Diabetic cardiomyopathy: from the pathophysiology of the cardiac myocytes to current diagnosis and management strategies

Figures & data

Figure 1 The pathophysiological substrate of diabetic cardiomyopathy: in diabetes, hyperglycemia, excess free fatty acid (FFA) release, and insulin resistance, engender adverse metabolic events that affect the cardiac myocytes. Hyperglycemia is associated with decreased glucose transportation (GLUT), uptake, and oxidation, as well as increased formation of advanced glycation end products (AGEs) and increased activation of protein kinase C (PKC). Excess FFA release is followed by cardiac lipotoxicity, ie, increased cardiac lipid accumulation and increased generation of reduced reactive oxygen species (ROS) at the level of the electron transport chain. Together with insulin resistance and impaired insulin action and signaling, these metabolic paths augment vasoconstriction, produce and further aggravate arterial hypertension, increase inflammation with liberation of leukocyte-attracting chemokines, increase production of inflammatory cytokines, and augment expression of cellular adhesion molecules. Thrombosis is further promoted, together with platelet activation.

Table 1 Main and recent echocardiographic, population-based studies on diabetic cardiomyopathy

Reference	Population sample	Findings	Incidence of DCM
[^Citation46]	1,986 men + 2,529 women (111 with DM + 381 with IGT)	↑ LV wall thickness, ↑ relative wall thickness, ↑ LV end-diastolic dimension, ↑ LV mass	13.9% in men 16.1% in women
[^Citation127]	5,201 men + women (2,697 with DM or IGT, age ≥ 65 years)	↑ ventricular septal thickness, ↑ posterior wall thickness, ↑ left ventricular mass, ↑ early and late diastolic transmitral peak flow velocities	40% in both sexes
[^Citation43]	1.810 men + women with DM	↑ LV mass, ↑ LV wall thicknesses ↓ LV fractional shortening, ↓ midwall shortening, ↓ stress-corrected midwall shortening	14% in women 12% in men
[^Citation128]	1,950 men + women with HTN (386 with DM)	↑ LV mass, ↑ LV relative wall thickness, concentric LV geometry, ↓ LV stress-corrected midwall shortening, ↓ myocardial function (↓ midwall and ↓ stress-corrected midwall fractional shortening)	38% in both sexes
[^Citation129]	3,628 men + women (457 men + women with IGT)	↑ LV mass, ↑ cardiac index, ↑ LV wall thicknesses and ↑ relative wall thickness	12.6% in both sexes
[^Citation130]	173 men + women with DM + HTN	↑ LV mass	30% in both sexes
[^Citation131]	39 boys + girls with type 1 DM	↑ LV mass, ↓ LV performance	30% in both sexes
[^Citation100]	148 men + women (74 with DM)	↑ LV mass index, ↑ TEI index	34% in both sexes
[^Citation92]	306 men + women (153 with MetS)	↑ LV mass index, ↑ TEI index	12% in both sexes
[^Citation116]	550 men + women (275 with MetS)	↑ TEI index	18% in both sexes
[^Citation142]	186 type 2 diabetes patients with normal ejection fraction	Systolic dysfunction: ↓ peak strain and ↓ strain rate ↑ calibrated IB (myocardial reflectivity)	15.8% in both sexes
[^Citation143]	41 diabetes patients with normal resting LV function and a normal dobutamine echo	↓ peak myocardial systolic velocity ↓ early diastolic velocity	16% subtle dysfunction in both sexes
[^Citation137]	35 type 2 diabetes patients	↓ longitudinal peak systolic velocity at rest and at peak stress, ↓ functional reserve, ↑ radial systolic velocity	20% in both sexes
[^Citation144]	134 type 2 diabetes patients	↓ mean peak systolic early + diastolic velocity, ↓ mean isovolumic relaxation time, ↑ systolic + diastolic synchronicity	20% in both sexes

Abbreviations: DCM, diabetic cardiomyopathy; DM, diabetes mellitus; IGT, impaired glucose tolerance; LV, left ventricular; HTN, hypertension; TEI, total ejection isovolumic; MetS, metabolic syndrome; IB, integrated backscatter.

