Cardiovascular and systemic determinants of exercise capacity in people with type 2 diabetes mellitus

Joanna M Bilak, Gaurav S Gulsin, Gerry P McCann, Joanna M Bilak, Gaurav S Gulsin, Gerry P McCann

Abstract

The global burden of heart failure (HF) is on the rise owing to an increasing incidence of lifestyle related diseases, predominantly type 2 diabetes mellitus (T2D). Diabetes is an independent risk factor for cardiovascular disease, and up to 75% of those with T2D develop HF in their lifetime. T2D leads to pathological alterations within the cardiovascular system, which can progress insidiously and asymptomatically in the absence of conventional risk factors. Reduced exercise tolerance is consistently reported, even in otherwise asymptomatic individuals with T2D, and is the first sign of a failing heart. Because aggressive modification of cardiovascular risk factors does not eliminate the risk of HF in T2D, it is likely that other factors play a role in the pathogenesis of HF. Early identification of individuals at risk of HF is advantageous, as it allows for modification of the reversible risk factors and early initiation of treatment with the aim of improving clinical outcomes. In this review, cardiac and extra-cardiac contributors to reduced exercise tolerance in people with T2D are explored.

Keywords: diabetic cardiomyopathy; exercise capacity; heart failure.

Conflict of interest statement

Conflict of interest statement: The authors declare that there is no conflict of interest.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
Contributors to reduced exercise capacity in T2D. Reduced exercise capacity in T2D is a net result of complex interactions between the biomechanics of obesity and frailty and the systemic and cardiovascular factors. Molecular mechanisms involved in the interactions between excess nutrients, adiposity, and chronic inflammation result in insulin resistance, which further propels the vicious cycle of metabolic dysregulation. Adapted from Del Buono MG, et al. J Am Coll Cardiol 2019;73(17):2209-25 BMI, body mass index; LA, left atrium; LV, left ventricular; T2D, type 2 diabetes mellitus.
Figure 2.
Figure 2.
Pathological alterations leading to diabetic cardiomyopathy in relation to stages of progression of heart failure. ACC/AHA, American College of Cardiology/American Heart Association; HF, heart failure; LA, left atrium; LV, left ventricular; NYHA, New York Heart Association; T2D, type 2 diabetes mellitus.

References

    1. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017; 3: 7.
    1. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002; 106: 3068–3072.
    1. Gulsin GS, Athithan L, McCann GP. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab 2019; 10.
    1. Facts & Figures - Diabetes UK. (2020, accessed 28 June 2020).
    1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993–1004.
    1. Zareini B, Blanche P, D’Souza M, et al. Type 2 diabetes mellitus and impact of heart failure on prognosis compared to other cardiovascular diseases: a nationwide study. Circ Cardiovasc Qual Outcomes 2020; 13: e006260.
    1. MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008; 29: 1377–1385.
    1. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 2015; 3: 105–113.
    1. National Diabetes Audit -2012-2013, Report 2 - NHS Digital. Accessed July 22, 2020
    1. Reusch JEB, Bridenstine M, Regensteiner JG. Type 2 diabetes mellitus and exercise impairment. Rev Endocr Metab Disord 2013; 14: 77–86.
    1. Bauer TA, Reusch JEB, Levi M, et al. Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes. Diabetes Care 2007; 30: 2880–2885.
    1. Nojima H, Yoneda M, Watanabe H, et al. Association between aerobic capacity and the improvement in glycemic control after the exercise training in type 2 diabetes. Diabetol Metab Syndr 2017; 9: 63.
    1. Khan H, Kunutsor S, Rauramaa R, et al. Cardiorespiratory fitness and risk of heart failure: a population-based follow-up study. Eur J Heart Fail 2014; 16: 180–188.
    1. Ribisl PM, Lang W, Jaramillo SA, et al. Exercise capacity and cardiovascular/metabolic characteristics of overweight and obese individuals with type 2 diabetes: the look AHEAD clinical trial. Diabetes Care 2007; 30: 2679–2684.
