; P = 0.69), perhaps due to lack of statistical power. There were no associations of remaining calf muscle measures with walking performance.

Conclusions: These findings are consistent with the hypothesis that calf skeletal muscle characteristics are related to walking performance, independently of severity of lower extremity arterial obstruction in people with PAD.
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http://dx.doi.org/10.1016/j.exger.2020.111048DOI Listing
October 2020

Clinical characteristics and response to supervised exercise therapy of people with lower extremity peripheral artery disease.

J Vasc Surg 2021 02 19;73(2):608-625. Epub 2020 May 19.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

Background: Among people with lower extremity peripheral artery disease (PAD), little is known about variation in response to supervised exercise therapy (SET). Clinical characteristics associated with greater responsiveness to SET have not been identified.

Methods: Data from participants with PAD in two randomized clinical trials comparing SET vs nonexercising control were combined. The exercise intervention consisted of three times weekly supervised treadmill exercise. The control groups received lectures on health-related topics.

Results: Of 309 unique participants randomized (mean age, 67.9 years [standard deviation, 9.3 years]; 132 [42.7%] women; 185 [59.9%] black), 285 (92%) completed 6-month follow-up. Compared with control, those randomized to SET improved 6-minute walk distance by 35.6 meters (95% confidence interval, 21.4-49.8; P < .001). In the 95 (62.1%) participants who attended at least 70% of SET sessions, change in 6-minute walk distance varied from -149.4 to +356.0 meters. Thirty-four (35.8%) had no 6-minute walk distance improvement. Among all participants, age, sex, race, body mass index, prior lower extremity revascularization, and other clinical characteristics did not affect the degree of improvement in 6-minute walk distance after SET relative to the control group. Participants with 6-minute walk distance less than the median of 334 meters at baseline had greater percentage improvement in 6-minute walk distance compared with those with baseline 6-minute walk distance above the median (+20.5% vs +5.3%; P for interaction = .0107).

Conclusions: Among people with PAD, substantial variability exists in walking improvement after SET. Shorter 6-minute walk distance at baseline was associated with greater improvement after SET, but other clinical characteristics, including age, sex, prior lower extremity revascularization, and disease severity, did not affect responsiveness to exercise therapy.
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http://dx.doi.org/10.1016/j.jvs.2020.04.498DOI Listing
February 2021

Correlations of Calf Muscle Macrophage Content With Muscle Properties and Walking Performance in Peripheral Artery Disease.

J Am Heart Assoc 2020 05 9;9(10):e015929. Epub 2020 May 9.

College of Health Sciences and Center for Muscle Biology University of Kentucky Lexington KY.

Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2-like macrophages positively correlated to satellite cell number (=0.461 [=0.023] and =0.416 [=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206- macrophages negatively correlated to 4-meter walk tests at normal (=-0.447, =0.036) and fast pace (=-0.510, =0.014). Extracellular matrix occupied more muscle area in PAD compared with non-PAD (8.72±2.19% versus 5.30±1.03%, <0.001) and positively correlated with capillary density (=0.656, <0.001). Conclusions Among people with PAD, higher CD206+ M2-like macrophage abundance was associated with greater satellite cell numbers and muscle fiber size. Lower CD206- macrophage abundance was associated with better walking performance. Further study is needed to determine whether CD206+ macrophages are associated with ongoing reparative processes enabling skeletal muscle adaptation to damage with PAD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: NCT00693940, NCT01408901, NCT0224660.
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http://dx.doi.org/10.1161/JAHA.118.015929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660852PMC
May 2020

Association of six-minute walk distance with subsequent lower extremity events in peripheral artery disease.

