Treatments and outcomes Arrhythmias: atrial brillation and sudden cardiac death[21] Classa Levelb Recommendation Aspirin and anticoagulant use as recommended for patients with atrial brillation should be rigorously applied in diabetic patients with atrial brillation to prevent stroke I C Chronic oral anticoagulant therapy in a dose adjusted to achieve a target international normalized ratio (INR) of 2 3 should be considered in all patients with atrial brillation and diabetes, unless contraindicated IIa C Control of glycaemia even in the pre-diabetic stage is important to prevent the development of the alterations that predispose to sudden cardiac death I C Microvascular disease and nephropathy are indicators of increased risk of sudden cardiac death in diabetic patients IIa B aClass of recommendation. bLevel of evidence. https://www.textbookofcardiology.org/wiki/Diabetes 12/23 7/4/23, 12:20 AM Diabetes - Textbook of Cardiology Aspirin and anticoagulant use as recommended for patients with atrial fibrillation should be rigorously applied in diabetic patients with atrial fibrillation to prevent heart stroke. Oral anticoagulation is most beneficial for patients at higher risk for stroke, whereas the risks outweigh the benefit in patients at low risk.[52] Thus, quantifying the risk of stroke is crucial for determining which atrial fibrillation patients would benefit most from anticoagulant therapy. Based on the CHADSVASC risk score, all patient with diabetes and atrial fibrillation have an indication for anti-coagulation.[53] Diabetic patients have a higher incidence of cardiac arrhythmias, including ventricular fibrillation and sudden death. The causes underlying the increased vulnerability of the electrical substrate in these patients are unclear and it is likely to be the consequence of the interplay of several concomitant factors. (i) Atherosclerosis [54] and (ii) microvascular disease [55] are increased in patients with diabetes and they concur to the development of ischemia that pre-disposes to cardiac arrhythmias. (iii) Diabetic autonomic neuropathy [56][57] leads to abnormal reflexes and innervation of the diabetic heart influencing electrical instability. (iv) The electrocardiogram of diabetic patients presents repolarization abnormalities manifesting as prolonged QT interval and altered T waves [57] that may reflect abnormal potassium currents.[58] Microvascular disease and nephropathy are indicators of increased risk of sudden cardiac death in diabetic patients and should be under well controlled. Control of glycaemia even in the pre-diabetic stage is important to prevent the development of the alterations that pre-dispose to sudden cardiac death. Microvascular disease and nephropathy are indications of increased risk of sudden cardiac death in diabetic patients. Peripheral and cerebrovascular diseases and diabetes Case Report Simone is a 72-year old lady. She could not remember when she was diagnosed of type 2 diabetes. In one afternoon, while she was eating her late lunch with her husband, he noticed that she was no longer answering his questions and her lower jaw is slightly misplaced. Her husband tried to put on some cold packs to somehow soften the hardened jaw part but it didn t work. So he drove her to the local hospital for check-up, but her doctor ordered for admission immediately. As the consequence, Simone was diagnosed with an embolic stroke and atrial fibrillation at the time of admission. A few days after admission, Simone was getting worse. She could hardly speak and open her eyes, and was unable to swallow fluids. Her doctor had to order nasogastric tube insertion and oxygen administration. Her vital signs were: body temperature of 37.2 degree Celsius, blood pressure of 142/94 mmHg, pulse rate of 84 beats per minute of irregular rhythm, and respiratory rate of 24 cycles per minute. She looked generally weak and did not respond to questions, and not even to painful stimuli, and she elicited rates and crackling sounds during respiration, and was diagnosed of type 2 diabetes with emblic stroke with hemorrhagic conversion. Introduction https://www.textbookofcardiology.org/wiki/Diabetes 13/23 7/4/23, 12:20 AM Diabetes - Textbook of Cardiology Diabetes and cerebrovascular diseases are peripheral vascular disease and stroke. Peripheral vascular disease (PVD, also known as peripheral artery disease, PAD) is a term used to refer to atherosclerotic blockages found in