Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date

Table 1 Myocardial triglyceride content in type 2 diabetes

Study details (Author,Year)	Sample population	Exclusion	Results
Jankovic et al[92], 2012	n = 18	Previous MI, CAD, HF, digitalis use or thiazolidinediones, previous insulin use or T1D	Baseline IT myocardial lipid content 0.42% ± 0.12% vs 0.80% ± 0.11% water signal, (aP = 0.034).
	IT (n = 10)
	Mean age 56 ± 2	Patients on insulin must have had insufficient control on oral, HbA1C > 8% and on oral therapy	Myocardial lipid content decreased by 80% after 10 d IT (P = 0.008). No significant change in hepatic lipid content. After 181 ± 49 d, myocardial lipid content returned to baseline (0.37 ± 0.06, P = 0.692) Hepatic lipid content decreased by 31% (bP < 0.001)
	DM duration 9 ± 2 yr
	6 males
	HbA1c 11.1 ± 0.4
	Oral therapy (OT) (n = 8)
	Mean age 53 ± 2
	DM duration 3 ± 1 yr
	4 males
	HbA1c 9.8% ± 0.7%
Korosoglou et al[119], 2012	n = 58	Unstable condition, clinical signs of heart failure or angina contraindications for CMR, insulin use	Significant association between myocardial triglyceride content and mean diastolic strain rate (r = -0.71, cP < 0.001) and no association was found between triglyceride content and perfusion reserve (r = -0.08, P = NS)
	T2D (n = 42)
	Mean age 62 ± 6 yr
	26 male
	Mean BMI 31.6 ± 4.8 kg/m2
	HV (n = 16)
	Mean age 62 ± 3 yr
	10 male
	Mean age 62 ± 3 yr
	Mean BMI 23.9 ± 2.5
Van der Meer et al[101,155], 2009	n = 72 T2D	BP > 150/85 mmHg, previous insulin or thiazolidinedione use, previous positive stress echo or arrhythmia, diabetes related complications or significant medical problems	No significant change in myocardial fatty acid uptake at follow up on either arm. Metformin arm showed a significant decrease in fatty acid oxidation and myocardial glucose uptake. No significant change in myocardial triglyceride content in Pioglitazone or Metformin arm after therapy however there was a decrease in hepatic triglyceride content in the Pioglitazone arm
	All males
	Pioglitazone (n = 39)
	Metformin (n = 39)
	Baseline age 45-65
	HbA1C 6.5%-8.5%
	BMI 25-32
Rijzewijk et al[83], 2008	n = 66	Females, HbA1C > 8.5%, BP > 150/80, hepatic impairment or history of liver disease, substance abuse, known CVD, DM complications, contraindication to MRI, use of lipid lowering therapy.	Myocardial triglyceride content  in T2D vs controls (0.96% ± 0.07% vs 0.65% ± 0.05%). Hepatic triglyceride content  in T2D vs controls (8.6% vs 2.2%). Both cases, dP < 0.05 On univariate analysis, myocardial triglyceride content correlated with age, visceral adipose tissue, cholesterol, plasma glucose and insulin and hepatic triglyceride content (eP < 0.05 for all). E/A independently associated with myocardial triglyceride content on multivariate analysis (inverse correlation)
	T2D (n = 38)
	All males
	mean age 57 ± 1 yr
	BMI: 28.1 ± 0.6
	Controls (n = 28)
	All males
	Mean Age: 54 ± 1
	BMI: 26.9 ± 0.5
McGavock[82] 2007	n = 134	Age > 70 yr, known CAD, Previous MI, contraindications to MRI, thiazolidinedione treatment	↑Subcutaneous, visceral fat and hepatic triglyceride in O,I and T2D vs L, ↑myocardial triglyceride content in I and DM vs L (0.95 ± 0.60 vs 1.06 ± 0.62 vs 0.46 ± 0.30 fat/water content, fP < 0.05), this remained significant after adjusted for serum triglyceride, BMI, age and gender. In multiple regression model, Subcutaneous and visceral fat both independent determinants of myocardial triglyceride content (gP < 0.05) however myocardial triclyceride unrelated to hepatic triglyceride or diastolic function
	Lean(L) (n = 15)
	Age 35 ± 3 yr, 47% males
	BMI 23 ± 2, non T2D
	Overweight/Obese(O): (n = 21) Age 36 ± 12, BMI 32 ± 5, 48% males , non T2D
	Impaired glucose tolerance(I): (n = 20)
	Age 49 ± 9, 25% males, BMI 31 ± 6,
	T2D (n = 78),
	Age 47 ± 10, 47% males BMI 34 ± 7

DM: Diabetes mellitus; MI: Myocardial infarction; T1D: Type 1 diabetic; CAD: Coronary artery disease; BMI: Body mass index; IT: Insulin therapy.