Vasc Med 2020 08 27;25(4):319-327. Epub 2020 Apr 27.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The prognostic significance of the six-minute walk distance for lower extremity events in people with peripheral artery disease (PAD) is unknown. This longitudinal study assessed whether a poorer six-minute walk distance at baseline was associated with higher rates of subsequent lower extremity atherosclerotic disease events in PAD. A total of 369 patients (mean age 69.4 ± 10.0 years; mean ankle-brachial index (ABI) 0.67 ± 0.17; 31% women; 30% black individuals) from Chicago-area medical centers with PAD were enrolled. Participants underwent baseline six-minute walk testing and returned for annual study visits. Lower extremity events consisted of one or more of the following: ABI decline greater than 15% or medical record adjudicated lower extremity revascularization, critical limb ischemia, or amputation. At a mean follow-up of 33.3 months, lower extremity events occurred in 66/123 (53.7%) people in the first (worst) tertile of six-minute walk performance, 55/124 (44.4%) in the second tertile, and 56/122 (45.9%) in the third (best) tertile. After adjusting for age, sex, race, ABI, comorbidities, and other confounders, participants in the first (worst) tertile of six-minute walk distance at baseline had higher rates of lower extremity events during follow-up, compared to those in the best tertile at baseline (HR = 1.74, 95% CI 1.17-2.60, = 0.0067). Among people with PAD, a poorer six-minute walk distance was associated with higher rates of subsequent lower extremity PAD-related events after adjusting for confounders. Further study is needed to determine whether interventions that improve six-minute walk distance can reduce lower extremity adverse events in people with PAD.
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http://dx.doi.org/10.1177/1358863X20901599DOI Listing
August 2020

Meaningful change in 6-minute walk in people with peripheral artery disease.

J Vasc Surg 2021 01 23;73(1):267-276.e1. Epub 2020 Apr 23.

Department of Epidemiology, University of Maryland, College Park, Md.

Objective: The 6-minute walk test is a common outcome measure in clinical trials of people with lower extremity peripheral artery disease (PAD). However, what constitutes a meaningful change in the 6-minute walk distance has not been well defined for people with PAD. The present study related the change in the 6-minute walk distance to the degree of participant-reported improvement or decline in the 6-minute walk distance to define a meaningful change in the 6-minute walk distance for those with PAD.

Methods: Participants with PAD from three observational longitudinal studies completed the walking impairment questionnaire (WIQ) distance score and 6-minute walk at baseline and 1 year later. The WIQ distance score measures participants' perceived difficulty walking seven different distances without stopping (ranging from walking around the home to walking 5 blocks) on a 0 to 4 Likert scale, with 0 representing an inability to walk the distance and 4 representing no difficulty. The mean changes in the 6-minute walk distance corresponding to the participants' report of no change, 1-unit change, or 2-unit change, respectively, in the Likert scale score between the baseline and 1-year follow-up measures were calculated for each WIQ distance.

Results: A total of 777 participants with PAD (mean age, 71.2 ± 8.8 years; mean baseline 6-minute walk distance, 350.1 ± 118.1 meters) completed 5439 questions about their difficulty walking each WIQ distance at baseline and follow-up. Participants with PAD who reported no change in their difficulty in walking each WIQ distance between baseline and follow-up had a decline of 7.2 meters (95% confidence interval [CI], -11.6 to -2.8 meters) in the 6-minute walk test. Relative to those reporting no change in difficulty walking, the participants reporting 1- and 2-point improvements in walking ability showed 6-minute walk distance improvements of 7.8 meters (95% CI, -0.3 to 15.9 meters) and 20.1 meters (95% CI, 1.1-39.2 meters), respectively. Relative to those reporting no change in walking difficulty, those reporting 1- and 2-point declines in perceived walking difficulty showed declines of -11.2 meters (95% CI, -19.0 to -3.4 meters) and -23.8 meters (95% CI, -37.4 to -10.3 meters) in the 6-minute walk distance.

Conclusions: Among people with PAD, ∼8- and ∼20-meter improvements in the 6-minute walk distance represent small and large improvements in walking ability, respectively. People with PAD who reported no change in their ability to walk distances over 1 year simultaneously declined by a mean of 7 meters in the 6-minute walk test. These findings will be useful for interpreting the results from randomized trials of interventions to improve the walking performance of people with PAD.
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http://dx.doi.org/10.1016/j.jvs.2020.03.052DOI Listing
January 2021

Associations of abdominal muscle area and density with coronary artery calcium volume and density: The multi-ethnic study of atherosclerosis.

