DM is frequently accompanied by additional cardiovascular risk factors and nearly doubles the risk of CVDs independent of other risk factors [8,9]. The underlying mechanism of CAD in patients with DM is accelerated atherosclerosis, and the prevalence of DM among patients with established CAD in Western countries exceeds 30% [10]. Additionally, nearly 20% of CAD patients have undiagnosed DM, and about 25% have prediabetes or impaired glucose tolerance [10]. CAD is the leading cause of morbidity and mortality in patients with DM [11]. The risk of cardiovascular mortality is approximately 1.7 times higher in adults with DM than in non-diabetic adults in 2014 [11]. In Korea, CVDs accounted for 20.8% of death in patients with diabetes in 2015 [1].

Although mortality from CVDs remains high in patients with DM, cardiovascular mortality has decreased over time, potentially due to the increased use of pharmacotherapy for cardiovascular risk factors [1,12,13]. Therefore, early detection of CVDs in patients with diabetes can impede disease progression and prevent future adverse cardiovascular events.

Patients with DM and CAD may present with chronic or acute coronary syndromes with typical angina, but some DM patients with CAD may not experience typical chest pain. They may only complain of dyspnea or may be asymptomatic and present with electrocardiographic (ECG) abnormalities and/or elevated cardiac biomarkers [14]. This phenomenon, so called silent myocardial ischemia or infarction, is often due to diabetic neuropathy and loss of pain sensation [15,16].

According to the American College of Cardiology/American Heart Association treatment guidelines for HF [17], HF can be classified into four stages. Stage A, at-risk for HF, includes individuals with cardiovascular risk factors for developing HF such as DM, hypertension, obesity, and metabolic syndrome, but without structural heart disease or HF symptoms. Stage B, pre-HF, means the presence of structural heart disease without HF symptoms. Diabetic patients without HF symptoms can be classified as stage A or B HF, and therapeutic interventions are recommended to prevent progression of HF [17,18]. Stage C and D HF refer to symptomatic and advanced HF, respectively. HF can be classified into three types based on the left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF; LVEF <40%), HF with mildly reduced ejection fraction (HFmrEF, LVEF=40% to 49%), and HF with preserved ejection fraction (HFpEF; LVEF ≥50%) [18].

DM and HF have a bidirectional relationship, and patients with diabetes have a 2-to 5-fold increased risk of incident HF [19-21], and in Korea, 67.6% of HF patients have DM [22]. In one clinical trial with antidiabetic medication, HF was present in 23.6% of patients with T2DM [23]. The prevalence of prediabetes or diabetes was 34.4% among patients with symptomatic HF who participated in an HF trial comparing sacubitril/valsartan versus ramipril [24].

In patients with diabetes, HF can be caused by ischemic or nonischemic cardiomyopathies [21]. Myocardial ischemia is one of the possible causes of HF associated with CAD [9]. Diabetic patients with CAD have a 3.3-fold increased risk of developing HF [21].

Diabetic cardiomyopathy (DiaCM) is a form of nonischemic HF in patients with diabetes, and it is defined as structural or functional changes in the myocardium that arise from longstanding DM without any specific cause of ventricular dysfunction, such as uncontrolled hypertension, significant valvular heart disease (VHD), or CAD [25]. In the early stages of DiaCM, left ventricular (LV) hypertrophy, myocardial fibrosis, and abnormal cell signaling can be found without symptoms of HF [26]. The estimated prevalence of LV hypertrophy is approximately 70% in adult patients with DM [27]. Chronic hyperglycemia, insulin resistance, hyperinsulinemia, impaired insulin metabolic signaling, increased oxidative stress, metabolic imbalance, inflammation, inadequate immune response, microvascular dysfunction, activation of renin-angiotensin-aldosterone system, and sympathetic nervous system, and accumulation of advanced glycation end-products can all adversely affect cardiac function, resulting in DiaCM [21,26,28]. Abnormal LV remodeling is associated with longstanding glycemic abnormalities, and the longer duration of abnormal glucose control, the worse the degree of LV hypertrophy and diastolic dysfunction [29]. The prevalence of diastolic dysfunction is about 20% to 60%, depending on the diagnostic criteria and study populations [30,31].

