Diabetic cardiomyopathy

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure,^[1] with accumulation of fluid in the lungs (pulmonary edema) or legs (peripheral edema). Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.^[2]

Signs and symptoms

One particularity of DCM is the long latent phase, during which the disease progresses but is completely asymptomatic. In most cases, DCM is detected with concomitant hypertension or coronary artery disease. One of the earliest signs is mild left ventricular diastolic dysfunction with little effect on ventricular filling. Also, the diabetic patient may show subtle signs of DCM related to decreased left ventricular compliance or left ventricular hypertrophy or a combination of both. A prominent “a” wave can also be noted in the jugular venous pulse, and the cardiac apical impulse may be overactive or sustained throughout systole. After the development of systolic dysfunction, left ventricular dilation and symptomatic heart failure, the jugular venous pressure may become elevated, the apical impulse would be displaced downward and to the left. Systolic mitral murmur is not uncommon in these cases. These changes are accompanied by a variety of electrocardiographic changes that may be associated with DCM in 60% of patients without structural heart disease, although usually not in the early asymptomatic phase. Later in the progression, a prolonged QT interval may be indicative of fibrosis. Given that DCM’s definition excludes concomitant atherosclerosis or hypertension, there are no changes in perfusion or in atrial natriuretic peptide levels up until the very late stages of the disease,^[3] when the hypertrophy and fibrosis become very pronounced.

Pathophysiology

Defects in cellular processes such as autophagy and mitophagy are thought to contribute to the development of diabetic cardiomyopathy.^[1] Diabetic cardiomyopathy is characterized functionally by ventricular dilation, enlargement of heart cells, prominent interstitial fibrosis and decreased or preserved systolic function^[4] in the presence of a diastolic dysfunction.^[5][6][7]

While it has been evident for a long time that the complications seen in diabetes are related to the hyperglycemia associated to it, several factors have been implicated in the pathogenesis of the disease. Etiologically, four main causes are responsible for the development of heart failure in DCM: microangiopathy and related endothelial dysfunction, autonomic neuropathy, metabolic alterations that include abnormal glucose use and increased fatty acid oxidation, generation and accumulation of free radicals, and alterations in ion homeostasis, especially calcium transients.

Microangiopathy

Microangiopathy can be characterized as subendothelial and endothelial fibrosis in the coronary microvasculature of the heart. This endothelial dysfunction leads to impaired myocardial blood flow reserve as evidence by echocardiography.^[8] About 50% of diabetics with DCM show pathologic evidence for microangiopathy such as sub-endothelial and endothelial fibrosis, compared to only 21% of non-diabetic heart failure patients.^[9] Over the years, several hypotheses were postulated to explain the endothelial dysfunction observed in diabetes. It was hypothesized that the extracellular hyperglycemia leads to an intracellular hyperglycemia in cells unable to regulate their glucose uptake, most predominantly, endothelial cells. Indeed, while hepatocytes and myocytes have mechanisms allowing them to internalize their glucose transporter, endothelial cells do not possess this ability. The consequences of increased intracellular glucose concentration are fourfold, all resulting from increasing concentration of glycolytic intermediates upstream of the rate-limiting glyceraldehyde-3-phosphate reaction which is inhibited by mechanisms activated by increased free radical formation, common in diabetes.^[10] Four pathways, enumerated below all explain part of the diabetic complications. First, it has been widely reported since the 1960s that hyperglycemia causes an increase in the flux through aldose reductase and the polyol pathway. Increased activity of the detoxifying aldose reductase enzyme leads to a depletion of the essential cofactor NADH, thereby disrupting crucial cell processes.^[11] Second, increasing fructose 6-phosphate, a glycolysis intermediate, will lead to increased flux through the hexosamine pathway. This produces N-acetyl glucosamine that can add on serine and threonine residues and alter signaling pathways as well as cause pathological induction of certain transcription factors.^[10] Third, hyperglycemia causes an increase in diacylglycerol, which is also an activator of the Protein Kinase C (PKC) signaling pathway. Induction of PKC causes multiple deleterious effects, including but not limited to blood flow abnormalities, capillary occlusion and pro-inflammatory gene expression.^[12] Finally, glucose, as well as other intermediates such as fructose and glyceraldehyde-3-phosphate, when present in high concentrations, promote the formation of advanced glycation endproducts (AGEs). These, in turn, can irreversibly cross link to proteins and cause intracellular aggregates that cannot be degraded by proteases and thereby, alter intracellular signalling.^[13] Also, AGEs can be exported to the intercellular space where they can bind AGE receptors (RAGE). This AGE/RAGE interaction activates inflammatory pathways such as NF-κB, in the host cells in an autocrine fashion, or in macrophages in a paracrine fashion. Neutrophil activation can also lead to NAD(P)H oxidase production of free radicals further damaging the surrounding cells.^[14] Finally, exported glycation products bind extracellular proteins and alter the matrix, cell-matrix interactions and promote fibrosis.^[15] A major source of increased myocardial stiffness is crosslinking between AGEs and collagen. In fact, a hallmark of uncontrolled diabetes is glycated products in the serum and can be used as a marker for diabetic microangiopathy.^[16]