Metabolism 2020 06 13;107:154230. Epub 2020 Apr 13.

Department of Family Medicine and Public Health, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0965, United States of America. Electronic address:

Background: Due to the opposing cardiovascular risk profiles of CAC volume and density, we tested the hypothesis that increased abdominal muscle area (AMA) and density (AMD) were significantly associated with lower coronary arterial calcium (CAC) volume and higher CAC density.

Methods: Using data from 787 participants from the Multi-Ethnic Study of Atherosclerosis, Ancillary Body Composition Study, we analyzed abdominal and chest computed tomography (CT) scans. Abdominal scans were scored for muscle area, muscle density (attenuation) and visceral and subcutaneous fat. Chest scans were scored for CAC volume and Agatston values, which were used to derive CAC density scores.

Results: The mean (SD) age and BMI of the participants was 67.8 (9.0) years and 27.9 (4.8) kg/m, respectively. Forty-one percent were female, 46% were Caucasian, 60% had hypertension, 17% had diabetes, and 46% had dyslipidemia. AMA was positively associated with CAC volume (p < .001) and inversely associated with CAC density (p < .001). Conversely, AMD was inversely associated with CAC volume and positively associated with CAC density in minimally adjusted models (p < .001), but not significant in confounder adjusted models.

Conclusion: AMA and AMD had differing associations with CAC volume and density, with AMA significantly associated with a higher risk CAC profile (high volume, low density) and AMD not significantly associated with CAC volume or density. Future research needs to account for the unique components of both muscle composition and CAC.
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http://dx.doi.org/10.1016/j.metabol.2020.154230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986552PMC
June 2020

Burden of Peripheral Artery Disease on Mortality and Incident Cardiovascular Events.

Am J Epidemiol 2020 09;189(9):951-962

Using data from the Multi-Ethnic Study of Atherosclerosis (United States, 2000-2015), 6,527 racially/ethnically diverse adults (mean age, 62 (standard deviation, 10) years) free of known cardiovascular (CVD) had ankle brachial index (ABI) assessment of their bilateral dorsalis pedis/posterior tibial arteries (4 vessels total) and were followed for total mortality and incident CVD events/mortality. Individuals were classified into categories of 0-, 1-, 2-, 3- or 4-vessel peripheral artery disease (PAD) (ABI of ≤0.9). There were 1,202 deaths (18%), 656 incident CVD events (10%), and 282 CVD deaths (4.3%). Of the 6,527 individuals, 5,711 (87.5%) had 0-, 460 (7.0%) had 1-, 218 (3.3%) had 2-, 69 (1.1%) had 3-, and 69 (1.1%) had 4-vessel PAD, respectively. In multivariable Cox models, higher number of vessels with PAD was associated with higher risk of mortality (P for trend <0.001), CVD events (P for trend = 0.002), and CVD mortality (P for trend = 0.001). Compared with individuals who had 0-vessel disease, hazard ratios for mortality were 1.29 (95% confidence interval (CI): 1.06, 1.59) for 1-, 1.45 (95% CI: 1.14, 1.86) for 2-, 1.58 (95% CI: 1.13, 2.21) for 3-, and 2.15 (95% CI: 1.58, 2.94) for 4-vessel disease. A similar pattern was seen for CVD events/mortality. These results suggest the importance of accounting for ABI values of all 4 leg arteries in clinical practice and research.
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http://dx.doi.org/10.1093/aje/kwaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607965PMC
September 2020

Associations of Perirenal Fat Thickness with Renal and Systemic Calcified Atherosclerosis.

Endocrinol Metab (Seoul) 2020 03;35(1):122-131

Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.

Background: We investigated associations between perirenal fat thickness and atherosclerotic calcification in six different vascular beds.