Traditionally, DiaCM has been considered a progressive disease with two successive stages: an early concentric phenotype with diastolic dysfunction, and a late fibrotic, dilated phenotype with systolic and advanced diastolic dysfunction (Fig. 1) [25,32]. Recently, Seferovic and Paulus [33] proposed two distinct subtypes of DiaCM: dilated and restrictive phenotypes. The dilated phenotype is characterized pathologically by apoptosis and necrosis of cardiomyocytes and subsequent replacement fibrosis, and clinically presents as HFrEF. The restrictive phenotype is characterized pathologically by cardiomyocyte hypertrophy and reactive interstitial fibrosis, functionally by increased myocardial stiffness, and clinically by HFpEF.

Dyspnea, shortness of breath, is a common and nonspecific symptom that can be caused by diverse causes. Since patients with diabetes are at risk of developing HF and may have dyspnea instead of chest pain in cases with CAD, cardiogenic dyspnea should be included as one of the differential diagnoses (Fig. 4). If a diabetic patient presents acute dyspnea, physicians should rule out acute myocardial infarction (AMI) and acute pulmonary embolism (PE). Patients with AMI might experience sweating, indigestion, nausea, and pain or discomfort in the chest, shoulders, jaw, or back in addition to acute dyspnea. Patients with acute PE can present with acute chest pain, exacerbated by inspiration or cough, as well as unilateral leg swelling.

Chronic dyspnea is one of the most common symptoms encountered in daily clinical practice, and the two most common causes are respiratory and cardiac diseases [36]. The symptoms and signs of respiratory diseases include cough, sputum, and abnormal breathing sounds. Patients with significant CAD or HF can have chronic dyspnea which worsens during exercise. Orthopnea, i.e., dyspnea that worsens as the patient lays down, paroxysmal nocturnal dyspnea, and nocturnal cough can occur in HF patients.

Chest pain is another common symptom, and pressure, heaviness, tightness, squeezing, or burning in the chest are regarded as angina-equivalent symptoms. The proposed diagnostic algorithm is summarized in Fig. 5. History taking is the most important step in the diagnosis of myocardial ischemia. Chest pain produced by myocardial ischemia is characterized by being centrally located, deep-sited, difficult to localize and diffuse (typical chest pain). If the chest pain is aggravated by exercise or emotional stress, and relieved by rest or sublingual nitroglycerin, the symptoms are highly suggestive of CVDs (typical chest pain). Typical chest pain is associated with obstructive CAD. In AMI, the chest pain usually lasts longer than 30 minutes and is not relieved by sublingual nitroglycerin. Pericarditis-related chest pain is worsened by a deep breathing or coughing. The pain of aortic dissection or aortic intramural hematoma is typically severe and occurs suddenly in the back or between the shoulder blades. The pain is frequently described as a tearing or ripping sensation that migrates upward or downward depending on the propagation of the lesion. Chest pain from acute PE occurs suddenly and is similar to pleuritic chest pain, which is common in pericarditis.

Along with history taking and physical examination, a chest radiograph, ECG, and routine blood test can all assist with the diagnosis of CVD. An echocardiographic demonstration of RWMA consistent with the coronary artery territory is a representative finding of CAD. Echocardiography can also detect other causes of chest pain or dyspnea, such as aortic dissection or PE [37,38]. Echocardiography in conjunction with exercise or pharmacologic stress can cause a mismatch in myocardial oxygen demand-supply, which allows for a provocative test in patients with stable effort-related chest pain and normal echocardiographic results at rest. Stress echocardiography is also an important supplemental diagnostic test for the evaluation of myocardial viability prior to coronary revascularization [7].

