scholarly journals P1234SNF472 IMPROVES LIMB BLOOD PERFUSION AND WALKING ABILITY IN A PERIPHERAL ARTERY DISEASE VASCULAR CALCIFICATION RAT MODEL

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Firas Bassissi ◽  
Miguel David Ferrer Reynes ◽  
M Mar Pérez ◽  
Joan Perelló ◽  
Carolina Salcedo
Keyword(s):  
Peripheral Artery Disease ◽  
Vascular Calcification ◽  
Rat Model ◽  
Blood Perfusion ◽  
Walking Distance ◽  
Arterial Calcification ◽  
Walking Ability ◽  
Peripheral Artery ◽  
Increased Risk ◽  
Artery Disease

Abstract Background and Aims Peripheral Artery disease (PAD) is a common vascular disease associated with functional impairment and increased risk of cardiovascular events in End Stage Kidney Disease (ESKD) patients undergoing dialysis. Poor limb salvage outcomes and high post-amputation mortality in hemodialysis (HD) patients highlight the need for earlier medical therapies. Cilostazol and pentoxifylline are approved for PAD. Their use in HD patients stays limited and cilostazol use requires caution in this population. Clinical studies demonstrate associations between arterial calcification and adverse outcomes in PAD patients. SNF472, a selective calcification inhibitor that interferes in the formation and growth of hydroxyapatite, is in Phase 3 for calciphylaxis treatment. This study aims to evaluate the effects of SNF472 on limb functional recovery and blood perfusion in a Vitamin D3 (VitD)-induced arterial calcification rat model. Method Arterial calcification was induced in 32 Sprague Dawley rats by 3 consecutive daily s.c. doses of 120 kIU/kg VitD. Rats were divided into four groups and treated during 12 days by: placebo s.c, placebo p.o, SNF472 (20 mg/kg/day, s.c.) or cilostazol (20 mg/kg/day, p.o.). An additional group of 8 rats without VitD received vehicle only (sham). Efficacy was evaluated at day 12 and 17 (5 days after treatment stop). Posterior limb blood perfusion was measured using Laser Doppler Imaging and limb walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a treadmill. Rats were sacrificed at day 26 (14 days after treatment stop), and aortas were collected for calcium analysis. Results VitD-induced arterial calcification was associated with decreased blood perfusion and impairment of limb walking ability (MWT and MWD) compared to sham. SNF472 reduced aorta calcification by 41% compared to placebo. No effects of cilostazol on vascular calcification were observed. The inhibition of calcification in SNF472-treated animals was associated with significant higher limb blood perfusion compared to placebo or Cilostazol (1.28 and 1.37-fold higher, respectively at day 12: p< 0.001) and it was translated into a significant improvement in walking ability compared to placebo (515±114 meters vs 334±187 meters, respectively: p<0.05). Conclusion SNF472 shows improvements in vascular calcification, blood perfusion and a functional parameter like walking distance in a PAD vascular calcification rat model. These results suggest that SNF472 may represent a new therapeutic approach for the treatment of PAD associated with high vascular calcification such as in renal disease.

FC 107SNF472 ATTENUATES THE PROGRESSION OF FEMORAL ARTERY CALCIFICATION AND RECOVERS LIMB BLOOD PERFUSION AND WALKING ABILITY IN A RAT MODEL OF PERIPHERAL ARTERY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Firas Bassissi ◽  
Miguel David Ferrer Reynes ◽  
M Mar Pérez ◽  
Marc Blasco ◽  
Joan Perelló ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Femoral Artery ◽  
Rat Model ◽  
Blood Perfusion ◽  
Limb Ischemia ◽  
Arterial Calcification ◽  
Walking Ability ◽  
Peripheral Artery ◽  
Femoral Arteries ◽  
Artery Disease