Methods: Using a community-based cohort (=3,919), perirenal fat thickness was estimated from computed tomography scans. It was classified as Q1 (the lowest quartile) to Q4 (the highest quartile) in each sex. Calcification in the carotid arteries, coronary arteries, thoracic aorta, abdominal aorta, iliac arteries, and renal arteries was evaluated.

Results: Perirenal fat thickness was associated with older age (<0.01) and a higher prevalence of obesity, hypertension, and dyslipidemia (<0.01 for all). Perirenal fat thickness was independently associated with renal arterial calcification even after adjustment for age, sex, body mass index, hypertension, dyslipidemia, smoking history, and family history of heart diseases in first-degree relatives (odds ratio [OR] per quartile of perirenal fat thickness, 1.25; 95% confidence interval [CI], 1.09 to 1.44). Compared to Q1, the odds of renal arterial calcification in Q4 was about two times higher (OR, 2.05; 95% CI, 1.29 to 3.25). After adjustment for renal arterial calcification and atherosclerotic risk factors, the only other vascular bed where perirenal fat thickness showed a significant association with calcification was the abdominal aorta (OR, 1.11; 95% CI, 1.00 to 1.23; =0.045).

Conclusion: Perirenal fat thickness was independently associated with vascular calcification in the renal artery and abdominal aorta.
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http://dx.doi.org/10.3803/EnM.2020.35.1.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090296PMC
March 2020

Associations of Peripheral Artery Disease With Calf Skeletal Muscle Mitochondrial DNA Heteroplasmy.

J Am Heart Assoc 2020 04 21;9(7):e015197. Epub 2020 Mar 21.

National Institutes on Health National Institute on Aging Baltimore MD.

Background Patients with peripheral artery disease (PAD) undergo frequent episodes of ischemia-reperfusion in lower extremity muscles that may negatively affect mitochondrial health and are associated with impaired mobility. We hypothesized that skeletal muscle from PAD patients will show high mitochondrial DNA heteroplasmy, especially in regions more susceptible to oxidative damage, such as the displacement loop, and that the degree of heteroplasmy will be correlated with the severity of ischemia and mobility impairment. Methods and Results Mitochondrial mutations and deletions and their relative abundance were identified by targeted mitochondrial DNA sequencing in biopsy specimens of gastrocnemius muscle from 33 PAD (ankle brachial index <0.9) and 9 non-PAD (ankle brachial index >0.9) subjects aged ≥60 years. The probability of heteroplasmy per DNA base was significantly higher for PAD subjects than non-PAD within each region. In adjusted models, PAD was associated with higher heteroplasmy than non-PAD (=0.003), but the association was limited to microheteroplasmy, that is heteroplasmy found in 1% to 5% of all mitochondrial genomes (=0.004). Heteroplasmy in the displacement loop and coding regions were significantly higher for PAD than non-PAD subjects after adjustment for age, sex, race, and diabetes mellitus (=0.037 and 0.004, respectively). Low mitochondrial damage, defined by both low mitochondrial DNA copy number and low microheteroplasmy, was associated with better walking performance. Conclusions People with PAD have higher "low frequency" heteroplasmy in gastrocnemius muscle compared with people without PAD. Among people with PAD, those who had evidence of least mitochondrial damage, had better walking performance than those with more mitochondrial damage. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02246660.
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http://dx.doi.org/10.1161/JAHA.119.015197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428597PMC
April 2020

Sedentary time and peripheral artery disease: The Hispanic Community Health Study/Study of Latinos.

Am Heart J 2020 04 8;222:208-219. Epub 2020 Feb 8.

University of California San Diego, La Jolla, CA, USA.

Background: Experimental evidence suggests that sedentary time (ST) may contribute to cardiovascular disease by eliciting detrimental hemodynamic changes in the lower limbs. However, little is known about objectively measured ST and lower extremity peripheral artery disease (PAD).