Table 2 Magnetic resonance imaging studies looking at left ventricular mass and concentric remodelling in diabetes

Study details (Author, Year)	Sample population	Exclusion criteria	Main findings
Ng et al[91], 2012	n = 69	Age < 18 yr, arrhythmia, CAD, MI, RWMA, segmental LGE, EF < 50%, valve disease	No difference between groups for LVEDVI, LVESVI, LVMI, LVEF.
	DMs (n = 50, 35 T1DM) Mean age 51 ± 10 yr, 54% males. BMI 26.3 ± 3.7
	Controls (n = 19), matched for age (45 ± 15), sex (63.2% males) an BMI 26.1 ± 4.4
Wilmot et al[93], 2014	T2D n = 20, mean age 31.8 ± 6.6, BMI 33.9 ± 5.8 kg/m2	Weight > 150 kg, contraindications to MRI. In diabetic group BMI > 30 (> 27.5 in South Asians)	↑ LVM (85.2 vs 80.8 g, jP = 0.002) and LVM/Volume (0.54 vs 0.45 g/m2, kP = 0.029) in participants with diabetes compared to lean controls. No significant difference in LVMI
	Lean Controls: n = 10, Mean age 30.9 ± 5.6, Mean BMI 33.4 ± 2.4, 60% males
	Obese Controls: n = 10, Mean age 30.0 ± 6.7, Mean BMI 21.9 ± 1.7, 50% males
Larghat et al[10], 2014	T2DM: n = 19 Mean age 59 ± 6, 68% males, BMI 30.81 ± 4.6	Coronary artery Stenosis > 30% luminal narrowing on angiography, previous MI, significant heart disease, contraindications to MRI or adenosine	↑ LVM (112.8 ± 39.7 vs 91.5 ± 21.3 g, lP = 0.01) in participants with diabetes. Participants with diabetes also showed an increase in LVEDV and SV, but non indexed
	Pre-DM: n = 30 Mean age 57 ± 8, 43% males, BMI 30.1 ± 5.0
	Non DM: n = 46, Mean age 57 ± 7, 41% male, BMI 29 ± 4.9
Levelt et al[62], 2016	T2DM: n = 39, Mean age 55 ± 9, 58% males, BMI 28.7 ± 5.6	History of CVD, chest pain, smoker, uncontrolled hypertension, contraindications to MRI, ischaemia on ECG, renal dysfunction, insulin use, significant CAD on CTCA	EF, LVM, LVMI, no significant difference between groups.
	Controls: n = 17, Mean age 50 ± 14 yr		← LVM/Volume (0.98 ± 0.21 vs 0.70 ± 0.12, mP < 0.001), LVDEV (125 ± 30 mL vs 161 ± 39 mL, nP = 0.001) and lower SV in diabetes
	53% males, BMI 27.1 ± 5.0

IT: Insulin therapy; OT: Oral therapy; BMI: Body mass index; CAD: Coronary artery disease; MI: Myocardial infarction; RWMA: Regional wall motion abnormality; LVEDVI: Left ventricular end diastolic volume index; LVESVI: Left ventricular end systolic volume index; LVMI: Left ventricular mass index; LVEF: Left ventricular ejection fraction.

Table 3 Studies on left ventricular function and myocardial strain in diabetes

Publication and imaging modality	Group and baseline characteristics	Exclusion	Main findings
Ernande et al[107], 2010	T2DM: n = 119, 69 males	LVEF < 56%, age < 35 or > 65, signs, symptoms or history of heart disease, no RWMA, valve disease, renal disease, T1DM, poor DM control (HbA1C > 12%)	↓GLS (-19.3% ± 3% vs -22% ± 2%) and GRS (50% ± 16% vs 56% ± 12%, nP < 0.003) in participants with diabetes vs participants without diabetes
Echocardiography	Controls: n = 39, 30 males		Multivariate analysis showed DM (t = 3.9, P < 0.001) and gender (t = 3.4, P = 0.001) independent determinants of GLS, DM only independent determinant of GRS.
Ng et al[91], 2012	n = 69	Age < 18 yr, arrhythmia, CAD, MI, RWMA, segmental LGE, EF < 50%, valve disease	↓GLS DM vs controls (-16.1% ± 1.4% vs 20.2% ± 1.0% pP < 0.001)
MRI	DMs (n = 50, 35 T1DM) Mean age 51 ± 10 yr, 54% males. BMI 26.3 ± 3.7		↓GLS DM T2DM vs T1DM (-15.3% ± 1.2% vs 16.4% ± 1.4%, qP = 0.009)
	Controls (n = 19), matched for age (45 ± 15), sex (63.2% males) an BMI 26.1 ± 4.4
Khan et al[11], 2014	T2D n = 20, Mean age 31.8 ± 6.6, BMI 33.9 ± 5.8 kg/m2	Weight > 150 kg, contraindications to MRI. In diabetic group BMI > 30 (> 27.5 in South Asians)	↓PEDSR in DMs vs Lean controls vs obese controls (1.51 ± 0.24 vs 1.97 ± 0.34 vs 1.78 ± 0.39 s-1) and PSSR (-21.20 ± 2.75 vs -23.48 ± 2.36 vs -23.3 ± 2.62s-1)
MRI	Lean Controls: n = 10, Mean age 30.9 ± 5.6, Mean BMI 33.4 ± 2.4, 60% males.
	Obese controls: n = 10, Mean age 30.0 ± 6.7, Mean BMI 21.9 ± 1.7, 50% males
Levelt et al[62], 2016	T2D: n = 39, Mean age 55 ± 9, 58% males.	History of CVD, chest pain, smoker, uncontrolled hypertension, contraindications to MRI, ischaemia on ECG, renal dysfunction, insulin use, significant CAD on CTCA	↓GLS (-9.6 ± 2.9 vs -11.4 ± 2.8 rP = 0.049) and  mid ventricular (-14.2 ± 2 vs -19.3, sP < 0.001) systolic strain (PCr/ATP ratio at rest and exercise, correlated with reduced systolic strain results; there was also a negative association between the myocardial lipid levels and systolic strain in this cohort)
MRI	Controls: n = 17, Mean age 50 ± 14 yr

CTCA: Computed topography coronary angiogram; GLS: Global longitudinal strain; GRS: Global radial strain; PEDSR: Peak early diastolic strain rate; PSSR: Peak systolic strain rate; RWMA: Regional wall motion abnormality.