Table 5.
Summary of Phases of Progression.
| Stages | Cellular mechanisms | Tissue and organ changes | Metabolism changes | Functional changes | Structural changes | Common complications | Means of auxiliary examination | ||
|---|---|---|---|---|---|---|---|---|---|
| Single clinical phenotype |
Dichotomy | Early stage | Hyperglycemia, insulin resistance, impaired Ca2+ handling, hyperactivation of the SNS and RAAS, and inflammation | / | Increased FFA and AGE deposition | Diastolic dysfunction, increase in left atrial filling pressure, and elevated LV end-diastolic pressure | LV concentric hypertrophy, increased ventricular stiffness, and left atrial enlargement | / | / |
| Advanced stage | Microvascular endothelial dysfunction, neurohormonal impairment, inflammation, impaired Ca2+ handling | Cardiac fibrosis and cardiomyocyte apoptosis | / | Diastolic dysfunction, systolic dysfunction | LV dilation, cardiac remodeling, and LV hypertrophy | / | / | ||
| Trichotomy | Early stage | Depletion of GLUT-1 and -4, Ca2+ homeostasis changes, hyperglycemia, insulin resistance, endothelial dysfunction, activated RAAS and SNS, oxidative stress, and inflammation | Very small pathophysiological changes in myocytes, such as cardiomyocyte substructural changes | Increased FFA and Carnitine deficiency | Prolonged isovolumetric relaxation, increased atrial filling, impaired early diastolic filling, increased cardiac relaxation and stiffness | Decreased myocardial blood flow reserve | / | Sensitive methods such as strain, strain rate, and myocardial tissue velocity, MRI, CTA, and IVUS | |
| Middle stage | Defects in Ca2+ transport, hormone disorders (increased AT II and TGF-β1, reduced IGF-I), activated RAAS, accumulation of AGEs, collagen deposition | Cardiomyocyte loss and fibrosis, high cardiomyocyte resting tone | / | Diastolic dysfunction, slightly impaired ejection function, increased left ventricular stiffness | Left ventricular hypertrophy, slightly increased LV mass, wall thickness or size | Mild CAN | Conventional echocardiography, sensitive methods (the same as techniques above) | ||
| Late stage | Myofibril reduction, contractile and regulatory protein expression abnormalities, increased formation and deposition of collagen | Advanced cardiac fibrosis, cardiomyocyte necrosis, microvascular changes and spasm | / | Significant deterioration of coronary microcirculation and systolic and diastolic function | Significantly increased LV size, wall thickness and mass | Hypertension, ischemic Heart Disease, Severe CAN | Conventional echocardiography | ||
| Four-division | Stage A (diastolic dysfunction) | Altered Ca2+ homeostasis, depletion of GLUT-1 and -4, increased ROS and inflammation, disregulated miRNA and exosomes | Steatosis | / | Diastolic dysfunction with normal EF, mild decrease in systolic strain of both atria and ventricles | Increased LV mass, decreased tissue velocities | / | LGE ,1H-Spectroscopy, and 31P-Spectroscopy | |
| Stage B (systolic and diastolic dysfunction) | Stage A mechanisms + Acticated RAAS, cytokine damage (reduced IGF-I and increased TGF-β1), hyperglycemia, AGE formation, insulin resistance | Apoptosis, necrosis, and fibrosis | loss of cardiac metabolic flexibility | Combined systolic and diastolic dysfunction, right and left atrial and ventricular involvement | Increased LV wall thickness and mild cavity dilatation | Mild CAN | LGE, 1H-Spectroscopy, and 31P-Spectroscopy | ||
| Stage C (mild complications) | Stage A and Stage B mechanisms + microvascular changes | Apoptosis, necrosis, and fibrosis | Overt DM | Diastolic dysfunction, systolic dysfunction, decreased LVEF, and pulmonary hypertension | Concentric hypertrophy or indeterminate hypertrophy (magnification) or eccentric hypertrophy, cavity dilatation, Abnormal EMB | Microvascular disease/coronary atherosclerosis without obstructive CHD, HTA, severe CAN | LGE, 1H-Spectroscopy, and 31P-Spectroscopy | ||
| Stage D (severe complications) | the same as Stage C mechanisms, but more severe | Apoptosis, necrosis, and fibrosis | Overt DM | Moderate-severe systolic dysfunction and biventricular refractory heart failure | Eccentric hypertrophy | Overt ischemia/infarct causing HF, micro- and macroangiopathic complications (e.g. CHD and CKD), severe CAN | LGE, 1H-Spectroscopy, and 31P-Spectroscopy | ||
| Six-division | / | Hyperglycemia, insulin resistance, changed Ca2+ homeostasis, increased ROS and inflammation, mitochondrial damage, cytokine damage, inactive iNOs, endothelial cell dysfunction, activated SNS and RAAS (before I stage) | Interstitial inflammation, interstitial fibrosis, cardiomyocyte hypertrophy, myocyte apoptosis and necrosis, cardiac stiffness, arterial stiffness and increase of afterload (I stage) | Changed FFA metabolism, accumulation of AGEs (I stage) | LV mechanical impairment (II stage); LV diastolic dysfunction (III stage); HFpEF (V stage); HFrEF (VI stage) | LV hypertrophy (IV stage) | / | Conventional echocardiography and CMR (II and III stages) | |
| Double clinical phenotypes | HFpEF phenotype | Hyperglycemia, lipotoxicity, hyperinsulinemia, and insulin resistance | Coronary microvascular endothelial inflammation, coronary microvascular stenosis, stiff and hypertrophied cardiomyocyte with a high resting tension | Accumulation of AGEs, impaired glucose metabolism, collagen deposition | LV diastolic dysfunction | Concentric LV remodeling, normal-sized, hypertrophied, and stiff LV | / | / | |
| HFrEF phenotype | Autoimmunity, lipotoxicity, reactive interstitial fibrosis, replacement fibrosis, loss of sarcomeres | Cardiomyocyte apoptosis, cardiomyocyte necrosis, coronary microvascular stenosis | Accumulation of AGEs and collagen deposition | Diastolic dysfunction | Eccentric LV remodeling, enlarged LV | / | / | ||
| A hypothesis | Subclinical hyperfunction | Impaired mitochondrial metabolism, activation of RAAS, impaired collagen crosslinking, loss of t-tubule structure, impaired Ca2+ sequestration of the sarcoplasmic reticulum, and oxidative stress | / | Formation of AGEs | Increased LV contractility and impaired diastolic function | Increased LV torsion and altered myocardial perfusion | / | Quantitative stress echocardiography | |
AT, angiotensin; AGEs, advanced glycation end products; CAN, cardiac autonomic neuropathy; CHD, coronary heart disease; CKD, chronic kidney disease; CTA, computed tomography angiography; CMR, cardiac magnetic resonance; EMB, endomyocardial biopsy; FFA, free fatty acid; GLUT, glucose transporter; HTA, arterial hypertension; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IVUS, intravascular ultrasound; IGF, insulin-like growth factors; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging; PCr/ATP, phosphocreatine/adenosine triphosphate; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SNS, sympathetic nervous system; TGF-β, transforming growth factor beta.