Methods: We included 7,609 Hispanic/Latinos (ages 45-74) from the Hispanic Community Health Study/Study of Latinos. PAD was measured using the ankle brachial index (≤0.9). ST was measured using accelerometry. We used multivariable logistic regression to assess associations of quartiles of ST and PAD, and then used the same logistic models with restricted cubic splines to investigate continuous nonlinear associations of ST and PAD. Models were sequentially adjusted for traditional PAD risk factors, leg pain, and moderate- to vigorous-intensity physical activity (MVPA).

Results: Median ST was 12.2 h/d, and 5.4% of individuals had PAD. In fully adjusted restricted cubic splines models accounting for traditional PAD risk factors, leg pain, and MVPA, ST had a significant overall (P = .048) and nonlinear (P = .024) association with PAD. A threshold effect was seen such that time spent above median ST was associated with higher odds of PAD. That is, compared to median ST, 1, 2, and 3 hours above median ST were associated with a PAD odds ratio of 1.16 (95% CI = 1.02-1.31), 1.44 (1.06-1.94), and 1.80 (1.11-2.90), respectively.

Conclusions: Among Hispanic/Latino adults, ST was associated with higher odds of PAD, independent of leg pain, MVPA, and traditional PAD risk factors. Notably, we observed a threshold effect such that these associations were only observed at the highest levels of ST.
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http://dx.doi.org/10.1016/j.ahj.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085461PMC
April 2020

Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial.

Circ Res 2020 02 14;126(5):589-599. Epub 2020 Feb 14.

Department of Health Research and Policy, Stanford University, CA (L.T.).

Rationale: Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD).

Objective: In a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo.

Methods And Results: Six-month double-blind, randomized clinical trial in which participants with PAD were randomized to either cocoa beverage versus placebo beverage. The cocoa beverage contained 15 g of cocoa and 75 mg of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The 2 primary outcomes were 6-month change in 6-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A 1-sided <0.10 was considered statistically significant. Of 44 PAD participants randomized (mean age, 72.3 years [±7.1]; mean ankle brachial index, 0.66 [±0.15]), 40 (91%) completed follow-up. Adjusting for smoking, race, and body mass index, cocoa improved 6-minute walk distance at 6-month follow-up by 42.6 m ([90% CI, +22.2 to +∞] =0.005) at 2.5 hours after a final study beverage and by 18.0 m ([90% CI, -1.7 to +∞] =0.12) at 24 hours after a study beverage, compared with placebo. In calf muscle biopsies, cocoa improved mitochondrial COX (cytochrome c oxidase) activity (=0.013), increased capillary density (=0.014), improved calf muscle perfusion (=0.098), and reduced central nuclei (=0.033), compared with placebo.

Conclusions: These preliminary results suggest a therapeutic effect of cocoa on walking performance in people with PAD. Further study is needed to definitively determine whether cocoa significantly improves walking performance in people with PAD.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02876887. Visual Overview: An online visual overview is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141749PMC
February 2020

The Importance of Coronary Artery Calcium Density.

JAMA Cardiol 2020 03;5(3):290-291

Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, School of Medicine, San Diego.

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http://dx.doi.org/10.1001/jamacardio.2019.5745DOI Listing
March 2020

Comparing 6-minute walk versus treadmill walking distance as outcomes in randomized trials of peripheral artery disease.

J Vasc Surg 2020 03 23;71(3):988-1001. Epub 2019 Dec 23.

Intramural Research Program, National Institute on Aging, Baltimore, Md.

Background: Randomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD.

Methods: Data from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol.

Results: Of 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (-10.2 m; 95% confidence interval, -18.2 to -2.2; P = .013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P = .010; difference between change in 6-minute walk versus maximal treadmill walking distance: -37.3 m; 95% CI, -56.4 to -18.2; P < .001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P = .048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P < .001), suggesting a benefit from treadmill training on the treadmill outcome.

Conclusions: Maximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon.
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http://dx.doi.org/10.1016/j.jvs.2019.05.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141750PMC
March 2020

Associations of recreational and non-recreational physical activity with coronary artery calcium density vs. volume and cardiovascular disease events: the Multi-Ethnic Study of Atherosclerosis.