Abstract Background and Aims Peripheral artery disease (PAD) is a common co-morbidity in end-stage kidney disease (ESKD) patients undergoing dialysis. The prominent vascular calcification in these patients is associated with severity of symptoms and adverse outcomes. Although there are medical therapies approved for PAD, none of them has been specifically approved por PAD-ESKD. For example, cilostazol is approved for PAD but its use is limited in PAD-ESKD patients. Surgical interventions are challenging in these patients due to their specific vascular calcification and show worse outcomes. Therefore, the aims of this study were to evaluate the effects of the investigational drug SNF472, a selective inhibitor of vascular calcification, on blood perfusion and limb functional recovery in a Vitamin D3 (VitD)-induced rat model of arterial calcification and limb ischemia. Method Three consecutives daily subcutaneous (s.c) doses of VitD were administered to 66 male Sprague Dawley rats to induce limb ischemia. Rats were randomized into four groups at day 5 after the start of VitD treatment (when all parameters were measured in a satellite group) and were treated for nine days with placebo s.c., placebo peroral (p.o.), SNF472 (40 mg/kg/day, s.c.) or cilostazol (40 mg/kg/day, p.o.). An additional control group did not receive VitD (sham) and was administered with placebo s.c. during these last nine days. Posterior limb blood perfusion was measured using laser Doppler imaging at baseline (before calcification induction), day 4 (before treatment start) and day 13 (end of treatment). Walking ability was evaluated by measuring Maximum Walking Distance (MWD) and Maximum Walking Time (MWT) using a rat treadmill at baseline, day 4 and day 11. Rats were sacrificed at day 13, and heart and femoral arteries were collected for calcium analysis. Results Administration of VitD induced heart and femoral artery calcification by day 5. This calcification was associated with decreased limb blood perfusion and impairment of walking ability (both MWT and MWD) compared to sham. Treatment with SNF472 inhibited calcification progression in femoral arteries by 41% and in heart by 56% compared to placebo. The inhibition of calcification progression by SNF472 led to a 29% increase in limb blood perfusion (p< 0.001) and a significant improvement in walking ability (49% in MWD and 43% in MWT; p< 0.05) compared to placebo. Calcification inhibition in femoral arteries was positively correlated with both MWD and MWT (p< 0.0001). No effects of cilostazol were observed in tissue calcification, limb blood perfusion or walking ability. Conclusion SNF472 attenuates the progression of vascular calcification and improves blood perfusion and the functional parameters MWT and MWD in a rat model of PAD vascular calcification. These results support investigation of SNF472 as a potential therapy for PAD-ESKD patients who have vascular dysfunction due to a high degree of arterial calcification.

scholarly journals Don’t stop walking: an in-home rehabilitation program for peripheral artery disease patients during the COVID-19 pandemic.

2020 ◽  
Author(s):  
Nicola Lamberti ◽  
Sofia Straudi ◽  
Roberto Manfredini ◽  
Alfredo De Giorgi ◽  
Vincenzo Gasbarro ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Ankle Brachial Index ◽  
Exercise Program ◽  
Rehabilitation Program ◽  
Walking Distance ◽  
Walking Ability ◽  
Peripheral Artery ◽  
Walking Program ◽  
External Conditions ◽  
Artery Disease

Abstract Aims: We studied the outcomes of peripheral artery disease (PAD) patients enrolled in a structured in-home walking program before the lockdown due to the SARS-CoV-2 epidemic emergency, to determine whether this intervention ensured the maintenance of mobility in the case of strict movement restrictions.Methods: We considered 83 patients (age 72±11, males n=65) enrolled in a rehabilitation program based on two daily 8-minute sessions of slow intermittent in-home walking at a prescribed cadence with circa-monthly hospital visits. During the lockdown period, the program was updated by phone. The 6-minute (6MWD) and pain-free walking distance (PFWD) were measured pre- and postlockdown. Body weight (BW), blood pressure (BP), and the ankle-brachial index (ABI) were also determined.Results: Sixty-six patients were measured 117±23 days after their previous visit. A safe, pain-free execution the prescribed sessions, with a median distance covered of 74 km, was reported. Overall, the 6MWD was stable, while PFWD improved (p<0.001). Decreased BW with stable BP and ABI values were also recorded. When considering the outcome values according to the time of enrollment before the lockdown, new-entry subjects (≤3 months; n=35) obtained significant improvements, while those previously enrolled (>3 months; n= 31) were stable.Conclusion: In PAD patients, a structured exercise program easily performed in a home corridor and guided with phone assistance was adhered to by patients and showed effectiveness in maintaining mobility and risk factor control during the COVID-19 pandemic. Safe structured exercise may involve frail subjects regardless of walking ability, type of home and external conditions.