Autonomic neuropathy

While the heart can function without help from the nervous system, it is highly innervated with autonomic nerves, regulating the heart beat according to demand in a fast manner, prior to hormonal release. The autonomic innervations of the myocardium in DCM are altered and contribute to myocardial dysfunction. Unlike the brain, the peripheral nervous system does not benefit from a barrier protecting it from the circulating levels of glucose. Just like endothelial cells, nerve cells cannot regulate their glucose uptake and suffer the same type of damages listed above. Therefore, the diabetic heart shows clear denervation as the pathology progresses. This denervation correlates with echocardiographic evidence of diastolic dysfunction and results in a decline of survival in patients with diabetes from 85% to 44%. Other causes of denervation are ischemia from microvascular disease and thus appear following the development of microangiopathy.

Treatment

At present, there is no effective specific treatment available for diabetic cardiomyopathy. Treatment centers around intense glycemic control through diet, oral hypoglycemics and frequently insulin and management of heart failure symptoms. There is a clear correlation between increased glycemia and risk of developing diabetic cardiomyopathy, therefore, keeping glucose concentrations as controlled as possible is paramount. Thiazolidinediones are not recommended in patients with NYHA Class III or IV heart failure secondary to fluid retention.

As with most other heart diseases, ACE inhibitors can also be administered. An analysis of major clinical trials shows that diabetic patients with heart failure benefit from such a therapy to a similar degree as non-diabetics.^[17] Similarly, beta blockers are also common in the treatment of heart failure concurrently with ACE inhibitors.

References

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2. Avogaro A, Vigili de Kreutzenberg S, Negut C, Tiengo A, Scognamiglio R (April 2004). "Diabetic cardiomyopathy: a metabolic perspective". Am. J. Cardiol. 93 (8A): 13A–16A. doi:10.1016/j.amjcard.2003.11.003. PMID 15094099.
3. Ferri C, Piccoli A, Laurenti O, et al. (March 1994). "Atrial natriuretic factor in hypertensive and normotensive diabetic patients". Diabetes Care 17 (3): 195–200. doi:10.2337/diacare.17.3.195. PMID 8174447.
4. Fonarow GC, Srikanthan P (September 2006). "Diabetic cardiomyopathy". Endocrinol. Metab. Clin. North Am. 35 (3): 575–99, ix. doi:10.1016/j.ecl.2006.05.003. PMID 16959587.
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6. Severson DL (October 2004). "Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes". Can. J. Physiol. Pharmacol. 82 (10): 813–23. doi:10.1139/y04-065. PMID 15573141.
7. Karvounis HI, Papadopoulos CE, Zaglavara TA, et al. (2004). "Evidence of left ventricular dysfunction in asymptomatic elderly patients with non-insulin-dependent diabetes mellitus". Angiology 55 (5): 549–55. doi:10.1177/000331970405500511. PMID 15378118.
8. Moir S, Hanekom L, Fang ZY, et al. (October 2006). "Relationship between myocardial perfusion and dysfunction in diabetic cardiomyopathy: a study of quantitative contrast echocardiography and strain rate imaging". Heart 92 (10): 1414–9. doi:10.1136/hrt.2005.079350. PMC 1861031. PMID 16606865.
9. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A (November 1972). "New type of cardiomyopathy associated with diabetic glomerulosclerosis". Am. J. Cardiol. 30 (6): 595–602. doi:10.1016/0002-9149(72)90595-4. PMID 4263660.
10. Du XL, Edelstein D, Rossetti L, et al. (October 2000). "Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation". Proc. Natl. Acad. Sci. U.S.A. 97 (22): 12222–6. doi:10.1073/pnas.97.22.12222. PMC 17322. PMID 11050244.
11. Lee AY, Chung SS (January 1999). "Contributions of polyol pathway to oxidative stress in diabetic cataract". FASEB J. 13 (1): 23–30. PMID 9872926.
12. Koya D, King GL (June 1998). "Protein kinase C activation and the development of diabetic complications". Diabetes 47 (6): 859–66. doi:10.2337/diabetes.47.6.859. PMID 9604860.
13. Giardino I, Edelstein D, Brownlee M (July 1994). "Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes". J. Clin. Invest. 94 (1): 110–7. doi:10.1172/JCI117296. PMC 296288. PMID 8040253.
14. Abordo EA, Thornalley PJ (August 1997). "Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts". Immunol. Lett. 58 (3): 139–47. doi:10.1016/S0165-2478(97)00080-1. PMID 9293394.
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16. Aso Y, Inukai T, Tayama K, Takemura Y (2000). "Serum concentrations of advanced glycation endproducts are associated with the development of atherosclerosis as well as diabetic microangiopathy in patients with type 2 diabetes". Acta Diabetol 37 (2): 87–92. doi:10.1007/s005920070025. PMID 11194933.
17. Shekelle PG, Rich MW, Morton SC, et al. (May 2003). "Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials". J. Am. Coll. Cardiol. 41 (9): 1529–38. doi:10.1016/S0735-1097(03)00262-6. PMID 12742294.