Untangling the Mechanisms of the Diabetic Heart

Diabetes frequently accompanies heart failure (HF) and HF is observed in up to 15% of patients with type 2 diabetes (T2D). The relationship between diabetes and the heart is, however, complex. It has long been known that diabetes is an important risk factor for coronary artery disease, resultant myocardial ischemia and infarctions leading to HF. But the direct effect of diabetes on the heart muscle is less clear.

The existence of a non-ischemic diabetic cardiomyopathy, disease of the cardiac muscle that is directly related to diabetes and not due to coronary atherosclerosis, has been a longstanding topic for debate. The recent EMPAREG-OUTCOME study in which patient assignment to the sodium-glucose co-transporter-2 (SGLT-2) inhibitor, empagliflozin, was associated with a reduction in HF hospitalizations by 35%¹ (for unclear reasons) has reignited this discussion.

Does a diabetic cardiomyopathy unrelated to atherosclerotic disease actually exist and, if so, how frequently is it responsible for the frequent HF plaguing diabetics? If it does exist, then what are the underlying mechanisms of diabetic cardiomyopathy that might be responsive to physiologically-tailored pharmacotherapies? As discussed in the recent webinar The Diabetic Heart: A Focus On Heart Failure, these questions continue to inspire the study of this intricate connection between T2D and the HF syndrome.

The History of Diabetic Cardiomyopathy

The concept of diabetes-induced cardiomyopathy was first noted in the early 1950s when Lundbæk published a Lancet journal article entitled “Diabetic Angiopathy”.² He suggested that diabetics could have heart disease without coronary artery blockage, and later coined the term diabetic “cardiopathy” in the late 1960s.³

The next connection was noted in the 1970s when Rubler reported the autopsy results of four patients with HF that had no evidence of coronary artery disease. She observed ventricular hypertrophy and fibrosis in these hearts and suggested a metabolic cause for these findings.⁴

Rubler’s observations were confirmed a few years later by Regan who performed catheterizations on patients with clean coronary arteries and HF, noting that the hearts were stiff and had increased filling pressures.⁵ Biopsies also revealed an increase of fibrosis as well as triglyceride and cholesterol deposition in the ventricular walls. These observations supported Rubler’s earlier findings and align with data gathered from today’s advanced cardiac imaging techniques and hemodynamic assessments suggesting that many patients with diabetes and HF have stiff left ventricles (LVs), the main pumping chambers of the heart.

Examining the Role of Hyperglycemia-related Cardiomyopathy

Diabetes-associated HF is very common and presents in many forms. There is a growing notion that perhaps 50% of HF patients in the general population have preserved ejection fraction (HFpEF). LV ejection fraction is a crude, though commonly employed, index of LV contractility. These patients have impaired relaxation and/or reduced passive LV compliance leading to elevated left ventricular filling pressure which backs up to the lungs and pulmonary arterial circuit and is referred to as “backwards failure.” Exercise-induced stroke volume reserve is also reduced in patients with a stiff heart thereby leading to a reduction in cardiac output and increase in fatigue so there is an element of “forward failure” as well.

The precise split between HFpEF and the other form of HF where the ejection fraction is reduced (HFrEF) is unknown in diabetics but there is growing evidence, which we discuss in our blog “Exploring the Epidemiology of Diabetic Heart Failure”, that HFpEF may be even more common in diabetics than it is in non-diabetics. This concept adds further complexity to the diabetic cardiomyopathy story.

There are multiple mechanisms by which hyperglycemia and hyperinsulinemia can have direct toxic effects on the heart and cause both HFpEF and HFrEF apart from coronary artery disease. Some of these have been documented to date exclusively in animal models.

Most importantly, there is growing awareness that systemic inflammation, commonly seen with obesity and diabetes, causes increased superoxide production and reduces nitric oxide synthase levels and nitric oxide production in endothelial cells which then limits coronary vasodilatory/flow reserve. Thus, exercise-induced ischemia of the heart muscle cell (myocyte) can occur without overt evidence of atherosclerosis. In addition, chronic elevations in insulin levels present in T2D patients can induce LV hypertrophy and reduce myocyte relaxation. LV relaxation can also be impaired by hypophosphorlyation of the giant “titin” molecular spring as well as impairment of calcium signaling, the latter critical to contraction and relaxation of the heart muscle. Stiff ventricles caused by these mechanisms may lead to HFpEF and associated morbidity and mortality.