Abstract 251: Effects of n-3 Fatty Acids Supplementation on Endothelial Function and Inflammation in Peripheral Artery Disease: The OMEGA-PAD Trial

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Marlene Grenon ◽  
Christopher Owens ◽  
Hugh Alley ◽  
Karen Chong ◽  
Priscilla Yen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endothelial Function ◽  
San Francisco ◽  
Peripheral Artery Disease ◽  
Ankle Brachial Index ◽  
Walking Distance ◽  
Omega 3 ◽  
Peripheral Artery ◽  
Increased Risk ◽  
Artery Disease

Background Patients with peripheral artery disease (PAD) have an increased risk for cardiovascular events, likely related to inflammation and impaired endothelial function. n-3 polyunsaturated fatty acids (n3-PUFAs) have been shown to improve endothelial function and reduce inflammation in other cohorts. We hypothesized that n3-PUFAs would improve endothelial function and the inflammatory profile in patients with PAD. Methods This is a randomized, double-blind, placebo-controlled trial: the OMEGA-PAD trial ( NCT01310270 ). Eighty patients aged 50 and more with intermitted claudication and an ankle-brachial index (ABI) of <0.9 presenting to vascular surgery clinic at the Veterans Affairs Medical Center in San Francisco will be randomized to n3-PUFAs 2.2 g orally twice daily (total of 4.4gm/day) or a matched placebo for 1 month. Outcome measurements are done at baseline and after 1 month. The primary endpoint is a change in endothelial function measured by brachial artery flow mediated, endothelium-dependent vasodilation (FMD). Secondary endpoints include a change in inflammatory markers (C-reactive protein, IL-6, sICAM-1 and TNF-α), improvement in lipid profile (LDL, triglycerides, HDL), blood pressure and walking distance by questionnaire. The omega-3 index will be measured to ensure physiological treatment effect. Results Recruitment for the OMEGA-PAD trial started in April 2011. Fifty male veterans have been enrolled and randomized. The mean age is 67 ± 9 years. Mean index limb ABI is 0.8 ± 0.2. CAD is present in 36%, hypertension in 92%, and diabetes mellitus in 32%. 47% are current smokers and 45% are former smokers. Mean HgA1c is 8±1, LDL 93±37 mg/dL, triglycerides 160±98 mg/dL and HDL 43 ±12 mg/dL. Baseline brachial FMD is 7±4% indicating an overall impairment of endothelial function in this cohort. The inflammatory burden of this cohort is substantial as evidenced by hsCRP 5±5 mg/L. The baseline omega-3 index is 5±2%. Conclusions The OMEGA-PAD trial will test the novel hypothesis that n3-PUFAs supplementation improves functional and inflammatory parameters in a cohort at high vascular risk. The results of this study will provide valuable mechanistic insight into PUFAs as well as inform on this class of agents for cardiovascular outcome trials.

Novel Oral Anticoagulants in Peripheral Artery Disease: Current Evidence

2019 ◽  
Vol 24 (38) ◽  
pp. 4511-4515 ◽  
Author(s):  
A. Koutsoumpelis ◽  
C. Argyriou ◽  
K.M. Tasopoulou ◽  
E.I. Georgakarakos ◽  
G.S. Georgiadis
Keyword(s):  
Peripheral Artery Disease ◽  
Oral Anticoagulants ◽  
Novel Oral Anticoagulants ◽  
Current Evidence ◽  
Peripheral Artery ◽  
Cardiac Events ◽  
Traditional Therapy ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Artery Disease