    1. Sacre JW, Jellis CL, Haluska BA, et al. Association of exercise intolerance in type 2 diabetes with skeletal muscle blood flow reserve. JACC Cardiovasc Imaging 2015; 8: 913–921.
    1. Avogaro A, Albiero M, Menegazzo L, et al. Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care 2011; 34(Suppl. 2): S285–S290. doi:10.2337/dc11-s239
    1. Womack L, Peters D, Barrett EJ, et al. Abnormal skeletal muscle capillary recruitment during exercise in patients with type 2 diabetes mellitus and microvascular complications. J Am Coll Cardiol 2009; 53: 2175–2183.
    1. Santoro C, Sorrentino R, Esposito R, et al. Cardiopulmonary exercise testing and echocardiographic exam: an useful interaction. Cardiovasc Ultrasound 2019; 17: 29.
    1. Del Buono G, Arena R, Borlaug BA, et al. Exercise tolerance in patients with heart failure. JACC State of the Art Review. J Am Coll Cardiol 2019; 73: 2210–2225
    1. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017; 127: 1–4.
    1. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132: 2169–2180.
    1. Tsalamandris S, Antonopoulos AS, Oikonomou E, et al. The role of inflammation in diabetes: current concepts and future perspectives. Euro Cardiol Rev 2019; 14: 50–59.
    1. Calle MC, Fernandez ML. Inflammation and type 2 diabetes. Diabetes and Metab 2012; 38: 183–191.
    1. Lundberg M, Seiron P, Ingvast S, et al. Insulitis in human diabetes: a histological evaluation of donor pancreases. Diabetologia 2017; 60: 346–353.
    1. Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Invest 2006; 116: 3015–3025.
    1. Hopps E, Canino B, Caimi G. Effects of exercise on inflammation markers in type 2 diabetic subjects. Acta Diabetol 2011; 48: 183–189.
    1. Eder K, Baffy N, Falus A, et al. The major inflammatory mediator interleukin-6 and obesity. Inflam Res 2009; 58: 727–736.
    1. Schmidt MI, Duncan BB, Sharrett AR, et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999; 353: 1649–1652.
    1. Vepsäläinen T, Soinio M, Marniemi J, et al. Physical activity, high-sensitivity C-reactive protein, and total and cardiovascular disease mortality in type 2 diabetes. Diabetes Care. 2011; 34: 1492–1496.
    1. Visser M, Bouter LM, McQuillan GM, et al. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282: 2131–2135.
    1. Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 1997; 389: 610–614.
    1. Melo LC, Dativo-Medeiros J, Menezes-Silva CE, et al. Physical exercise on inflammatory markers in type 2 diabetes patients: a systematic review of randomized controlled trials. Oxid Med Cell Longev 2017; 2017: 1–10.
    1. Kawata T, Daimon M, Miyazaki S, et al. Coronary microvascular function is independently associated with left ventricular filling pressure in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2015; 14: 98.
    1. Shivu GN, Phan TT, Abozguia K, et al. Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus. Circulation. 2010; 121: 1209–1215.
    1. Sara JD, Taher R, Kolluri N, et al. Coronary microvascular dysfunction is associated with poor glycemic control amongst female diabetics with chest pain and non-obstructive coronary artery disease. Cardiovasc Diabetol 2019; 18.
    1. Potier L, Chequer R, Roussel R, et al. Relationship between cardiac microvascular dysfunction measured with 82Rubidium-PET and albuminuria in patients with diabetes mellitus. Cardiovasc Diabetol 2018; 17: 11.
    1. Bers DM, Eisner DA, Valdivia HH. Sarcoplasmic reticulum Ca2+ and heart failure. Circ Res 2003; 93: 487–490.
    1. Costa Melo L, Dativo-Medeiro J, Menzes-Silva CE, et al. Physical exercise on inflammatory markers in type 2 diabetes patients: a systemic review of randomized controlled trials. Oxid Med Cell Longev 2017; 8523728.
    1. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 2015; 125: 478–486.
    1. Sugita Y, Ito K, Sakurai S, et al. Epicardial adipose tissue is tightly associated with exercise intolerance in patients with type 2 diabetes mellitus with asymptomatic left ventricular structural and functional abnormalities. J Diabetes Complications 2020; 34.