Since STE can identify myocardial segments with decreased myocardial strain suggestive of CAD, it can aid in the detection of significant CAD and eliminate the subjective view of the observer in the evaluation of RWMA associated with conventional echocardiography [3,5,39]. However, invasive coronary angiography remains the gold standard for the diagnosis of obstructive CAD (Fig. 3).

Similar to the evaluation of other CVDs, a detailed history taking, and physical examination are required. A chest X-ray, ECG, and routine blood tests are necessary to diagnose HF. The echocardiographic examination is a fundamental imaging method for the diagnosis of HF presenting with typical symptoms and elevated levels of brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT proBNP) [17]. HF guidelines recommend measuring natriuretic peptides as one of the initial diagnostic steps in cases of suspected HF [17,18]. A BNP <35 pg/mL or NT proBNP <125 pg/mL suggests that HF is unlikely, while elevated levels of BNP or NT proBNP support an HF diagnosis [17,18]. The existence of alternative potential cardiac and noncardiac causes aside from HF that trigger elevated concentrations of natriuretic peptides should be noted [40,41]. LVEF assessed by conventional echocardiography is used to classify types of HF (HFrEF, HFmrEF, and HFpEF). Echocardiography can also detect combined VHD, RWMA, and pericardial effusion, as well as provide information about prognosis and treatment response [17,18]. The traditional 2D echocardiographic technique is usually used to calculate LVEF. To supplement the 2D echocardiography, 3D measurements are recommended as they provide more accurate data for quantification of LV volume, despite the limitations of lower temporal resolution and higher dependency on image quality [42,43]. The 3D echocardiographic modality is also useful for the evaluation of right ventricular volume and function [44].

HFrEF and HFmrEF can be identified if the LVEF is less than 50%. However, HFpEF can be diagnosed when the LVEF greater than 50%, echocardiographic parameters of diastolic dysfunction are present, and BNP/NT proBNP level is elevated. HFpEF involves a wide range of proposed mechanisms, including diastolic dysfunction, left atriopathy, endothelial dysfunction, volume overload, and cardiometabolic abnormalities [26]. An elevated E/e’ (>9) and the presence of pulmonary hypertension (estimated pulmonary arterial systolic pressure [PASP] >35 mm Hg) are two parameters of H₂FPEF score used to diagnose HFpEF [45]. An E/e’ is the ratio of mitral E velocity and mitral annular e’ velocity in early diastole measured by Doppler echocardiography and is associated with LV filling pressure [46]. Estimated PASP is calculated using the maximal velocity of tricuspid regurgitation (TR Vmax) by the continuous wave Doppler and right atrial pressure. H₂FPEF scoring system is useful for diagnosing HFpEF, especially in euvolemic patients [47,48].

It was recently discovered that LVGLS can be used to supplement LVEF, particularly in patients with HFpEF [3,6,49]. Decreased LVGLS is a marker of myocardial dysfunction that indicates subclinical LV dysfunction before clinical symptoms develop [3,50,51]. Furthermore, strain echocardiography can detect early diastolic dysfunction by calculating left atrial strain [52,53]. Strain echocardiography, it has been suggested, can aid in the early detection of myocardial dysfunction in patients with DiaCM [54]. A study by Yang et al. [55] demonstrated that LVGLS was significantly impaired T2DM patients with microvascular complications, more so than in without complications, while no significant difference in LVEF was observed between the two groups. A recent meta-analysis showed that 3D echocardiography-measured LVGLS was reduced in asymptomatic patients with diabetes [56].

Additional imaging modalities such as cardiac magnetic resonance imaging and cardiac computed tomographic angiography can provide information if routine transthoracic echocardiography is unavailable or falls short in providing sufficient information [57-59]. If a patient with dyspnea only on exertion and suspected HFpEF has normal echocardiographic results at rest, exercise stress echocardiography may be warranted to uncover exercise-induced hemodynamic abnormalities such as diastolic dysfunction or pulmonary hypertension [60,61].