Background: Peripheral artery disease is a common manifestation of systemic atherosclerosis which strongly correlates to cardiovascular morbidity and mortality. In addition, the progression of peripheral artery disease leads to an increased risk of limb loss. In order to reduce these events, the benchmark of treatment and research over the last years has been the antiplatelet therapy which aims at inhibition of platelet aggregation. Over the last years, new studies combining antiplatelet agents in different therapeutic schemes have been proven efficacious. Unfortunately, patients remain still at high risk of CV events. Novel Oral Anticoagulants have been introduced as alternatives to warfarin, in the prevention and treatment of venous thromboembolism. The rationale of using medication which acts on platelet activation and the coagulation pathway of thrombosis has led investigators to examine the role of Noac's in preventing CV events in patients with peripheral artery disease, stable or unstable. Methods: The aim of this study is to review the current evidence with respect to recently published studies concerning the use of Novel anticoagulants in peripheral artery disease. Results: The Compass trial has shown that a combination of rivaroxaban with traditional therapy may produce promising results in reducing amputation rates, stroke, cardiac events, and mortality, however, there are still safety issues with bleeding requiring acute care. The ePAD study has provided us with insight concerning safety and efficacy after peripheral angioplasty or stenting and actually the need for further research. The Voyager Pad study, following the steps of Compass, is studying the effect and safety of the addition of rivaroxaban to traditional therapy in the highest risk population aka patients undergoing peripheral revascularization. The evidence concerning patients with concomitant atrial fibrillation appears to be insufficient, however, recent guidelines propose the use of novel oral anticoagulants. Conclusion: For the time being, novel oral anticoagulants in combination with aspirin may provide an alternative treatment in PAD, however, it is deemed necessary to identify patient subgroups who will benefit the most.

Individual Differences in Response to Supervised Exercise Therapy for Peripheral Artery Disease

2020 ◽  
pp. 019394592097747
Author(s):  
Mary O. Whipple ◽  
Erica N. Schorr ◽  
Kristine M.C. Talley ◽  
Julian Wolfson ◽  
Ruth Lindquist ◽  
...  
Keyword(s):  
Older Adults ◽  
Peripheral Artery Disease ◽  
Exercise Therapy ◽  
Poor Response ◽  
Walking Distance ◽  
Peripheral Artery ◽  
Meaningful Improvement ◽  
Supervised Exercise ◽  
Patient Reported ◽  
Artery Disease

Nonresponse to exercise has been extensively examined in young athletes but is seldom reported in studies of aerobic exercise interventions in older adults. This study examined the prevalence of nonresponse and poor response to exercise in functional and quality of life outcomes and response patterns between and among older adults undergoing 12-weeks of supervised exercise therapy for the management of peripheral artery disease ( N = 44, mean age 72.3 years, 47.7% female). The prevalence of nonresponse (no change/decline in performance) in walking distance was 31.8%. The prevalence of poor response (lack of a clinically meaningful improvement) was 43.2%. Similar patterns of response were observed in both objective and patient-reported measures of physical function. All participants improved in at least one outcome; only two participants improved in all measured outcomes. Additional research should examine modifiable predictors of response to inform programming and maximize an individual’s potential benefit from exercise therapy.

A Targeted Literature Review of the Disease Burden in Patients With Symptomatic Peripheral Artery Disease

Angiology ◽  
2019 ◽  
Vol 71 (4) ◽  
pp. 303-314
Author(s):  
Rupert Bauersachs ◽  
Sebastian Debus ◽  
Mark Nehler ◽  
Maria Huelsebeck ◽  
Janita Balradj ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Disease Burden ◽  
Ankle Brachial Index ◽  
Peripheral Artery ◽  
Economic Burden Of Disease ◽  
Surgical Interventions ◽  
Treatment Practice ◽  
Patient Profile ◽  
Increased Risk ◽  
Artery Disease