Eur Heart J Cardiovasc Imaging 2020 02;21(2):132-140

Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, 9500 Gilman Dr. La Jolla, CA 92093, USA.

Aims: The benefits of physical activity (PA) on cardiovascular disease (CVD) are well known. However, studies suggest PA is associated with coronary artery calcium (CAC), a subclinical marker of CVD. In this study, we evaluated the associations of self-reported recreational and non-recreational PA with CAC composition and incident CVD events. Prior studies suggest high CAC density may be protective for CVD events.

Methods And Results: We evaluated 3393 participants of the Multi-Ethnic Study of Atherosclerosis with prevalent CAC. After adjusting for demographics, the highest quintile of recreational PA was associated with 0.07 (95% confidence interval 0.01-0.13) units greater CAC density but was not associated with CAC volume. In contrast, the highest quintile of non-recreational PA was associated with 0.08 (0.02-0.14) units lower CAC density and a trend toward 0.13 (-0.01 to 0.27) log-units higher CAC volume. There were 520 CVD events over a 13.7-year median follow-up. Recreational PA was associated with lower CVD risk (hazard ratio 0.88, 0.79-0.98, per standard deviation), with an effect size that was not changed with adjustment for CAC composition or across levels of prevalent CAC.

Conclusion: Recreational PA may be associated with a higher density but not a higher volume of CAC. Non-recreational PA may be associated with lower CAC density, suggesting these forms of PA may not have equivalent associations with this subclinical marker of CVD. While PA may affect the composition of CAC, the associations of PA with CVD risk appear to be independent of CAC.
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http://dx.doi.org/10.1093/ehjci/jez271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850103PMC
February 2020

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Nat Genet 2019 11 28;51(11):1580-1587. Epub 2019 Oct 28.

National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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http://dx.doi.org/10.1038/s41588-019-0514-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858575PMC
November 2019

Clinical Characteristics and Outcomes of Patients With Heart Failure and Methamphetamine Abuse.

J Card Fail 2020 Mar 13;26(3):202-209. Epub 2019 Oct 13.

Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California.

Background: Despite a global epidemic of methamphetamine abuse, methamphetamine-associated heart failure (MethHF) remains poorly understood. We sought to evaluate characteristics and outcomes for patients with MethHF.

Methods: We reviewed the electronic health records of the University of California, San Diego, from 2005 to 2016. We compared characteristics and outcomes between 896 patients with MethHF and 20,576 patients with heart failure (HF) identified using diagnosis codes, urine toxicology, and natriuretic peptides.

Results: Compared with HF, patients with MethHF were younger (50±10 vs 67±16 years), predominantly male (72% vs 54%), and had more psychiatric and substance use comorbidities, including mood/anxiety disorders (29% vs 16%) and opioid use (44% vs 7%). MethHF had a higher 5-year HF readmission rate (64±4% vs 45±1%; hazard ratio [HR] 1.53, P < .001) and a lower 10-year total mortality rate (25±3% vs 28±1%; HR 0.85, P = .09). Predictors of poor outcomes included mood/anxiety disorders (HF readmission HR 1.41, P = .04) and opioid abuse (mortality HR 1.52, P = .04).

Conclusions: Patients with MethHF are frequently encumbered by psychiatric and substance abuse comorbidities, and carry a substantial risk of HF readmission and mortality. Comprehensive efforts are needed to stem this emerging epidemic.
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http://dx.doi.org/10.1016/j.cardfail.2019.10.002DOI Listing
March 2020

Variants Associated with the Ankle Brachial Index Differ by Hispanic/Latino Ethnic Group: a genome-wide association study in the Hispanic Community Health Study/Study of Latinos.

Sci Rep 2019 08 6;9(1):11410. Epub 2019 Aug 6.

Applied Sciences, Premier, Inc, Charlotte, NC, USA.