Table 2 Major studies on treatment strategies of diabetic cardiomyopathy

Reference	Type of diabetes	Intervention	Purpose	Follow-up period	Treatment regimen	Results
[^Citation145]	2	Diet/exercise	↓ incidence of DCM	6 y	Control (n = 195) vs exercise (n = 211) vs diet + exercise (n = 194)	33% ↓ in the diet group 47% ↓ in the exercise group 38% ↓ in the diet + exercise
[^Citation146,Citation147]	2/IGT	Behavioral diet + physical therapy	↓ onset of diabetes ↓ DCM incidence	3.2 y	Individualized counseling vs general oral and written information about diet/exercise	58% ↓ in the intervention group of diabetes 56% ↓ in the intervention group of DCM
[^Citation149]	2, newly diagnosed	Prolonged dietary management	↓ DCM incidence ↓ of cardiovascular mortality	10 y	Diet alone (n = 219) vs diet + tolbutamide 500 mg/metformin twice a day (n = 140) vs insulin (n = 73)	1.04 RR for MI per ↑ 1 mmol/L in fasting plasma glucose, no difference between treatments for the risk of MI
[^Citation150]	2, newly diagnosed	Intensified health education	↓ MI incidence ↓ all-cause mortality	11 y	a. Usual care (n = 378) vs b. intensified health education (n = 334) vs b + 1.6 clofibric acid/day (n = 332)	15.2% patients suffered from MI and 19.2% died, postprandial glucose levels were independent risk factors for CVD death
[^Citation152]	2	none	Evaluation of hyperglycemia exposure to the incidence of DCM	10 y	Not applicable	Each 1% ↓ in HbA1c was associated with: 14% ↓ in risk for MI 16% ↓ in risk for HF
[^Citation153]	2	Simvastatin 20 to 40 mg	Prevention of recurrent CVD in DCM	5.4 y	Placebo vs simvastatin 20 to 40 mg per day	55% ↓ in CVD risk
[^Citation154]	2	Gemfibrozil 1,200 mg/day	Changes in plasma lipids could reduce major CVD events	7 y	Placebo (n = 1.267) vs gemfibrozil 1,200 mg/day (n = 1.264)	22%↓ of CVD events for every 5 mg/dL ↑ in HDL-C, there was an 11% ↓ in CVD events
[^Citation155]	2	Gemfibrozil 1,200 mg/day	Efficacy of gemfibrozil in varying glucose levels association between hyperglycemia and CVD risk	7 y	Placebo (n = 1.267) vs gemfibrozil 1,200 mg/day (n = 1.264)	Fasting insulin ≥ 271 pmol/L was associated with: 31% ↑ CVD risk 41% ↓ in CVD death
[^Citation158]	2	Diuretic or Ca-blocker or ACE	Differences in CVD risk between antihypertensive regiments	4.9 y	Diuretic (chlorthalidone 12.5 to 25 md/d, n = 15.255) or Ca-blocker (amlodipine 2.5 to 10 mg/d, n = 9.048), or ACE inhibitor (lisinopril 10 to 40 mg/d, n = 9.054)	10.2% ↑ risk of HF with amlodipine 19% ↑ risk of HF with lisinopril 33.3% ↑ risk of DCM with lisinopril, better blood pressure control with chlorthalidone
[^Citation159]	2	Ramipril 10 mg/day	Prevention death from CVD, MI, allcause mortality, HF, DCM, development of diabetes	5 y	Placebo (n = 4.652) vs ramipril (n = 4.645)	6.1% ↓ of CVD death 9.9% ↓ of MI 10.4% ↓ of all-cause death 9% ↓ of HF 6.4% ↓ of DCM 3.6% ↓ in new diabetes
[^Citation160]	2	Felodipine 5 mg/day	Achievement of blood pressure targets with the addition of ASA and association to DCM and CVD risk	3.8 y	Felodipine 5 mg/d + ASA vs felodipine 5 mg/d + placebo	51% ↓ of CVD risk in target ≤135/80 mm Hg + 15% ↓ of CVD risk with ASA and 36% ↓ in MI
[^Citation161]	2	Losartan 50 to 100 mg/d	↓ of CVD risk with losartan vs atenolol	4.7 y	Losartan 50–100 mg/d (n = 586) vs atenolol 50–100 mg/d (n = 609)	76% ↓ of relative CVD risk
[^Citation162]	2	Blood pressure control <150/80 mm Hg	↓ of CVD risk	8.4 y	Captopril (50–100 mg/d, n = 400) vs atenolol (50–100 mg/d, n = 358)	24% ↓ of CVD risk 32% ↓ of death 56% ↓ of HF
[^Citation164]	2	Irbesartan 300 mg/d vs amlodipine 10 mg/d	↓ of blood pressure provides protection against progression of nephropathy	2.6 y	Irbesartan (300 mg/d, n = 579) vs amlodipine (10 mg/d, n = 567) vs placebo	With irbesartan: 37% ↓ risk of doubling serum creatinine 23% ↓ risk of end-stage renal disease 23% ↓ risk of HF
[^Citation166]	2	Clopidogrel 300 mg/d bolus, followed by clopidogrel 75 mg/d for 3–12 mo	↓ of CVD mortality	1 y	Clopidogrel 300 mg/d bolus, followed by clopidogrel 75 mg/d for 3–12 mo vs placebo	15% ↓ of MI rate

Abbreviations: DCM, diabetic cardiomyopathy; IGT, impaired glucose tolerance; RR, relative risk; MI, myocardial infarction; CVD, cardiovascular disease death; HF, heart failure; HDL-C, high density lipoprotein-cholesterol levels; Ca-blocker, calcium channel blocker; ACE, angiotensin-converting-enzyme; ASA, acetylsalicylic acid.

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