Patients with peripheral artery disease (PAD) have an increased risk of cardiovascular (CV) and limb events, but the disease is frequently underdiagnosed and treatment options are limited. This review examines the disease burden of symptomatic PAD as well as key guideline recommendations. Publications were identified using the ProQuest portal to access the Medline, Medline In-Process, and Embase databases. Search terms for symptomatic PAD were combined with terms relevant to epidemiology, burden, treatment practice, and physiopathology. Articles in English published between January 2001 and September 2016 were screened according to the population, interventions, comparator, outcomes, and study design criteria. Relevant publications (n = 200) were identified. The reported incidence and prevalence of PAD varied depending on the definitions used and the study populations. Patients generally had a poor prognosis, with an increased risk of mortality, CV, and limb events and decreased quality of life. Guideline recommendations included ankle–brachial index measurements, exercise testing, and angiography for diagnosis and risk factor modification, antiplatelets, cilostazol, exercise therapy, or surgical interventions for treatment, depending on the patient profile. The clinical, humanistic, and economic burden of disease in patients with symptomatic PAD is substantial and needs to be reduced through improved PAD management.

scholarly journals Association between cholesterol efflux capacity and peripheral artery disease in coronary heart disease patients with and without type 2 diabetes: from the CORDIOPREV study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Elena M. Yubero-Serrano ◽  
Juan F. Alcalá-Diaz ◽  
Francisco M. Gutierrez-Mariscal ◽  
Antonio P. Arenas-de Larriva ◽  
Patricia J. Peña-Orihuela ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Secondary Prevention ◽  
Peripheral Artery Disease ◽  
Cholesterol Efflux ◽  
Newly Diagnosed ◽  
Peripheral Artery ◽  
Cholesterol Efflux Capacity ◽  
Increased Risk ◽  
Artery Disease

Abstract Background Peripheral artery disease (PAD) is recognized as a significant predictor of mortality and adverse cardiovascular outcomes in patients with coronary heart disease (CHD). In fact, coexisting PAD and CHD is strongly associated with a greater coronary event recurrence compared with either one of them alone. High-density lipoprotein (HDL)-mediated cholesterol efflux capacity (CEC) is found to be inversely associated with an increased risk of incident CHD. However, this association is not established in patients with PAD in the context of secondary prevention. In this sense, our main aim was to evaluate the association between CEC and PAD in patients with CHD and whether the concurrent presence of PAD and T2DM influences this association. Methods CHD patients (n = 1002) from the CORDIOPREV study were classified according to the presence or absence of PAD (ankle-brachial index, ABI ≤ 0.9 and ABI > 0.9 and < 1.4, respectively) and T2DM status. CEC was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma was performed. Results The presence of PAD determined low CEC in non-T2DM and newly-diagnosed T2DM patients. Coexisting PAD and newly-diagnosed T2DM provided and additive effect providing an impaired CEC compared to non-T2DM patients with PAD. In established T2DM patients, the presence of PAD did not determine differences in CEC, compared to those without PAD, which may be restored by glucose-lowering treatment. Conclusions Our findings suggest an inverse relationship between CEC and PAD in CHD patients. These results support the importance of identifying underlying mechanisms of PAD, in the context of secondary prevention, that provide potential therapeutic targets, that is the case of CEC, and establishing strategies to prevent or reduce the high risk of cardiovascular events of these patients. Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00924937. Unique Identifier: NCT00924937

Abstract 11: Effects of Canakinumab in Patients With Peripheral Artery Disease

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kerry S Russell ◽  
Denise Yates ◽  
Andrea Feller ◽  
Tianke Wang ◽  
Ping Chen ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Vascular Function ◽  
Cardiovascular Events ◽  
Ankle Brachial Index ◽  
Unmet Need ◽  
Walking Distance ◽  
Plaque Progression ◽  
Peripheral Artery ◽  
Plaque Volume ◽  
Artery Disease

