Diabetic retinopathy is associated with diastolic dysfunction in type 2 diabetic patients with non-ischemic dilated cardiomyopathy

Diabetes is responsible for various cardiovascular complications, such as myocardial infarction, stroke, and peripheral vascular disease [7]. These diseases are at least twofold more common in patients with type 2 diabetes than in individuals without diabetes [4]. CVD is the most important complication in diabetic people, and coronary artery disease is the main cause of death in over 50% of patients with type 2 diabetes [15]. Traditionally, microvascular and macrovascular complications were studied and treated as distinct aspects of diabetes, while many evidences suggested common pathophysiological features between these diabetic complications [16]. However, a close relationship between microvascular complication (DR) and macrovascular complication (CVD) recently. DR in patients with normal renal function and without cardiovascular disease was associated with a higher atherosclerotic burden in the carotid arteries [16]. The presence of DR was independently associated with diastolic and systolic impaired function, both at rest and stress, evaluated by global longitudinal strain and diastolic function reserve index, and might be a useful predictor of major adverse cardiac events such as cardiac death, myocardial infarction, and acute heart failure following percutaneous coronary intervention [21, 22]. The progression of DR, the presence of proliferative DR (PDR), was associated with higher risk of having coronary heart disease (CHD), and was correlated with the severity of CHD [20]. In similar contexts, the impairment of the heart muscle perfusion at stress and rest in PDR patients was more frequent than in the non-proliferative DR (NPDR) patients and diabetic patients without DR suggesting PDR as a useful indicator of heart muscle perfusion disturbance in SPECT studies [18].

In addition to these macrovascular complications, there is evidence of microvascular damage in the hearts of patients with diabetes [1, 7]. The disease entity of “diabetic cardiomyopathy” has been introduced and is characterized by the presence of myocardial dysfunction with non-significant coronary arteries [2, 7, 8]. The exact pathophysiology of diabetic cardiomyopathy is unknown, but metabolic changes such as hyperglycemia, dyslipidemia, insulin resistance, and activation of the renin-angiotensin system are thought to result in myocardial fibrosis [1, 2]. Structural changes such as endothelial swelling and/or degeneration and thickening of the capillary basement membrane are also present in diabetic cardiomyopathy, which suggests a similar pathogenesis with microangiopathy [1, 23]. Based on these findings, the clinical phenotype of diabetic cardiomyopathy mostly corresponded to dCMP characterized by left ventricular dilatation and left ventricular systolic dysfunction [2, 6, 24].

The presence of microangiopathy in the heart was reported to show thickening of the capillary basement membrane, microvascular spasm, and capillary microaneurysms [25]. These are also representative features of DR, which suggests a common pathophysiology in the heart. The metabolic complications of diabetes originate from hyperglycemia, which results in the formation of advanced glycation end products and production of reactive oxygen species, followed by vascular endothelial dysfunction [25‐27]. Moreover, recent study proposed that hyperglycemia-related hyperosmolarity promoted inflammation and angiogenesis by COX-2 expression, and may have a role not only in microvascular disease but also in macrovascular disease [17]. These factors act alone or in combination to promote myocardial fibrosis due to diabetes-induced microangiopathy [25‐27].

Our study focused on the association of diabetes or DR with dCMP, and we especially investigated the detailed changes in echocardiographic findings. The systolic and diastolic parameters revealed no significant difference according to the presence of diabetes because the study population was confined to those diagnosed with dCMP. However, the parameters, such as E/A ratio, E′ or E/E′ ratio, that represent diastolic dysfunction, were impaired in patients with DR compared to those in patients with diabetes and without DR, which suggests that DR rather than diabetes may be associated with worsened form of diastolic dysfunction in dCMP [7, 28, 29]. It is believed that the use of ACEI/ARB for patients with diabetes as the first choice of antihypertensive drugs in general may protect against the fibrotic changes in the left ventricle, since increased activation of the renin-angiotensin-aldosterone pathway leads to fibrosis formation [28]. It is only after the small vessel diseases, such as retinopathy or nephropathy, are present, which indicate widespread systemic microcirculation diseases, that the characteristics of diabetic cardiomyopathy are prominently evident.

The presence of DR suggests that the patient is experiencing microvascular complications. DR, one of the major microvascular complications in patients with diabetes, has been investigated as a potential predictor for cardiovascular diseases [5, 19, 30, 31]. Studies performed with patients with type 2 diabetes have revealed that the presence of DR is associated with an excess risk of heart failure or cardiovascular mortality [5, 30]. Furthermore, decreased eGFR was noted in patients with diabetes compared to that in non-diabetic patients, as well as in patients with DR compared to patients with diabetes and without DR. The decreased eGFR shown in this study may suggest systemic microvascular damage along with DR, since the associations between diabetic nephropathy and retinopathy have been well documented [32]. These studies suggest a possible contribution of microvascular damage to macrovascular diseases in patients with diabetes [5, 30]. However, lower eGFR did not significantly increase the risk of diastolic dysfunction (OR 0.969, 95% CI 0.941–0.998, P = 0.039). Altogether, the presence of retinopathy rather than nephropathy could be used as a clinical feature to determine whether patients with diabetes are likely to have elevated LV filling pressure in dCMP (Fig. 1).

Among the systemic medications, statin use was associated with a lower degree of systolic dysfunction in patients with dCMP. There are several experimental studies that have reported the protective effect of statin use on diabetic cardiomyopathy [33, 34], while controversy exists in human studies [35, 36]. We previously demonstrated the protective effect of statin use in DR [37], which may also be protective in diabetes-induced cardiac microangiopathy as shown in this study. However, further larger scale studies are needed to verify the protective effect of statin on dCMP, as the small number of patients included in this study is a major limitation.

The present study has also other limitations with regard to the retrospective design; more detailed assessment of diastolic profiles such as pulmonary venous flow, left atrial volume, or tricuspid regurgitation pressure gradient was not available. Furthermore , the measurement of LV end-diastolic pressure by catheter examination would be informative, which was not available in this retrospective study. Cohort studies with larger numbers of subjects may be needed for further investigation of diabetes, DR, and cardiomyopathy. Some large ranges of 95% CI in the logistic regression analyses, which were especially common in the subgroup of patients with diabetes, may be narrowed with statistical significance if analyzed with a larger number of patients.