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10) for PAD in MESA Hispanics. Among three suggestive associations (p < 10) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.
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http://dx.doi.org/10.1038/s41598-019-47928-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684818PMC
August 2019

The Impact of Substance Abuse on Heart Failure Hospitalizations.

Am J Med 2020 02 29;133(2):207-213.e1. Epub 2019 Jul 29.

Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego. Electronic address:

Background: The burden of substance abuse among patients with heart failure and its association with subsequent emergency department visits and hospital admissions are poorly characterized.

Methods: We evaluated the medical records of patients with a diagnosis of heart failure treated at the University of California-San Diego from 2005 to 2016. We identified substance abuse via diagnosis codes or urine drug screens. We used Poisson regression to evaluate the incidence rate ratios (IRR) of substance abuse for emergency department visits or hospitalizations with a primary diagnosis of heart failure, adjusted for age, sex, race, medical insurance status, and medical diagnoses.

Results: We identified 11,268 patients with heart failure and 15,909 hospital encounters for heart failure over 49,712 person-years of follow-up. Substance abuse was diagnosed in 15.2% of patients. Disorders such as methamphetamine abuse (prevalence 5.2%, IRR 1.96, 95% confidence interval [CI] 1.85-2.07), opioid use and abuse (8.2%, IRR 1.54, 95% CI 1.47-1.61), and alcohol abuse (4.5%, IRR 1.51, 95% CI 1.42-1.60) were associated with a greater number of hospital encounters for heart failure, with associations that were comparable to diagnoses such as atrial fibrillation (37%, IRR 1.78, 95% CI 1.73-1.84), ischemic heart disease (24%, IRR 1.67, 95% CI 1.62-1.73), and chronic kidney disease (26%, IRR 1.57, 95% CI 1.51-1.62).

Conclusions: Although less prevalent than common medical comorbidities in patients with heart failure, substance-abuse disorders are significant sources of morbidity that are independently associated with emergency department visits and hospitalizations for heart failure. Greater recognition and treatment of substance abuse may improve outcomes among patients with heart failure.
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http://dx.doi.org/10.1016/j.amjmed.2019.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980459PMC
February 2020

Associations of Weight Change With Changes in Calf Muscle Characteristics and Functional Decline in Peripheral Artery Disease.

J Am Heart Assoc 2019 07 29;8(13):e010890. Epub 2019 Jun 29.

3 Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL.

Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle-brachial index <0.90 were identified from Chicago-area hospitals in 2002-2004. Weight and 6-minute walk distance were measured annually. Weight change categories were weight loss or gain (≥5 pounds/year at ≥1 visit) or stable (weight change <5 pounds at each visit). Participants reported whether weight loss was "intentional" or "unintentional." Calf muscle area was measured with computed tomography every 2 years. Associations of weight change with changes in calf muscle area and 6-minute walk distance were analyzed using mixed-effects models and adjusted for age, body mass index, ankle-brachial index, physical activity, and other confounders. Among 389 participants, mean ankle-brachial index was 0.63±0.16, mean age was 74.5±7.8, and mean body mass index was 28.1±5.1 kg/m. Over 3.23±1.37 years, muscle area declined more in adults with intentional weight loss versus stable or gain (pair-wise comparisons, P<0.001). Intentional weight loss was associated with less annual decline in 6-minute walk distance than weight gain (intentional loss, 3.7 m; stable, -14.0 m; gain, -28.5 m; unintentional loss, -20.8 m; pair-wise comparison intentional loss versus gain, P=0.003). Conclusions Despite a greater loss of calf muscle area, adults with peripheral artery disease who intentionally lost ≥5 pounds experienced less functional decline than those who gained weight. A randomized trial is needed to establish whether benefits of weight loss in peripheral artery disease outweigh potential adverse effects.
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http://dx.doi.org/10.1161/JAHA.118.010890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662373PMC
July 2019

The association between liver fat and systemic calcified atherosclerosis.

J Vasc Surg 2020 01 29;71(1):204-211.e4. Epub 2019 May 29.