the lower extremity, and it causes either acute or chronic ischemia (lack of blood supply). It has a two- to four-fold increased in subjects with diabetes, which is present in 15% of diabetic patients. The ankle/brachial index, systolic a peripheral noninvasive measure in vascular disease, epidemiological The symptomatic manifestations of peripheral vascular disease are intermittent claudication and limb ischemia. Impairment of the circulation in the foot owing to diabetic macro- and microvascular diseases is the most common non-traumatic reason for limb amputation. The prevalence of peripheral vascular disease increases with advancing age, duration of diabetes, and peripheral neuropathy. The latter condition may mask the symptoms of limb ischemia and thus disease progression may be advanced before patients and healthcare providers realize that peripheral vascular disease is present. About 20% of patients with mild peripheral vascular disease may be asymptomatic; other symptoms include:[61] related peripheral incidence blood pressure of Defect of the blood-brain barrier after stroke shown in MRI. is widely used studies.[59][60] Claudication like pain, weakness, numbness, or cramping in muscles Sores, wounds, or ulcers that heal slowly or not at all Noticeable change in color or temperature when compared to the other limb, or to both limbs Diminished hair and nail growth on affected limb and digits. Cerebrovascular disease is a group of brain dysfunctions related to problematic blood vessels supplying the brain, and hypertension is the most important cause.[62] The typical cerebrovascular disease in diabetes is brain stroke, which is the second leading cause of death worldwide. A transient ischemic attack (minor stroke) leaves little to no permanent damage in the brain, which symptoms include facial weakness, visual impairment, loss of coordination or balance, sudden headache, and mental confusion with unintelligible speech. And symptoms of a cerebral contralateral (opposite sided) include paralysis of a single body part; paralysis of one side of the body; localized tingling, numbness; hemianopia visual loss; aphasia (loss of speech); even loss of consciousness. Cerebrovascular mortality rates have been shown to be raised in patients with type 2 diabetes and have been reported that it is at least as great a risk factor in type 1 diabetes as in type 2. It is found that cerebrovascular mortality is raised at all ages in these patients.[63] Typical brain strokes can be classified into two categories: ischemic and hemorrhagic strokes.[62] Ischemic strokes are those that are caused by vessel occlusion mostly by embolism, while hemorrhagic strokes (intracerebral hemorrhage) are the ones which result from rupture of a blood vessel due to hypertension. About 80% of strokes are caused by ischemia, and the remainder by hemorrhage. Some hemorrhages develop inside the areas of ischemia, and thus it is unknown how many hemorrhages actually start as ischemic stroke. Evaluation https://www.textbookofcardiology.org/wiki/Diabetes 14/23 7/4/23, 12:20 AM Diabetes - Textbook of Cardiology Peripheral vascular diseases: An objective measure of peripheral vascular disease is the ankle brachial blood pressure index, defined as the ratio between the arterial pressure at the ankle level and in the brachial artery with the highest pressure,[59] which means that when the blood pressure reading in the ankles is lower than that in the arms, blockages in the arteries providing blood from the heart to the ankle are suspected. The ankle brachial blood pressure index should normally be 0.9. This measurement is valuable for early detection of peripheral artery disease and also for a better stratification of overall cardiovascular risk. A 0.5 or an ankle pressure as 50 mm Hg indicates severely impaired circulation to the foot, below 0.8 indicates moderate ischemic disease, and below 0.5 implies severe ischemic disease, alternatively a 0.4 is used as a threshold. An index above 1.3 indicates poorly compressible vessels as a result of stiff arterial walls, which in diabetic patients are due to atherosclerosis in the media layer of the arterial wall. Further traditional examinations include a lower limb Doppler ultrasound, an angiography where a catheter is inserted into the common femoral artery and selectively guided to the artery, or an X-ray by injecting a radio dense contrast agent to observe the artery directly. On the other hand, modern and non- invasive technologies like multislice computerized tomography (CT) scanners and magnetic resonance imaging (MRI) provide direct imaging of the aorta and lower limb arteries without the need for an injection of contrast agents and as an alternative to angiography. Cerebrovascular diseases: After transient ischemic attack or minor stroke, the risk of further stroke is substantially higher than previously thought, reaching as high as 30% within the first month in some subgroups.