In contrast to the decreasing burden of many cardiovascular risk factors, such as smoking, physical inactivity, and hyperlipidemia, the prevalence of diabetes mellitus (DM) continues to increase worldwide.¹ In the US, there are approximately 30 million adults with DM and this number is expected to increase by more than 50% in the upcoming decade.^1,2

It is well recognized that DM is a major risk factor for cardiovascular disease. In the recently published 2019 ESC/EAS Guidelines for the management of dyslipidemias, patients with DM and end-organ damage or at least three major risk factors are considered at very-high risk for atherosclerotic cardiovascular events, in a similar risk category as patients with previous ischemic events.³

DM is also an important risk factor for the development of heart failure (HF). The mechanisms contributing to HF in patients with diabetes include atherosclerosis and ischemia; sodium and volume retention due to up-regulation of the sodium-glucose cotransporter-2; microvascular dysfunction and impaired vasodilatory mechanisms; impaired oxygen delivery to skeletal muscle; increased proinflammatory cytokines and reactive oxygen species; myocyte hypertrophy and fibrosis; mitochondrial dysfunction due to insulin resistance; and autonomic dysfunction with chronotropic incompetence.^4-7

These mechanisms, together with co-morbidities commonly present in patients with diabetes, such as hypertension, obesity, and chronic kidney disease, can cause both systolic and diastolic dysfunction. Therefore, in the population of patients with diabetes, all these factors and co-morbidities likely contribute in different proportions to cause a wide spectrum of disease, ranging from subclinical myocardial dysfunction to clinical heart failure with reduced or preserved ejection fraction. This syndrome has been called "diabetic cardiomyopathy".⁷

The notion of a distinct primary entity of cardiomyopathy due to diabetes is supported by epidemiologic studies showing a relationship between increasing blood glucose levels and the risk of heart failure, independent of other risk factors such as hypertension, obesity, age, and congenital heart disease (CHD).^8,9 This association is particularly evident for heart failure with preserved ejection fraction (HFpEF). HFpEF is now the most common type of HF, affecting more than 3 million individuals in the US, and nearly 50% of patients with HFpEF have DM.⁶

Though the basic mechanisms leading to heart failure in patients with diabetes are fairly understood, less is known about the functional and morphological cardiovascular abnormalities that develop early in the disease course. Prior studies have demonstrated abnormal diastolic function and impaired left ventricular (LV) global longitudinal strain, a very sensitive marker for impaired systolic function, in asymptomatic patients with DM.^10,11 The effects of diabetes in other cardiac chambers early in the disease course is not well described in the literature.

In this regard, the timely study by Jensen and colleagues addresses an important knowledge gap.¹² The authors investigated 3,984 individuals from the UK Biobank Cardiovascular Magnetic Resonance (CMR) substudy. Patients were community volunteers aged 40 to 69 years old at the time of enrollment. In this report, those with known cardiovascular disease and low LV ejection fraction (<50%) were excluded. The mean age of the population was 61.3 years old. Individuals with DM (3.6% of study population) were more likely to be older and men and had a higher prevalence of other cardiovascular risk factors, such as hypertension, obesity, and physical inactivity.

In a multivariable adjusted model, DM was associated with a higher LV mass to volume ratio and smaller left and right ventricular end-diastolic indexed volumes. Stroke volume was also lower in patients with DM. Left and right ventricular ejection fraction were not significantly different between groups, whereas mid-cavity global circumferential strain (GCS) was reduced in patients with DM. In the atria, DM was associated with smaller left and right atrial volumes and a lower emptying fraction.¹²

There are a number of strengths that should be highlighted in this report. First, as the authors point out, the use of CMR to assess cardiac chamber volumes and function is more accurate and reproducible when compared to echocardiography. Second, the unselected population, free of cardiovascular disease, extends the generalizability of the results addressing early changes in cardiac morphology and function associated with DM. In fact, the authors report that UK Biobank participants are generally healthier than the background population, which only strengthens the argument that these changes are noted very early in the natural history of diabetic cardiomyopathy. Thirdly, a sensitivity analysis with propensity score matching confirmed the results of the regression coefficients.

The study is limited, however, by a lack of longitudinal follow-up. Causality cannot be assessed in this cross-sectional study. It would be particularly interesting to study whether there is a dose-response relationship between the abnormal structural and functional findings and the development of clinical heart failure. Another important limitation is the lack of statistical correction for multiple testing.

Perhaps the most important finding in the study is that unselected individuals with DM without overt cardiovascular disease have global changes in all cardiac chambers, mainly decreased chamber volumes. Furthermore, patients with DM have an increased LV mass/volume ratio without an increase in indexed LV mass. The authors hypothesize that these changes are likely due to fibrosis and perhaps hypertrophy as well. The lack of tissue analysis, such as post-contrast T1 mapping to measure the extracellular volume or late gadolinium enhancement imaging, prevents definitive conclusions, but this hypothesis is consistent with other reports in the literature.