Background: Peripheral artery disease (PAD) affects 8.5 million people in the US. PAD patients are at high risk for cardiovascular events, and their quality of life is often significantly impaired by decreased mobility. Interleukin-1β (IL-1β) may play an important role in this disease by promoting inflammatory responses that drive atherosclerotic plaque progression and impair vascular function. We sought to test whether interruption of IL-1β signaling would improve patient mobility and decrease plaque progression in the lower extremities. Methods: 38 patients (mean age 65; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive Canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. Plaque volume in the superficial femoral artery (SFA) was assessed serially using 3.0T MRI. Mobility was assessed serially using the 6-minute walk test (maximum and pain-free walking distance). Results: Canakinumab was safe and well-tolerated. 12 patients discontinued (8 placebo, 4 Canakinumab). MRI data (from 31 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA at either time point in placebo-treated patients; nor was there a change in plaque volume in the Canakinumab-treated group. There was a serial and significant improvement in placebo-adjusted maximum and pain-free walking distance observed as early as 3 months after treatment with Canakinumab (58-meter improvement over placebo in pain-free distance at 3 months, P=0.01). Two placebo-treated patients required peripheral vascular interventions due to progression of disease; however, no Canakinumab-treated patients required revascularization during the study. Canakinumab decreased markers of systemic inflammation (IL-6 and hsCRP). Conclusions: Treatment with Canakinumab may improve maximum and pain-free walk distance in patients with symptomatic PAD. In conjunction with results soon to be reported for the CANTOS trial of Canakinumab for secondary prevention of cardiovascular events, additional studies may provide support that inhibition of IL-1β signaling can improve symptoms and function in this patient population with high unmet need.

scholarly journals Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Michael G Levin ◽  
Derek Klarin ◽  
Venexia M Walker ◽  
Dipender Gill ◽  
Julie Lynch ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Calcium Channel ◽  
Peripheral Artery Disease ◽  
Genetic Correlations ◽  
Channel Blockers ◽  
Peripheral Artery ◽  
Antihypertensive Medications ◽  
Increased Risk ◽  
Genes Encoding ◽  
Artery Disease

Aims: We aimed to estimate the effect of blood pressure and blood pressure lowering medications (via genetic proxies) on peripheral artery disease. Methods and Results: GWAS summary statistics were obtained for BP (International Consortium for Blood Pressure + UK Biobank GWAS; N = up to 757,601 individuals), peripheral artery disease (PAD; VA Million Veteran Program; N = 24,009 cases, 150,983 controls), and coronary artery disease (CAD; CARDIoGRAMplusC4D 1000 Genomes; N = 60,801 cases, 123,504 controls). Genetic correlations between systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and CAD and PAD were estimated using LD score regression. The strongest correlation was between SBP and CAD (rg = 0.36; p = 3.9 x 10-18). Causal effects were estimated by two-sample MR using a range of pleiotropy-robust methods. Increased SBP, DBP, and PP increased risk of both PAD (SBP OR 1.25 [1.19-1.31] per 10mmHg increase, p = 3 x 10-18; DBP OR 1.27 [1.17-1.39], p = 4 x 10-8; PP OR 1.51 [1.38-1.64], p = 1 x 10-20) and CAD (SBP OR 1.37 [1.29-1.45], p = 2 x 10-24; DBP OR 1.6 [1.45-1.76], p = 7 x 10-22; PP OR 1.56 [1.4-1.75], p = 1 x 10-15). The effects of SBP and DBP were greater for CAD than PAD (pdiff = 0.024 for SBP, pdiff = 4.9 x 10-4 for DBP). Increased liability to PAD increased PP (beta = 1.04 [0.62-1.45] mmHg per 1 unit increase in log-odds in liability to PAD, p = 1 x 10-6). MR was also used to estimate the effect of BP lowering through different classes of antihypertensive medications using genetic instruments containing BP-trait associated variants located within genes encoding protein targets of each medication. SBP lowering via calcium channel blocker-associated variants was protective of CAD (OR 0.38 per 10mmHg decrease in SBP; 95% CI 0.19-0.77; p = 0.007). Conclusions: Higher BP is likely to cause both PAD and CAD but may have a larger effect on CAD risk. BP-lowering through calcium-channel blockers (as proxied by genetic variants) decreased risk of CAD.

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