[62] Patients at very high risk (>30%) of recurrence within 7 days can be identified on the basis of their ages, blood sugar levels, blood pressures, and other symptoms. Simple risk scores have been developed on the basis of these factors to predict those patients at greatest risk who might benefit the most from early risk-factor modifications. Both the ischemic and hemorrhagic strokes are diagnosed through the following techniques: a neurological body examination, Doppler ultrasound, arteriography, and CT and MRI scans of the brain. The imaging techniques will assist in determining the subtypes and causes of stroke. And blood tests may be helpful in finding out the causes of stroke. Treatments and outcomes Peripheral vascular disease[21] Classa Levelb Recommendation All patients with type 2 diabetes and CVD are recommended treatment with low-dose aspirin IIa B In diabetic patients with peripheral vascular disease, treatment with clopidogrel or low molecular weight heparin may be considered in certain cases IIa B Patients with critical limb ischaemia should, if possible, undergo revascularization procedures I B An alternative treatment for patients with critical limb ischaemia, not suited for revascularization, is prostacyclin infusion I A aClass of recommendation. bLevel of evidence. https://www.textbookofcardiology.org/wiki/Diabetes 15/23 7/4/23, 12:20 AM Diabetes - Textbook of Cardiology Peripheral vascular diseases: Preventions are most important strategies, such as regular exercises, the optimization of glycemic control, management of hypertension, smoking cessation, antiplatelet and anti- cholesterol medications like aspirin, clopidogrel and statins. For diabetic patients with peripheral vascular disease, general measures to reduce overall cardiovascular risk should be intensive, and treatment of hypertension should be vigorous. But in patients with critical limb ischemia and very low distal perfusion pressures, it may be dangerous to lower blood pressure too much for the foot, and thus blood pressure should be kept at a level permitting adequate arterial inflow to the distal extremity. Platelet inhibition with low-dose aspirin, in the magnitude of 75 250 mg per day, is indicated in all patients with severe peripheral vascular disease; further inhibition of platelet aggregation by clopidogrel or dipyridamole along with anticoagulation with low molecular weight heparin may be the first set of choice.[64][65][66] If anatomically possible, a revascularization procedure should be attempted in all patients with critical limb ischemia,[67] such as an angioplasty or a bypass grafting can be done on solitary lesions in large arteries like the femoral artery, but the revascularization may not have sustained benefits. A synthetic prostacyclin (Ilomedin, Iloprost) is the only pharmacological agent so far convincingly shown to have significant beneficial effects on ulcer healing and pain relief on patients with critical limb ischemia, which is given intravenously daily for a period of 2 4 weeks.[68] Stroke[21] Classa Levelb Recommendation For stroke prevention, blood pressure lowering is more important than the choice of drug. Inhibition of the renin angiotensin aldosterone system may have additional bene ts beyond blood pressure lowering per se IIa B Patients with acute stroke and diabetes should be treated according to the same principles as stroke patients without diabetes IIa C aClass of recommendation. bLevel of evidence. Cerebrovascular diseases: Stroke prevention should be based on a multifactorial strategy aimed at the treatment of hypertension, hyperlipidemia, microalbuminuria, hyperglycemia and the use of antiplatelet medications. Antiplatelet therapy reduces the incidence of stroke in diabetic patients and is indicated for both primary and secondary prevention.[69] Low dose Aspirin (75 250 mg daily) should be the initial choice, but in case of intolerance, clopidogrel 75 mg once daily should be given.