Nunoda and colleagues demonstrated over three decades ago that right ventricular biopsy in individuals with mild to moderate DM without hypertension or coronary artery disease revealed a significant amount of hypertrophy and fibrosis when compared with controls who did not have diabetes.¹³ In addition, imaging studies in other populations have linked the same findings to fibrosis. In the Multi-Ethnic Study of Atherosclerosis (MESA), which included men and women from four ethnic groups, free of cardiovascular disease at baseline, lower postcontrast T1 times on CMR (greater interstitial fibrosis) was associated with a lower end-diastolic volume index.¹⁴

The findings on systolic function were less conclusive. Torsion motion, as calculated by basal and apical strain measures on CMR, was not significantly different between those with and without DM in multivariable adjusted models, as was the case for most indices of GCS. Mid-ventricular GCS remained only marginally significant (p=0.045) in multivariable analysis and this should be interpreted with caution in the absence of adjustments for multiple statistical testing. It is plausible that systolic dysfunction may not be predominant so early in the natural history of cardiac disease in DM.

In conclusion, the study by Jensen and colleagues sheds some light on early changes in cardiac morphology and function in patients with diabetes who are free of clinical cardiovascular disease. In particular, the authors demonstrated reduced biatrial and biventricular volumes, reduced stroke volume, and impaired biatrial emptying as manifestations that occur early in the natural history of diabetes-related cardiac disease. These findings may be mediated by global myocardial fibrosis, though this remains to be determined.

Future studies in the field should continue to use imaging assessments by CMR, but also include further data on tissue characterization. In addition, future mechanistic studies would benefit from additional imaging techniques – such as computed tomography (CT) to evaluate for the association of these findings with epicardial coronary artery disease, or positron emission tomography (PET) to evaluate for the association with microvascular dysfunction. In addition, future studies should include longitudinal follow-up for incident cardiovascular disease. For the time being, clinicians should be aware that diabetes can affect all four cardiac chambers, and that such changes predate the development of clinical manifestations. As such, the prevention and treatment of diabetes remain of paramount importance in reducing the burden of cardiovascular disease.

References

1. Benjamin EJ, Muntner P, Alonso A, et al. Heart Disease and Stroke Statistics-2019 Update: a report from the American Heart Association. Circulation 2019;139:e56-e528.
2. Rowley WR, Bezold C, Arikan Y, Byrne E, Krohe S. Diabetes 2030: insights from yesterday, today, and future trends. Popul Health Manag 2017;20:6-12.
3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2019 [Epub ahead of print]
4. Dei Cas A, Khan SS, Butler J, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail 2015;3:136-45.
5. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752-72.
6. McHugh K, DeVore AD, Wu J, et al. Heart failure with preserved ejection fraction and diabetes: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:602-11.
7. Marwick TH, Ritchie R, Shaw JE, Kaye D. Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J Am Coll Cardiol 2018;71:339-51.
8. Lind M, Bounias I, Olsson M, Gudbjornsdottir S, Svensson AM, Rosengren A. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet 2011;378:140-6.
9. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12.
10. Boyer JK, Thanigaraj S, Schechtman KB, Perez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol 2004;93:870-75.
11. Ernande L, Bergerot C, Girerd N, et al. Longitudinal myocardial strain alteration is associated with left ventricular remodeling in asymptomatic patients with type 2 diabetes mellitus. J Am Soc Echocardiogr 2014;27:479-88.
12. Jensen MT, Fung K, Aung N, et al. Changes in cardiac morphology and function in individuals with diabetes mellitus: the UK Biobank Cardiovascular Magnetic Resonance substudy. Circ Cardiovasc Imaging 2019;12:e009476.
13. Nunoda S, Genda A, Sugihara N, Nakayama A, Mizuno S,Takeda R. Quantitative approach to the histopathology of the biopsied right ventricular myocardium in patients with diabetes mellitus. Heart Vessels 1985;1:43-47.
14. Ambale Venkatesh B, Volpe GJ, et al. Association of longitudinal changes in left ventricular structure and function with myocardial fibrosis: the Multi-Ethnic Study of Atherosclerosis study. Hypertension 2014;64:508-15.

Keywords: Diabetes Mellitus, Stroke Volume, Risk Factors, Gadolinium, Coronary Artery Disease, Reactive Oxygen Species, Blood Glucose, Cardiovascular Diseases, Insulin Resistance, Diabetic Cardiomyopathies, Cross-Sectional Studies, Propensity Score, Cytokines, Follow-Up Studies, Atrial Fibrillation, Biological Specimen Banks, Atherosclerosis, Hypertension, Renal Insufficiency, Chronic, Positron-Emission Tomography, Heart Failure, Echocardiography, Obesity, Tomography, X-Ray Computed, Dyslipidemias, Hyperlipidemias, Biopsy, Hypertrophy, Cardiovascular Abnormalities, Magnetic Resonance Spectroscopy, Muscle, Skeletal, Sodium-Glucose Transport Proteins, Mitochondria, Tomography, Prednisolone, Prednisolone, Epidemiologic Studies

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