    1. Babyak MA. What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med 2004; 66: 411–421.
    1. Vergès B, Patois-Vergès B, Iliou MC, et al. Influence of glycemic control on gain in VO2 peak, in patients with type 2 diabetes enrolled in cardiac rehabilitation after an acute coronary syndrome. The prospective DARE study. BMC Cardiovasc Disord 2015; 15.
    1. Kielstein JT, Impraim B, Simmel S, et al. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 2004; 109: 172–177.
    1. Fang ZY, Sharman J, Prins JB, et al. Determinants of exercise capacity in patients with type 2 diabetes. Diabetes Care 2005; 28: 1643–1648.
    1. Roberts TJ, Burns AT, MacIsaac RJ, et al. Exercise capacity in diabetes mellitus is predicted by activity status and cardiac size rather than cardiac function: a case control study. Cardiovasc Diabetol 2018; 17: 44.
    1. Byrkjeland R, Edvardsen E, Njerve IU, et al. Insulin levels and HOMA index are associated with exercise capacity in patients with type 2 diabetes and coronary artery disease. Diabetol Metab Syndr 2014; 6.
    1. Gulsin G, Henson J, Brady E, et al. Cardiovascular determinants of aerobic exercise capacity in adults with type 2 diabetes. Diabetes Care 2020; 43: 2248–2256.
    1. Vukomanovic V, Suzic-Lazic J, Celic V, et al. The relationship between functional capacity and left ventricular strain in patients with uncomplicated type 2 diabetes. J Hypertens 2019; 37: 1871–1876.
    1. Kosmala W.
    1. Regensteiner JG, Bauer TA, Reusch JEB, et al. Cardiac dysfunction during exercise in uncomplicated type 2 diabetes. Med Sci Sports Exerc 2009; 41: 977–984.
    1. Moser O, Eckstein ML, McCarthy O, et al. Poor glycaemic control is associated with reduced exercise performance and oxygen economy during cardio-pulmonary exercise testing in people with type 1 diabetes. Diabetol Metab Syndr 2017; 9: 93.
    1. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019; 381: 1609–1620.
    1. Seok WP, Goodpaster BH, Jung SL, et al. Excessive loss of skeletal muscle mass in older adults with type 2 diabetes. Diabetes Care 2009; 32: 1993–1997.
    1. Hanlon P, Nicholl BI, Jani BD, et al. Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493 737 UK Biobank participants. Lancet Public Health 2018; 3: e323-e332.
    1. Maisch B, Alter P, Pankuweit S. Diabetic cardiomyopathy – fact or fiction? Herz 2011; 36: 102–115.
    1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Euro Heart J 2016; 37: 2129–2200.
    1. Korosoglou G, Humpert PM, Ahrens J, et al. Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve. J Magn Reson Imaging 2012; 35: 804–811.
    1. Jonker JT, Djaberi R, van Schinkel LD, et al. Very-low-calorie diet increases myocardial triglyceride content and decreases diastolic left ventricular function in type 2 diabetes with cardiac complications. Diabetes Care 2014; 37: e1–e2.
    1. Rijzewijk LJ, van der Meer RW, Smit JWA, et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 2008; 52: 1793–1799.
    1. Levelt E, Rodgers CT, Clarke WT, et al. Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus. Euro Heart J 2016; 37: 3461–3469.
    1. Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 2016; 387: 1178–1186.
    1. Gianni D, Chan J, Gwathmey JK, et al. SERCA2a in heart failure: role and therapeutic prospects. J Bioenerg Biomembr 2005; 37: 375–380.
    1. Pereira L, Ruiz-Hurtado G, Rueda A, et al. Calcium signaling in diabetic cardiomyocytes. Cell Calcium 2014; 56: 372–380.
    1. Jaski BE, Jessup ML, Mancini DM, et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail 2009; 15: 171–181.
    1. Boonman-De Winter LJM, Rutten FH, Cramer MJM, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia 2012; 55: 2154–2162.
    1. Kanagala P, Arnold JR, Singh A, et al. Characterizing heart failure with preserved and reduced ejection fraction: an imaging and plasma biomarker approach. PLoS One 2020; 15: e0232280.