[70] In patients with recurrent stroke, a combination of aspirin and dipyridamol should be a better option. After a transient ischemic attack or stroke, since complications are more frequent in diabetic subjects compared with non-diabetic subjects, special attention should be paid to the overall risk for peri- and post-operative morbidity and mortality when making decision on surgical interventions, and a simple risk score that can be used to stratify patients into different risk groups for complications after surgery has been developed.[71] An alternative to endoarterectomy is carotid artery angioplasty and carotid artery stenting, which has been found to be not inferior to endoarterectomy and may prove to be a preferable method in high-risk patients.[72] https://www.textbookofcardiology.org/wiki/Diabetes 16/23 7/4/23, 12:20 AM Diabetes - Textbook of Cardiology The treatment in the acute phase of stroke in diabetic patients should follow the same principles as in the general population, and patients should be kept in stroke care units as the routine management to close surveillance of vital functions and optimization of circulation and metabolic conditions. [62]Thrombolysis like recombinant tPA is one of the most effective treatments but requires application within 3 4 h of stroke onset, which reduces mortality and disability from stroke, but is associated with a risk of hemorrhage. Because of the substantial effectiveness of tPA, efforts to increase the number of patients who are eligible for thrombolytic therapy, and combination of tPA with modern imaging technologies are underway.[62] Hemispheric decompression in young patients with malignant middle cerebral artery territory infarction and space occupying brain edema is supported by evidence. Mechanical thrombectomy and hemicraniectomy could be other options.[73][74] As reviewed recently, strict blood glucose control with intensive insulin therapy improved mortality and morbidity of adult diabetic stroke patients. Besides saving lives, intensive insulin therapy largely prevented several critical illness-associated complications including critical illness polyneuropathy, blood stream infections, anemia, and acute renal failure.[75] But arguments of the safety of the intensive insulin therapy on diabetic patients are ongoing, and new evidences show that diabetic critical-ill patients react differently to the therapy compared to non-diabetic ones, and a carbohydrate-restrictive strategy could be safer and as efficient as intensive insulin therapy, and thus could be a replacement in the near future.[76][77] References 1. Shoback, edited by David G. Gardner, Dolores (2011). Greenspan's basic & clinical endocrinology (9th ed.). New York: McGraw-Hill Medical. pp. Chapter 17. ISBN 0-07-162243-8 2. Dandona L, Dandona R, Naduvilath TJ, McCarty CA, and Rao GN. Population based assessment of diabetic retinopathy in an urban population in southern India. Br J Ophthalmol. 1999 Aug;83(8):937- 40. 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Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, and INTERHEART Study Investigators. Effect of potentially modifiable risk factors https://www.textbookofcardiology.org/wiki/Diabetes 19/23 7/4/23, 12:20 AM Diabetes - Textbook of Cardiology associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52. DOI:10.1016/S0140-6736(04)17018-9 | 36. Haffner SM. Coronary heart disease in patients with diabetes. N Engl J Med. 2000 Apr 6;342(14):1040-2. DOI:10.1056/NEJM200004063421408 | 37. Berry C, Tardif JC, and Bourassa MG. Coronary heart disease in patients with diabetes: part I: recent advances in prevention and noninvasive management. J Am Coll Cardiol. 2007 Feb 13;49(6):631-42. DOI:10.1016/j.jacc.2006.09.046 | 38. Authors/Task Force Members, Ryd n L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL, ESC Committee for Practice Guidelines (CPG), Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Document Reviewers, De Backer G, Sirnes PA, Ezquerra EA, Avogaro A, Badimon L, Baranova E, Baumgartner H, Betteridge J, Ceriello A, Fagard R, Funck-Brentano C, Gulba DC, Hasdai D, Hoes AW, Kjekshus JK, Knuuti J, Kolh P, Lev E, Mueller C, Neyses L, Nilsson PM, Perk J, Ponikowski P, Reiner Z, Sattar N, Sch chinger V, Scheen A, Schirmer H, Str mberg A, Sudzhaeva S, Tamargo JL, Viigimaa M, Vlachopoulos C, and Xuereb RG. 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