Department of Family Medicine and Public Health, University of California San Diego, La Jolla, Calif.

Background: The association of nonalcoholic fatty liver disease (NAFLD) with systemic calcified atherosclerosis, other than the coronary arteries, has not been clearly elucidated. We investigated the association between NAFLD and calcification in eight different vascular beds.

Methods: In a community-based cohort with computed tomography scans for carotid artery, coronary artery, thoracic aorta, abdominal aorta, iliac artery, renal artery, celiac trunk, and superior mesenteric artery, the association between NAFLD and arterial calcification was evaluated with adjustment for age, sex, hypertension, dyslipidemia, diabetes, obesity, current smoking status, and family history of heart disease in the first-degree relatives.

Results: In age- and sex-adjusted models, NAFLD was significantly associated with calcification in the coronary artery, carotid artery, thoracic aorta, celiac trunk, and superior mesenteric artery vascular beds (P < .05). However, adjustment for the traditional chronic venous disease risk factors attenuated the associations, except in the case of the thoracic aorta (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.09-1.78) and celiac trunk (OR, 2.05; 95% CI, 1.16-3.65). In addition, NAFLD was independently associated with multiarterial calcification (four or more [OR, 1.33; 95% CI, 1.01-1.74], five or more [OR, 1.46; 95% CI, 1.09-1.97], and six or more [OR, 1.58; 95% CI, 1.09-2.30] of eight evaluated arterial segments).

Conclusions: The association between NAFLD and arterial calcification is mainly mediated by conventional risk factors. The independent association between NAFLD and calcification in the thoracic aorta and celiac trunk as well as in a larger number of vascular beds needs confirmation in future prospective studies in diverse populations.
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http://dx.doi.org/10.1016/j.jvs.2019.03.044DOI Listing
January 2020

Racial Differences in the Effect of Granulocyte Macrophage Colony-Stimulating Factor on Improved Walking Distance in Peripheral Artery Disease: The PROPEL Randomized Clinical Trial.

J Am Heart Assoc 2019 01;8(2):e011001

10 Department of Surgery University of North Carolina Charlotte NC.

Background The effects of race on response to medical therapy in people with peripheral artery disease ( PAD ) are unknown. Methods and Results In the PROPEL (Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD) Trial, PAD participants were randomized to 1 of 4 groups for 6 months: supervised treadmill exercise+granulocyte-macrophage colony-stimulating factor ( GM - CSF ) (Group 1), exercise+placebo (Group 2), attention control+ GM - CSF (Group 3), or attention control+placebo (Group 4). Change in 6-minute walk distance was measured at 12- and 26-week follow-up. In these exploratory analyses, groups receiving GM - CSF (Groups 1 and 3), placebo (Groups 2 and 4), exercise (Groups 1 and 2), and attention control (Groups 2 and 4) were combined, maximizing statistical power for studying the effects of race on response to interventions. Of 210 PAD participants, 141 (67%) were black and 64 (30%) were white. Among whites, GM - CSF improved 6-minute walk distance by +22.0 m (95% CI : -4.5, +48.5, P=0.103) at 12 weeks and +44.4 m (95% CI : +6.9, +82.0, P=0.020) at 26 weeks, compared with placebo. Among black participants, there was no effect of GM - CSF on 6-minute walk distance at 12-week ( P=0.26) or 26-week (-5.0 m [-27.5, +17.5, P=0.66]) follow-up, compared with placebo. There was an interaction of race on the effect of GM - CSF on 6-minute walk change at 26-week follow-up ( P=0.018). Exercise improved 6-minute walk distance in black ( P=0.006) and white ( P=0.034) participants without interaction. Conclusions GM - CSF improved 6-minute walk distance in whites with PAD but had no effect in black participants. Further study is needed to confirm racial differences in GM - CSF efficacy in PAD . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01408901.
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http://dx.doi.org/10.1161/JAHA.118.011001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497365PMC
January 2019
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