    1. Mazumder PK, O’Neill BT, Roberts MW, et al. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 2004; 53: 2366–2374.
    1. Athithan L, Gulsin GS, McCann GP, et al. Diabetic cardiomyopathy: pathophysiology, theories and evidence to date. World J Diabetes 2019; 10: 490–510.
    1. Skali H, Shah A, Gupta DK, et al. Cardiac structure and function across the glycemic spectrum in elderly men and women free of prevalent heart disease: the atherosclerosis risk in the community study. Circ Heart Fail 2015; 8: 448–454.
    1. Ng ACT, Delgado V, Bertini M, et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2009; 104: 1398–1401.
    1. Liu X, Yang ZG, Gao Y, et al. Left ventricular subclinical myocardial dysfunction in uncomplicated type 2 diabetes mellitus is associated with impaired myocardial perfusion: A contrast-enhanced cardiovascular magnetic resonance study. Cardiovasc Diabetol 2018; 17.
    1. Roos CJ, Scholte AJ, Kharagjitsingh AV, et al. Changes in multidirectional LV strain in asymptomatic patients with type 2 diabetes mellitus: a 2-year follow-up study. Eur Heart J Cardiovasc Imaging 2014; 15: 41–47.
    1. Hasselberg NE, Haugaa KH, Sarvari SI, et al. Left ventricular global longitudinal strain is associated with exercise capacity in failing hearts with preserved and reduced ejection fraction. Eur Heart J Cardiovasc Imaging 2015; 16: 217–224.
    1. She F, Ma Y, Li Y, et al. Influence of heart rate control on exercise capacity and quality of life in patients with permanent atrial fibrillation. BMC Cardiovasc Disord 2019; 19.
    1. Sørensen MH, Bojer AS, Pontoppidan JRN, et al. Reduced myocardial perfusion reserve in type 2 diabetes is caused by increased perfusion at rest and decreased maximal perfusion during stress. Diabetes Care 2020; 43: 1285–1292.
    1. Sørensen MH, Bojer AS, Broadbent DA, et al. Cardiac perfusion, structure, and function in type 2 diabetes mellitus with and without diabetic complications. Eur Heart J Cardiovasc Imaging. Epub ahead of print 23 October 2019. DOI:10.1093/ehjci/jez266.
    1. Steadman CD, Jerosch-Herold M, Grundy B, et al. Determinants and functional significance of myocardial perfusion reserve in severe aortic stenosis. JACC: Cardiovasc Imaging. 2012; 5: 182–189.
    1. Jensen MT, Fung K, Aung N, et al. Changes in cardiac morphology and function in individuals with diabetes mellitus: the UK biobank cardiovascular magnetic resonance substudy. Circ Cardiovasc Imaging 2019; 12.
    1. Ugowe FE, Jackson LR, Thomas KL. Atrial fibrillation and diabetes mellitus: can we modify stroke risk through glycemic control? Circ Arrhythm Electrophysiol 2019; 12: e007351.
    1. Nakade T, Shirakura T, Murata M. Effect of atrial fibrillation on cardiac output, exercise tolerance and heart rate response during exercise. Eur Heart J 2017; 38.
    1. Hohendanner F, Messroghli D, Bode D, et al. Atrial remodelling in heart failure: recent developments and relevance for heart failure with preserved ejection fraction. ESC Heart Fail 2018; 5: 211–221.
    1. Prioli A, Marino P, Lanzoni L, et al. Increasing degrees of left ventricular filling impairment modulate left atrial function in humans. Am J Cardiol 1998; 82: 756–761.
    1. von Roeder M, Rommel K-P, Kowallick JT, et al. Influence of left atrial function on exercise capacity and left ventricular function in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging 2017; 10.
    1. Kusunose K, Motoki H, Popovic ZB, et al. Independent association of left atrial function with exercise capacity in patients with preserved ejection fraction. Heart. 2012; 98: 1311–1317.
    1. Ratanasit N, Karaketklang K, Chirakarnjanakorn S, et al. Left atrial volume as an independent predictor of exercise capacity in patients with isolated diastolic dysfunction presented with exertional dyspnea. Cardiovasc Ultrasound 2014; 12: 19.