Hyperglycemia also activates the renin-angiotensin-aldosterone system leading to pleiotropic effects including an increase in reactive oxygen species, endothelial dysfunction and fibrosis. Fibrotic collagen remodeling, particularly of type 1 collagen, is found both in diabetic hearts as well as other forms of non-diabetic HFpEF. This effects both systolic and diastolic ventricular dysfunction and contributes to reduced LV passive compliance (stiffening). In addition, an increase in advanced glycation end products (AGEs) can be detected in both diabetics and the elderly. AGEs are proteins to which glucose is non-enzymatically attached (glycation). AGEs cross-linking can lead to LV stiffening and impaired production of local nitric oxide in vascular endothelial cells, again limiting exercise-associated vascular flow reserve⁶ contributing to both depression of LV systolic and diastolic function.

Metabolism and the Energy-starved Heart

Metabolic changes also affect the diabetic heart as it relies on energy provided by a balanced burning of glucose and free fatty acids.⁷ Insulin resistance leads to a decreased uptake of glucose in the myocyte, with a compensatory uptake of free fatty acids (a less efficient source of energy production) which are oxidized and used as a fuel in place of glucose. This oxidation can trigger an increased production of reactive oxygen species, leading to cellular damage or programmed cell death (apoptosis).

The Link to Lipotoxicity

Switching of the heart’s main energy source to fatty acids can also lead to increased lipid deposition in the myocardium resulting in “lipotoxicity” or direct toxic effects of lipids on cardiac function. Novel technologies like NMR proton spectroscopy have been used to noninvasively evaluate cardiac lipid deposition. A recent study found an association between spectroscopic measurement of myocardial lipid deposition or “steatosis” and Doppler echocardiographic evidence of ventricular diastolic dysfunction in a diabetic population.⁸

Destabilization of Small Vessels

Exploring another angle in the diabetic-CV linkage, Hinkel et al.,⁹ observed destabilized microvascular anatomy and reduced capillary density of the myocardium on histological staining in diabetics. Whether this effect is due to AGEs or a reduction in vascular endothelial growth factor (VEGF), the end result is a depression in myocardial blood perfusion and oxygen and nutrient delivery to the muscle cells.

Summary

In summary, there are many potential mechanisms in which diabetes can play a role in cardiomyopathy and eventual HF. This is an exciting time for research into mechanisms of the diabetic heart. Novel translational medical approaches can test pre-clinically-based mechanisms of action in the clinic. Advanced diagnostic imaging techniques have opened up new areas of inquiry that may result in a better understanding of diabetic mechanisms of myocyte injury and LV dysfunction. Hopefully a combination of these approaches will clarify the relationship between diabetes and heart failure and determine whether “diabetic cardiomyopathy” is a true entity. This new knowledge may result in targeted/tailored therapies for the diabetic heart and associated HFpEF and HFrEF.

While this article only scratches the surface of the complex metabolic changes and mechanisms affecting the diabetic heart, you can learn more by listening to the on-demand webinar: The Diabetic Heart: A Focus On Heart Failure.

Read more in the next series of this blog: Antihyperglycemic Agents and Heart Failure: An Examination of Recent Studies.

References

Zinman B et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med (2015) 373:2117-2128.
Lundbaek K. Diabetic Angiopathy: a specific vascular disease. Lancet (1954) 266(6808):377-9.
Lundbaek K. Is there a diabetic cardiopathy? in: Schettler G. (ed.). Pathogenetische faktoren des myokardinfarkts. Schattauer, Stuttgart, 1969, p.63-71.
Rubler S et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol (1972) 30:595-602.
Regan TJ et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest. (1977) 60:885-899.
van Heerebeek L et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. (2008) 117:43–51.
Ferrannini E et al. CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care 2016. Epub.
Rijzewijk LJ et al. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. (2008) 52(22):1793-9.
Hinkel R et al. Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol. (2017) 69(2):131-43.

The History of Diabetic Cardiomyopathy

Examining the Role of Hyperglycemia-related Cardiomyopathy

Metabolism and the Energy-starved Heart

The Link to Lipotoxicity

Destabilization of Small Vessels

Summary

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The History of Diabetic Cardiomyopathy

Examining the Role of Hyperglycemia-related Cardiomyopathy

Metabolism and the Energy-starved Heart

The Link to Lipotoxicity

Destabilization of Small Vessels

Summary

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