    1. Tsang TSM, Barnes ME, Gersh BJ, et al. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002; 90: 1284–1289.
    1. Hoit BD. Left atrial size and function: Role in prognosis. J Am Col Cardiol 2014; 63: 493–505.
    1. Tan YT, Wenzelburger F, Lee E, et al. Reduced left atrial function on exercise in patients with heart failure and normal ejection fraction. Heart. 2010; 96: 1017–1023.
    1. Kadappu KK, Boyd A, Eshoo S, et al. Changes in left atrial volume in diabetes mellitus: more than diastolic dysfunction? Euro Heart J Cardiovasc Imaging 2012; 13: 1016–1023.
    1. Poulsen MK, Dahl JS, Henriksen JE, et al. Left atrial volume index: relation to long-term clinical outcome in type 2 diabetes. J Am Coll Cardiol 2013; 62: 2416–2421.
    1. Melenovsky V, Hwang SJ, Redfield MM, et al. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ Heart Fail 2015; 8: 295–303.
    1. Santos ABS, Kraigher-Krainer E, Gupta DK, et al. Impaired left atrial function in heart failure with preserved ejection fraction. Euro J Heart Fail 2014; 16: 1096–1103.
    1. Ha J-W, Oh JK, Pellikka PA, et al. Diastolic stress echocardiography: a novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr 2005; 18: 63–68.
    1. Arruda ALM, Pellikka PA, Olson TP, et al. Exercise capacity, breathing pattern, and gas exchange during exercise for patients with isolated diastolic dysfunction. J Am Soc Echocardiogr 2007; 20: 838–846.
    1. Skaluba SJ, Litwin SE. Mechanisms of exercise intolerance: insights from tissue Doppler imaging. Circulation 2004; 109: 972–977.
    1. Grewal J, McCully RB, Kane GC, et al. Left ventricular function and exercise capacity. JAMA 2009; 301: 286–294.
    1. Rider OJ, Francis JM, Ali MK, et al. Beneficial cardiovascular effects of bariatric surgical and dietary weight loss in obesity. J Am Coll Cardiol 2009; 54: 718–726.
    1. Rider OJ, Francis JM, Tyler D, et al. Effects of weight loss on myocardial energetics and diastolic function in obesity. Int J Cardiovasc Imaging 2013; 29: 1043–1050.
    1. Weiss EP, Racette SB, Villareal DT, et al. Lower extremity muscle size and strength and aerobic capacity decrease with caloric restriction but not with exercise-induced weight loss. J Appl Physiol 2007; 102: 634–640.
    1. Villareal DT, Chode S, Parimi N, et al. Weight loss, exercise, or both and physical function in obese older adults. N Engl J Med 2011; 364: 1218–1229.
    1. Weiss EP, Jordan RC, Frese EM, et al. Effects of weight loss on lean mass, strength, bone, and aerobic capacity. Med Sci Sports Exerc 2017; 49: 206–217.
    1. Gulsin GS, Swarbrick DJ, Athithan L, et al. Effects of low-energy diet or exercise on cardiovascular function in working-age adults with type 2 diabetes: a prospective, randomized, open-label, blinded end point trial. Diabetes Care 2020; 43: 1300–1310.
    1. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019; 381: 841–851.
    1. Newman AA, Grimm NC, Wilburn JR, et al. Influence of sodium glucose cotransporter 2 inhibition on physiological adaptation to endurance exercise training. J Clin Endocrinol Metab 2019; 104: 1953–1966.
    1. Lee DM, Battson ML, Jarrell DK, et al. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc Diabetol 2018; 17.
    1. Bekki M, Tahara N, Tahara A, et al. Switching dipeptidyl peptidase-4 inhibitors to tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2 improve arterial stiffness evaluated by cardio-ankle vascular index in patients with type 2 diabetes: a pilot study. Curr Vasc Pharmacol 2019; 17: 411–420.
    1. Ji L, Ma J, Li H, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Therap 2014; 36.
    1. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016; 65: 1190–1196.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner