Introduction

abchf

ABC Heart Fail Cardiomyop

2764-3107

Sociedade Brasileira de Cardiologia - SBC

10.36660/abchf.20230021

Review Article

Diabetic Cardiomyopathy and Heart Failure

0000-0003-0034-4981

Jorge

Antonio José Lagoeiro

Conception and design of the research Writing of the manuscript Critical revision of the manuscript for important intellectual content ¹ ² Carvalho

Marcio Roberto Moraes de

Conception and design of the research Writing of the manuscript Critical revision of the manuscript for important intellectual content ²

1 Programa de Pós-graduação em Ciências Cardiovasculares Universidade Federal Fluminense

Niterói

Brazil Programa de Pós-graduação em Ciências Cardiovasculares – Universidade Federal Fluminense (UFF), Niterói, RJ – Brazil 2 Faculdade de Medicina Universidade Federal Fluminense

Niterói

Brazil Faculdade de Medicina, Universidade Federal Fluminense (UFF), Niterói, RJ – Brazil

Mailing Address: Antonio José Lagoeiro Jorge • Avenida Marques do Paraná, 303, 6º andar. Postal code 24030-215, Centro, Niterói, RJ – Brazil E-mail: antoniolagoeiro@id.uff.br

Potential conflict of interest

No potential conflict of interest relevant to this article was reported.

10 07 2023

06 2023

3 1

e20230021

07 04 2023 14 04 2023 14 04 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Diabetes Mellitus Cardiomyopathies Heart Failure

Introduction

The global prevalence of diabetes, especially type 2 diabetes mellitus (T2DM), has been on a concerning upward trend over the years.¹ The most recent estimates published in the International Diabetes Federation Diabetes Atlas account for more than 450 million adults with diabetes worldwide, with 693 million persons estimated to have T2DM by the year 2045.² This diabetes pandemic will impose a significant burden on society, both in terms of substantial costs to the healthcare system and poor health outcomes for T2DM patients.²

The Framingham Heart Study demonstrated the epidemiological linkage between diabetes and increased risk of heart failure (HF).³ It is well established that diabetes not only increases the risk of HF, but also increases its incidence by approximately 2.5-fold regardless of age or other comorbidities.¹ Diabetic patients now represent up to one-third of participants in HF clinical trials, with diabetes being an independent predictor of poor outcome^{4 , 5} and a leading driver of the worldwide HF epidemic.⁶

Diabetic cardiomyopathy can be defined by the development of structural and functional abnormalities in the myocardium in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, or significant valve disease, in individuals with diabetes.⁷ The term diabetic cardiomyopathy was first used by Rubler in 1972 to describe a small cohort of 4 patients. The author demonstrated that there was no evidence of coronary artery disease on postmortem examination of the 4 study patients with diabetic glomerulosclerosis and HF.⁷ Myocardial hypertrophy and fibrosis were observed in these patients, suggesting a role of altered metabolism in these findings. Rubler’s findings meet the contemporary European Society of Cardiology definition of cardiomyopathy.⁸ Further supporting this work, Regan⁹ in 1977 performed postmortem examinations in 11 patients with uncomplicated diabetes and found that 9 did not have coronary artery disease and most had died of HF. Multiple specimens from the left ventricle (LV) and interventricular septum revealed increased levels of triglycerides and cholesterol compared to controls. Therefore, the presence of a diffuse extravascular abnormality has been suggested as the basis for diabetic cardiomyopathy.⁹

Clinical features of diabetes-associated cardiomyopathy

Studies show that the prevalence of HF in patients with diabetes ranges from 19% to 26%, and this association was independent of obesity, hypertension, dyslipidemia, and coronary artery involvement.³ One study showed that the incidence of HF was higher in diabetics (39%) compared to non-diabetics (23%), with a relative risk of 1.3 for developing HF after 43 months of observation.¹⁰ Additional data from population-based observational studies such as the Cardiovascular Health Study (CHS),¹¹ the Strong Heart Study (SHS),¹² and the Multi-Ethnic Study of Atherosclerosis (MESA)¹³ demonstrated differences in LV wall mass and thickness and increased rates of diastolic and systolic dysfunction in diabetic patients compared to non-diabetic subjects. In patients with T2DM, every 1% increase in glycated hemoglobin levels was associated with an 8% increase in the risk of HF, independent of other risk factors such as obesity, smoking, hypertension, dyslipidemia, and coronary artery disease, suggesting that gradual increases in blood glucose are a powerful promoter of HF in diabetes.¹⁴

Hyperglycemia and systemic insulin resistance are the core clinical abnormalities of diabetes, and both are involved in the pathogenesis of diabetic cardiomyopathy.¹⁵ In its early stages, diabetic cardiomyopathy is usually asymptomatic. One of the first manifestations is LV hypertrophy and/or decreased LV compliance, characterized by impaired early diastolic filling, increased atrial filling, and prolonged isovolumic relaxation time. LV enlargement and symptomatic HF follow the development of systolic dysfunction.¹⁵ Cardiomyocyte stiffness and hypertrophy, as well as myocardial fibrosis, contribute to this abnormality ( Figure 1 ). The CHS found that, in a cohort of 5,201 men and women, ventricular septal and left posterior myocardial wall thicknesses were greater in diabetic than in non-diabetic subjects, and that this finding was associated with impaired systolic and/or diastolic function.¹¹

Figure 1 – Pathophysiological mechanisms of diabetic cardiomyopathy. Hyperglycemia, insulin resistance, and metabolic derangements within the cardiomyocyte induce insulin resistance and metabolic disorders that increase mitochondrial dysfunction, inflammation, autonomic neuropathy, oxidative stress, renin-angiotensin-aldosterone system (RAAS) activation, and advanced glycation end-products (AGE) production, leading to cardiomyocyte death as well as microvascular dysfunction. These pathophysiological abnormalities promote cardiac stiffness, hypertrophy, and fibrosis, resulting in cardiac diastolic dysfunction, systolic dysfunction, and heart failure. Adapted from Jia et al. <xref ref-type="bibr" rid="B14">14</xref>

The clinical course of diabetic cardiomyopathy can be divided into two stages. The first stage is clinically asymptomatic and characterized by increased fibrosis and stiffness; there is a reduction in early diastolic filling, remodeling of atrial volumes, and an increase in LV end-diastolic pressure.¹⁶ Underlying pathological factors include hyperglycemia, systemic and cardiac insulin resistance, increased levels of free fatty acids (FFA), systemic and local inflammation, and oxidative stress ( Figure 1 ). Reduced activity of the calcium (Ca₂⁺) pump, manifested by inefficient sequestration of Ca₂⁺ by the sarcoplasmic reticulum, is considered to play an important role in the development of cardiac diastolic dysfunction in these patients.¹⁷

The second stage of diabetic cardiomyopathy is characterized by LV hypertrophy, cardiac remodeling, worsening of diastolic dysfunction, and consequent emergence of clinical manifestations of HF with preserved ejection fraction (HFpEF). As diabetic cardiomyopathy progresses, diastolic dysfunction and reduced cardiac compliance may coexist with systolic dysfunction, leading to the reduced ejection fraction (HFrEF) phenotype.¹⁵

The pathophysiology of diabetes-associated cardiomyopathy

Abnormalities such as fibrosis, hypertrophy, and worsening of coronary microvascular perfusion have been evaluated in the setting of diabetes-associated cardiomyopathy. These are now known to be characteristics of the diabetic heart, both in clinical and experimental settings. Changes ranging from indices of cardiac remodeling to impairment of coronary microvascular perfusion have been recorded. These morphological defects may contribute to the functional deficiencies identified in the diabetic human heart.

Other mechanisms for the development of diabetes-induced cardiomyopathy ( Figure 2 ) include such well-established mediators as inflammation, oxidative stress, metabolic derangements, insulin signaling, gene regulation, stress, neurohumoral activation, and cardiac cell death.^{18 , 19}

Figure 2 – Protective mechanisms of SGLT2 inhibitors in heart failure. There are several mechanisms by which sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent and improve heart failure. These include metabolic effects, hemodynamic effects, and additional mechanisms involving decreased activity of the sympathetic system and of the late sodium current. Late-INa, late component of cardiac sodium channel current. Adapted from Nakamura et al. <xref ref-type="bibr" rid="B19">19</xref>

The endothelium is the largest organ in the human body and is responsible for maintaining normal vessel function. It acts by regulating the release of secretory factors in response to mechanical stimuli. The main role of the endothelium is to ensure adequate blood flow, which depends on the proper balance between vasodilators and vasoconstrictors. Vasodilators include prostacyclin I₂ (PGI₂) and nitric oxide (NO), while vasoconstrictors, including endothelin-1 (ET1) and thromboxane A2 (TXA₂), act as a counterbalance to excessive vasodilation and maintain vascular tone. Insulin resistance and diabetes are known to be associated with endothelial dysfunction, which is also found in conditions such as obesity, physical inactivity, and smoking. These findings suggest that the complex pathophysiology of endothelial dysfunction involves multiple mechanisms and plays a role in several diseases, including in the development of diabetic cardiomyopathy.²⁰

Impaired NO signaling is closely related to tissue damage in diabetes mellitus, characterized by dysregulation of NO generation and NO bioavailability.²¹ Studies²² have found cardiac abnormalities in diabetic rats and suggested a key role of NO in the pathophysiology of diabetic cardiomyopathy. In addition, inhibition of NO synthesis (NOS) has been found to reduce levels of NO, nitrotyrosine, and reactive oxygen species (ROS), suggesting endothelial NOS uncoupling in diabetic hearts.²³ ROS-induced tetrahydrobiopterin oxidation and increased asymmetric dimethylarginine (ADMA) content contribute to endothelial NOS uncoupling in T2DM.^{23 , 24}

NOS is catalyzed by L-arginine and nicotinamide adenine dinucleotide phosphate (NADPH) in the presence of oxygen. However, in diabetic vessels, NOS is affected. Some studies have suggested that the cause of NO inactivation and, therefore, NO deficiency is the increase in free radicals per se rather than downregulation of endothelial NOS activity or expression.^{25 , 26}

Abnormal metabolism and mitochondrial dysfunction are associated with the metabolic derangements seen in diabetic cardiomyopathy. Hyperglycemia has been reported to cause oxidative damage to mitochondrial DNA in endothelial cells by increasing mitochondrial ROS.²⁷

Inflammation is a major mechanism underlying diabetic cardiomyopathy. To address factors that cause damage, endothelial cells are activated and produce interleukins, chemokines, interferons, monocyte chemoattractant protein-1 (MCP-1), and other pro-inflammatory factors.²⁸ Monocytes and neutrophils are recruited to the activated endothelium after the release of these mediators, and initiate inflammation. Elevated pro-inflammatory factors stimulate endothelial cells to secrete even more pro-inflammatory factors, which in turn induce secretion of various acute-phase reactants and modulate chronic inflammation.²⁰

Furthermore, inflammatory levels rise when endothelial cells are exposed to hyperinsulinemic serum. Mitochondrial dysfunction induces endothelial dysfunction and promotes inflammation through excess production of ROS.^{29 , 30} The inflammatory state triggered by endothelial activation may thus be a consequence of an imbalance between excess ROS and insufficient antioxidants, resulting in oxidative stress and cell damage.²⁰

Vascular endothelial cells are prone to damage from hyperglycemia due to their characteristics and location. Damaged endothelial cells cause increased vessel permeability, barrier dysfunction, and impaired vasodilation.³¹ Hemodynamic studies suggest that the endothelium-dependent vasodilator response is altered in diabetes.^{32 , 33} In diabetic cardiomyopathy, excessive release of various vasoconstrictors by endothelial cells is observed, interfering with the coronary vascular structure and ensuring normal blood flow. The balance between vasoconstrictors and vasodilators is lost in this scenario.²⁰

In diabetic cardiomyopathy, levels of vasodilators such as NO and PGI2 are elevated, as are those of vasoconstrictors such as ET1 and TXA2. ET1 is upregulated in T2DM target organs, including the heart and kidneys.³⁴ ET1 is predominantly expressed in cardiac endothelial cells compared to cardiomyocytes in normal adult cardiac tissue, highlighting the important role of endothelial cells in diabetic cardiomyopathy.³⁵ Furthermore, increased endothelin production in the diabetic heart can lead to vessel hypertrophy and increased myocardial fibrosis, both of which are characteristic of diabetic cardiomyopathy.²⁶

The first evidence of diabetes-associated cardiac fibrosis in the human heart was largely derived from postmortem or biopsy specimens.³⁶ Increased deposition of type I and III interstitial collagen is evident in diabetic compared to non-diabetic human myocardial biopsies.³⁶ Recent approaches using cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement (LGE) imaging have proven useful in the noninvasive detection of cardiac fibrosis in humans.^{37 , 38} These modalities reveal that diabetes is associated with increased cardiac fibrosis, even in the absence of prior ischemic injury,^{5 , 39 , 40} although some authors suggest that fibrosis may arise later in the course of the disease, even after deficits in cardiac function are already manifest.⁴

T2DM leads to LV diastolic dysfunction, restrictive LV remodeling, and HFpEF, due to induction of a pro-inflammatory state followed by deterioration of endothelial function in the coronary microvasculature. In patients with HFpEF, coronary microvascular endothelial inflammation and cardiomyocytes exposed to altered paracrine endothelial signaling contribute mainly to concentric LV remodeling.⁴¹

Another stage of diabetic cardiomyopathy is characterized by LV hypertrophy, cardiac remodeling, worsening of cardiac diastolic dysfunction and consequent emergence of HFpEF.¹⁵ As diabetic cardiomyopathy progresses, diastolic dysfunction and reduced cardiac compliance may coexist, with systolic dysfunction leading to reduced ejection fraction, LV enlargement, and reduced ejection time as a consequence of reduced LV compliance. In this setting, abnormalities in the expression of contractile and regulatory proteins account for mechanical defects in cardiac contraction.¹⁵

The association between decreased NO bioavailability in the coronary microcirculation and worsening diastolic function is complex, involving multiple pathways. Protein kinase G-dependent hypophosphorylation is responsible for delayed active relaxation and reduced passive distensibility of the LV. Depressed coronary flow reserve (CFR) is also a major contributor to diastolic dysfunction.²⁰

Diagnosis of diabetes-associated cardiomyopathy

Cardiac dysfunction is often clinically silent in diabetes and often goes undetected until its advanced stages. Even among asymptomatic, normotensive patients with well-controlled diabetes, approximately 50% will have some degree of cardiac dysfunction. It is widely accepted that one of the hallmarks of the diabetic heart is LV diastolic dysfunction – indeed, it is one of the first signs of diabetic cardiomyopathy, often detectable before clinically significant LV systolic dysfunction occurs.^{14 , 42}

Until recently, the presence of isolated diastolic dysfunction as an indicator of diabetic cardiomyopathy was disputed, as patients in the early stages of diabetes were not routinely subjected to careful assessment of diastolic function. Cardiac complications of diabetes were usually only investigated after overt symptoms of HF became evident. With the advent of more sensitive imaging techniques and the more frequent recognition of HF in people affected by diabetes, this approach may change. Whether in a clinical or preclinical/laboratory setting, CMR is widely considered the gold-standard modality for assessment of cardiac function.⁵

However, although diabetes is associated with altered LV diastolic function parameters on CMR, this technique is not always readily available, with access particularly limited in some regional and/or low-income settings. Advances in echocardiography in recent years, both in clinical and experimental settings, now allow for relatively high-resolution, detailed, noninvasive serial assessment of cardiac function without the time-consuming nature or availability and access restrictions usually imposed by CMR; as such, echocardiography is now the imaging approach of choice for most routine clinical and preclinical cardiac and interventional research studies.⁴³

Early changes in LV diastolic function that are considered characteristic of diabetes-induced cardiomyopathy include changes in LV filling and relaxation, often in the absence of changes in LV systolic function.^{5 , 44} As described in detail in the most recent guidelines published by the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging, a wide range of Doppler-based signals can be used for the assessment of various parameters of diastolic function. These parameters include those determined at end-diastole (which correlate with LV end-diastolic pressure), which are obtained by measuring the velocity of blood flow through the mitral valve (via Doppler) or the analogous velocity of movement of adjacent myocardial tissue (tissue Doppler imaging).¹

Echocardiographic examination produces two main phases of movement: an initial phase, referred to as E (Doppler flow) and e’ (tissue Doppler), and a later atrial phase, referred to as A on Doppler and a’ on tissue Doppler.⁴⁵ Mitral peak A velocity and tissue Doppler-derived mitral annular a’ velocity, as well as measurements obtained earlier in diastole, such as the mitral E/A ratio, E-wave deceleration time, and the E/e’ ratio, are common echocardiographic parameters. Among these examples, E/e’ is one of the most reproducible and reliable parameters.⁴³ Isovolumic relaxation time (IVRT) has also been widely used to assess diastolic function, but is highly dependent on heart rate and afterload.⁴³ Additional approaches include evaluation of atrial strain. Atrial cardiomyopathy is one of the aspects of diabetes-related cardiomyopathy. Dogdus et al. described impaired atrial functions (both reservoir and contractile) in obese diabetic patients.⁴⁶ They also note that the presence of interatrial block in these patients is an early disease marker at the preclinical stage of HF. Dysfunction in the diabetic heart progresses from subclinical cardiac abnormalities, such as LV fibrosis, to diastolic dysfunction and, ultimately, systolic dysfunction with reduced ejection fraction. Several noninvasive techniques, including echocardiography, computed tomography, and CMR, can be used to detect changes in cardiac structure and function (particularly fibrosis).⁴⁷ In addition, elevated levels of atrial natriuretic peptide, B-type natriuretic peptide (BNP), and N -acetylglucosamine (O-GlcNAc), among other laboratory parameters, may also serve as markers of diabetic cardiomyopathy and HF.¹⁵

Heart failure with preserved ejection fraction and the diabetic heart

The HFpEF phenotype is more prevalent than the HFrEF phenotype, secondary to the increased overall prevalence of diabetes, obesity, and hypertension in an aging population.^{48 - 50} HFpEF represents a spectrum of various etiologies, including hypertension, obesity, and aging, in addition to other risk factors and comorbidities. Women (particularly older women) and people with diabetes are overrepresented in the HFpEF population compared to the HFrEF population.^{49 , 51 , 52}

However, one should not make the mistake of considering HFpEF as a single phenotype; this disorder is particularly heterogeneous, with at least three distinct groups identified.⁵¹ These include the obesity-cardiometabolic phenotype, which has classically been associated with HFpEF – patients with high body mass index and marked diastolic dysfunction, commonly with concomitant diabetes and/or hypertension. Other subgroups include the natriuretic peptide deficiency syndrome – obese patients with low BNP who are often also hypertensive – and, finally, the cardiorenal phenotype, with right ventricular failure.^{53 , 54} Of these three groups, event-free survival is highest for those in the natriuretic peptide deficiency group and worst in the cardiorenal syndrome group.⁴⁹ Overlap and intersection between these groups of phenotypes also appears evident.⁴⁸

The growing emergence and awareness of HFpEF within the field of HF research may lead some to consider diabetic cardiomyopathy simply as the manifestation of HFpEF when it coexists with diabetes, as both share several features in common. In fact, however, diabetic patients may have HFpEF or HFrEF.^{55 , 56} If these diabetic patients also have microvascular complications, then an HFpEF phenotype rather than an HFrEF phenotype is more prevalent, and the prognosis is worse.⁵⁵ Postmortem features of human myocardium in HFpEF include clear evidence of increases in both cardiac mass and fibrosis, with reduced microvascular density.⁵⁷ These findings are also detectable on echocardiography.⁴⁸ It is likely that a large component of the increased cardiac mass is attributable to fibrosis rather than hypertrophy per se, as clinically significant hypertrophy may be evident in only approximately 50% of patients with HFpEF.⁵⁷ In addition to cardiac fibrosis and microvascular dysfunction, inflammation and cardiac stiffness are also evident.⁵¹ Unlike what is seen in HFpEF cohorts,⁵⁸ diabetic cardiomyopathy seems to have no gender predilection.⁵⁹ Thus, although diabetic cardiomyopathy is a more complex condition than merely a manifestation of HFpEF coexisting with diabetes, it is clear that the HFpEF phenotype is enriched in diabetes.

Treatment of diabetes-associated cardiomyopathy

HF treatment is similar for patients with and without diabetes. However, antidiabetic drugs have different effects in patients with HF, and clinicians must prioritize drugs that are safe in this setting and reduce HF-related events.⁶⁰

Poor glycemic control unquestionably contributes to the increased risk of HF in patients with diabetes, with HF risk correlating with glycated hemoglobin (HbA1c) levels.⁶¹ Prior to the current era, intensive glucose-lowering therapies largely failed to reduce the risk of incident HF and could even exacerbate the risk of HF – e.g., thiazolidinediones, sulfonylureas, certain dipeptidyl peptidase-4 (DPP-4) inhibitors, and, potentially, insulin and glucagon (GLP-1) agonists.^{62 , 63} Although the GLP-1 agonist dulaglutide was shown to be safe and tolerable in patients with T2DM in the REWIND trial, with evidence of sustained glucose lowering (reduction in HbA1c of 0.61 percentage points over 5 months) compared with placebo over a 5-year follow-up, no differences were observed in the cumulative incidence of cardiovascular outcomes.⁶⁴

However, the advent of sodium-glucose cotransporter-2 inhibitors (SGLT2i) ( Figure 2 ) led to a major change in treatment of these patients.^{65 , 66} The EMPA-REG OUTCOME trial⁶⁷ provided the first evidence that SGLT2i provided robust cardioprotection as well as effective glucose-lowering therapy. The risk of HF hospitalization and cardiovascular mortality was reduced by 35%–50% with empagliflozin compared to placebo in T2DM patients.⁶⁶ Similar findings regarding benefits in HFrEF hospitalization and cardiovascular mortality rates were subsequently observed in clinical trials of canagliflozin^{68 - 70} (CANVAS, CREDENCE, CVD-REAL) and dapagliflozin^{71 , 72} (DECLARE-TIMI 58) in T2DM. Reduction in HF hospitalization thus emerged as a class effect.⁷³ Furthermore, SGLT2i therapy appears equally beneficial in T2DM patients with HFpEF or HFrEF.⁶³

The mechanisms that contribute to SGLT2i cardioprotection, particularly with regard to their benefit in HF in the context of diabetes, remain unclear, with myriad putative mechanisms reported in the literature.⁷⁴ Whether beneficial effects on cardiac remodeling and/or dysfunction are evident in the diabetic heart at this time remains to be established. Although it has been suggested that the benefits of SGLT2i simply reflect mechanisms such as increased glycosuria, natriuresis, and BP reduction,⁷⁵ a consensus on their mechanism of cardioprotective action has not yet been reached. SGLT2 is not detected in the heart,^{76 , 77} therefore, the cardioprotective effects are probably extracardiac in nature; furthermore, it is likely that more than one mechanism is implicated. Although increased glycosuria and natriuresis are likely to provide renoprotection, they are probably not sufficient to fully explain the cardiac benefit, particularly in the presence of HF.^{76 , 77}

Despite this lack of consensus on the mechanism responsible, this benefit of SGLT2i has been accepted as certain and with great enthusiasm. Indeed, clinical trials are underway for SGLT2i in HF even in the absence of diabetes, and evidence is already emerging that SGLT2i are effective in in non-diabetic patients with HF.⁷⁸ The DAPA-HF phase 3 trial, for instance, in which over 4700 HF patients with LVEF <40% were randomized to receive dapagliflozin or placebo in addition to standard care, revealed a markedly reduced risk of HF worsening or cardiovascular death in diabetics and non-diabetics alike.⁷⁹

Conclusion

The core features of diabetic cardiomyopathy include cardiac stiffness, fibrosis, and ventricular hypertrophy with diastolic dysfunction and progression to systolic dysfunction and HF. Endothelial dysfunction has been considered a crucial link in the development of diabetic cardiomyopathy. Importantly, hyperglycemia and systemic insulin resistance are independently associated with the development and progression of cardiac dysfunction and HF in diabetes. SGLT2i therapy is currently one of the most effective treatments for diabetes-associated cardiomyopathy. Effective treatment of myocardial lipotoxicity, however, remains elusive.

References 1

1. Ritchie RH, Abel ED. Basic Mechanisms of Diabetic Heart Disease. Circ Res. 2020;126(11):1501-25. doi: 10.1161/CIRCRESAHA.120.315913.

Ritchie

Abel

Basic Mechanisms of Diabetic Heart Disease

Circ Res 2020 126 11 1501 1525

10.1161/CIRCRESAHA.120.315913

2. Cho NH, Shaw JE, Karuranga S, Huang Y, Fernandes JDR, Ohlrogge AW, et al. IDF Diabetes Atlas: Global Estimates of Diabetes Prevalence for 2017 and Projections for 2045. Diabetes Res Clin Pract. 2018;138:271-81. doi: 10.1016/j.diabres.2018.02.023.

Cho

Shaw

Karuranga

Huang

Fernandes

JDR

Ohlrogge

et al

IDF Diabetes Atlas: Global Estimates of Diabetes Prevalence for 2017 and Projections for 2045

Diabetes Res Clin Pract 2018 138 271 281

10.1016/j.diabres.2018.02.023

3. Kannel WB, Hjortland M, Castelli WP. Role of Diabetes in Congestive heArt Failure: The Framingham Study. Am J Cardiol. 1974;34(1):29-34. doi: 10.1016/0002-9149(74)90089-7.

Kannel

Hjortland

Castelli

Role of Diabetes in Congestive heArt Failure: The Framingham Study

Am J Cardiol 1974 34 1 29 34

10.1016/0002-9149(74)90089-7

4. 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(3):339-51. doi: 10.1016/j.jacc.2017.11.019.

Marwick

Ritchie

Shaw

Kaye

Implications of Underlying Mechanisms for the Recognition and Management of Diabetic Cardiomyopathy

J Am Coll Cardiol 2018 71 3 339 351

10.1016/j.jacc.2017.11.019

5. Miki T, Yuda S, Kouzu H, Miura T. Diabetic Cardiomyopathy: Pathophysiology and Clinical Features. Heart Fail Rev. 2013;18(2):149-66. doi: 10.1007/s10741-012-9313-3.

Miki

Yuda

Kouzu

Miura

Diabetic Cardiomyopathy: Pathophysiology and Clinical Features

Heart Fail Rev 2013 18 2 149 166

10.1007/s10741-012-9313-3

6. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The Incidence of Congestive Heart Failure in Type 2 Diabetes: An Update. Diabetes Care. 2004;27(8):1879-84. doi: 10.2337/diacare.27.8.1879.

Nichols

Gullion

Koro

Ephross

Brown

The Incidence of Congestive Heart Failure in Type 2 Diabetes: An Update

Diabetes Care 2004 27 8 1879 1884

10.2337/diacare.27.8.1879

7. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New Type of Cardiomyopathy Associated with Diabetic Glomerulosclerosis. Am J Cardiol. 1972;30(6):595-602. doi: 10.1016/0002-9149(72)90595-4.

Rubler

Dlugash

Yuceoglu

Kumral

Branwood

Grishman

New Type of Cardiomyopathy Associated with Diabetic Glomerulosclerosis

Am J Cardiol 1972 30 6 595 602

10.1016/0002-9149(72)90595-4

8. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classification of the Cardiomyopathies: A Position Statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2008;29(2):270-6. doi: 10.1093/eurheartj/ehm342.

Elliott

Andersson

Arbustini

Bilinska

Cecchi

Charron

et al

Classification of the Cardiomyopathies: A Position Statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases

Eur Heart J 2008 29 2 270 276

10.1093/eurheartj/ehm342

9. Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, et al. Evidence for Cardiomyopathy in Familial Diabetes Mellitus. J Clin Invest. 1977;60(4):884-99. doi: 10.1172/JCI108843.

Regan

Lyons

Ahmed

Levinson

Oldewurtel

Ahmad

et al

Evidence for Cardiomyopathy in Familial Diabetes Mellitus

J Clin Invest 1977 60 4 884 899

10.1172/JCI108843

10. Aronow WS, Ahn C. Incidence of Heart Failure in 2,737 Older Persons with and without Diabetes Mellitus. Chest. 1999;115(3):867-8. doi: 10.1378/chest.115.3.867.

Aronow

Ahn

Incidence of Heart Failure in 2,737 Older Persons with and without Diabetes Mellitus

Chest 1999 115 3 867 868

10.1378/chest.115.3.867

11. Lee M, Gardin JM, Lynch JC, Smith VE, Tracy RP, Savage PJ, et al. Diabetes Mellitus and Echocardiographic Left Ventricular Function in Free-Living Elderly Men and Women: The Cardiovascular Health Study. Am Heart J. 1997;133(1):36-43. doi: 10.1016/s0002-8703(97)70245-x.

Lee

Gardin

Lynch

Smith

Tracy

Savage

et al

Diabetes Mellitus and Echocardiographic Left Ventricular Function in Free-Living Elderly Men and Women: The Cardiovascular Health Study

Am Heart J 1997 133 1 36 43

10.1016/s0002-8703(97)70245-x

12. Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, et al. Impact of Diabetes on Cardiac Structure and Function: The Strong Heart Study. Circulation. 2000;101(19):2271-6. doi: 10.1161/01.cir.101.19.2271.

Devereux

Roman

Paranicas

O’Grady

Lee

Welty

et al

Impact of Diabetes on Cardiac Structure and Function: The Strong Heart Study

Circulation 2000 101 19 2271 2276

10.1161/01.cir.101.19.2271

13. Bertoni AG, Goff DC Jr, D’Agostino RB Jr, Liu K, Hundley WG, Lima JA, et al. Diabetic Cardiomyopathy and Subclinical Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2006;29(3):588-94. doi: 10.2337/diacare.29.03.06.dc05-1501.

Bertoni

Goff

Jr D’Agostino

Jr Liu

Hundley

Lima

et al

Diabetic Cardiomyopathy and Subclinical Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis (MESA)

Diabetes Care 2006 29 3 588 594

10.2337/diacare.29.03.06.dc05-1501

14. Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res. 2018;122(4):624-38. doi: 10.1161/CIRCRESAHA.117.311586.

Jia

Hill

Sowers

Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity

Circ Res 2018 122 4 624 638

10.1161/CIRCRESAHA.117.311586

15. Jia G, DeMarco VG, Sowers JR. Insulin Resistance and Hyperinsulinaemia in Diabetic Cardiomyopathy. Nat Rev Endocrinol. 2016;12(3):144-53. doi: 10.1038/nrendo.2015.216.

Jia

DeMarco

Sowers

Insulin Resistance and Hyperinsulinaemia in Diabetic Cardiomyopathy

Nat Rev Endocrinol 2016 12 3 144 153

10.1038/nrendo.2015.216

16. Westermeier F, Riquelme JA, Pavez M, Garrido V, Díaz A, Verdejo HE, et al. New Molecular Insights of Insulin in Diabetic Cardiomyopathy. Front Physiol. 2016;7:125. doi: 10.3389/fphys.2016.00125.

Westermeier

Riquelme

Pavez

Garrido

Díaz

Verdejo

et al

New Molecular Insights of Insulin in Diabetic Cardiomyopathy

Front Physiol 2016 7 125

10.3389/fphys.2016.00125

17. Talukder MA, Kalyanasundaram A, Zuo L, Velayutham M, Nishijima Y, Periasamy M, et al. Is Reduced SERCA2a Expression Detrimental or Beneficial to Postischemic Cardiac Function and Injury? Evidence from Heterozygous SERCA2a Knockout Mice. Am J Physiol Heart Circ Physiol. 2008;294(3):H1426-34. doi: 10.1152/ajpheart.01016.2007.

Talukder

Kalyanasundaram

Zuo

Velayutham

Nishijima

Periasamy

et al

Is Reduced SERCA2a Expression Detrimental or Beneficial to Postischemic Cardiac Function and Injury? Evidence from Heterozygous SERCA2a Knockout Mice

Am J Physiol Heart Circ Physiol 2008 294 3 H1426 H1434

10.1152/ajpheart.01016.2007

18. Tate M, Deo M, Cao AH, Hood SG, Huynh K, Kiriazis H, et al. Insulin Replacement Limits Progression of Diabetic Cardiomyopathy in the Low-Dose Streptozotocin-Induced Diabetic Rat. Diab Vasc Dis Res. 2017;14(5):423-33. doi: 10.1177/1479164117710390.

Tate

Deo

Cao

Hood

Huynh

Kiriazis

et al

Insulin Replacement Limits Progression of Diabetic Cardiomyopathy in the Low-Dose Streptozotocin-Induced Diabetic Rat

Diab Vasc Dis Res 2017 14 5 423 433

10.1177/1479164117710390

19. Nakamura K, Miyoshi T, Yoshida M, Akagi S, Saito Y, Ejiri K, et al. Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus. Int J Mol Sci. 2022;23(7):3587. doi: 10.3390/ijms23073587.

Nakamura

Miyoshi

Yoshida

Akagi

Saito

Ejiri

et al

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus

Int J Mol Sci 2022 23 7 3587

10.3390/ijms23073587

20. Wang M, Li Y, Li S, Lv J. Endothelial Dysfunction and Diabetic Cardiomyopathy. Front Endocrinol. 2022;13:851941. doi: 10.3389/fendo.2022.851941.

Wang

Endothelial Dysfunction and Diabetic Cardiomyopathy

Front Endocrinol 2022 13 851941

10.3389/fendo.2022.851941

21. Khanna S, Singh GB, Khullar M. Nitric Oxide Synthases and Diabetic Cardiomyopathy. Nitric Oxide. 2014;43:29-34. doi: 10.1016/j.niox.2014.08.004.

Khanna

Singh

Khullar

Nitric Oxide Synthases and Diabetic Cardiomyopathy

Nitric Oxide 2014 43 29 34

10.1016/j.niox.2014.08.004

22. Sampaio RC, Tanus-Santos JE, Melo SE, Hyslop S, Franchini KG, Luca IM, et al. Hypertension Plus Diabetes Mimics the Cardiomyopathy Induced by Nitric Oxide Inhibition in Rats. Chest. 2002;122(4):1412-20. doi: 10.1378/chest.122.4.1412.

Sampaio

Tanus-Santos

Melo

Hyslop

Franchini

Luca

et al

Hypertension Plus Diabetes Mimics the Cardiomyopathy Induced by Nitric Oxide Inhibition in Rats

Chest 2002 122 4 1412 1420

10.1378/chest.122.4.1412

23. Ren J, Duan J, Thomas DP, Yang X, Sreejayan N, Sowers JR, et al. IGF-I Alleviates Diabetes-Induced RhoA Activation, eNOS Uncoupling, and Myocardial Dysfunction. Am J Physiol Regul Integr Comp Physiol. 2008;294(3):R793-802. doi: 10.1152/ajpregu.00713.2007.

Ren

Duan

Thomas

Yang

Sreejayan

Sowers

et al

IGF-I Alleviates Diabetes-Induced RhoA Activation, eNOS Uncoupling, and Myocardial Dysfunction

Am J Physiol Regul Integr Comp Physiol 2008 294 3 R793 R802

10.1152/ajpregu.00713.2007

24. Roe ND, Thomas DP, Ren J. Inhibition of NADPH Oxidase Alleviates Experimental Diabetes-Induced Myocardial Contractile Dysfunction. Diabetes Obes Metab. 2011;13(5):465-73. doi: 10.1111/j.1463-1326.2011.01369.x.

Roe

Thomas

Ren

Inhibition of NADPH Oxidase Alleviates Experimental Diabetes-Induced Myocardial Contractile Dysfunction

Diabetes Obes Metab 2011 13 5 465 473

10.1111/j.1463-1326.2011.01369.x

25. Stockklauser-Färber K, Ballhausen T, Laufer A, Rösen P. Influence of Diabetes on Cardiac Nitric Oxide Synthase Expression and Activity. Biochim Biophys Acta. 2000;1535(1):10-20. doi: 10.1016/s0925-4439(00)00078-8.

Stockklauser-Färber

Ballhausen

Laufer

Rösen

Influence of Diabetes on Cardiac Nitric Oxide Synthase Expression and Activity

Biochim Biophys Acta 2000 1535 1 10 20

10.1016/s0925-4439(00)00078-8

26. Chen S, Evans T, Mukherjee K, Karmazyn M, Chakrabarti S. Diabetes-Induced Myocardial Structural Changes: Role of Endothelin-1 and Its Receptors. J Mol Cell Cardiol. 2000;32(9):1621-9. doi: 10.1006/jmcc.2000.1197.

Chen

Evans

Mukherjee

Karmazyn

Chakrabarti

Diabetes-Induced Myocardial Structural Changes: Role of Endothelin-1 and Its Receptors

J Mol Cell Cardiol 2000 32 9 1621 1629

10.1006/jmcc.2000.1197

27. Patel H, Chen J, Das KC, Kavdia M. Hyperglycemia Induces Differential Change in Oxidative Stress at Gene Expression and Functional Levels in HUVEC and HMVEC. Cardiovasc Diabetol. 2013;12:142. doi: 10.1186/1475-2840-12-142.

Patel

Chen

Das

Kavdia

Hyperglycemia Induces Differential Change in Oxidative Stress at Gene Expression and Functional Levels in HUVEC and HMVEC

Cardiovasc Diabetol 2013 12 142

10.1186/1475-2840-12-142

28. Chistiakov DA, Melnichenko AA, Grechko AV, Myasoedova VA, Orekhov AN. Potential of Anti-Inflammatory Agents for Treatment of Atherosclerosis. Exp Mol Pathol. 2018;104(2):114-24. doi: 10.1016/j.yexmp.2018.01.008.

Chistiakov

Melnichenko

Grechko

Myasoedova

Orekhov

Potential of Anti-Inflammatory Agents for Treatment of Atherosclerosis

Exp Mol Pathol 2018 104 2 114 124

10.1016/j.yexmp.2018.01.008

29. Chandel S, Sathis A, Dhar M, Giri H, Nathan AA, Samawar SKR, et al. Hyperinsulinemia Promotes Endothelial Inflammation via Increased Expression and Release of Angiopoietin-2. Atherosclerosis. 2020 Aug;307:1-10. doi: 10.1016/j.atherosclerosis.2020.06.016.

Chandel

Sathis

Dhar

Giri

Nathan

Samawar

SKR

et al

Hyperinsulinemia Promotes Endothelial Inflammation via Increased Expression and Release of Angiopoietin-2

Atherosclerosis 2020 08 307 1 10

10.1016/j.atherosclerosis.2020.06.016

30. Terriaca S, Fiorelli E, Scioli MG, Fabbri G, Storti G, Cervelli V, et al. Endothelial Progenitor Cell-Derived Extracellular Vesicles: Potential Therapeutic Application in Tissue Repair and Regeneration. Int J Mol Sci. 2021;22(12):6375. doi: 10.3390/ijms22126375.

Terriaca

Fiorelli

Scioli

Fabbri

Storti

Cervelli

et al

Endothelial Progenitor Cell-Derived Extracellular Vesicles: Potential Therapeutic Application in Tissue Repair and Regeneration

Int J Mol Sci 2021 22 12 6375

10.3390/ijms22126375

31. Sheetz MJ, King GL. Molecular Understanding of Hyperglycemia’s Adverse Effects for Diabetic Complications. JAMA. 2002;288(20):2579-88. doi: 10.1001/jama.288.20.2579.

Sheetz

King

Molecular Understanding of Hyperglycemia’s Adverse Effects for Diabetic Complications

JAMA 2002 288 20 2579 2588

10.1001/jama.288.20.2579

32. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, et al. Impaired Endothelium-Dependent and Independent Vasodilation in Patients with Type 2 (Non-Insulin-Dependent) Diabetes Mellitus. Diabetologia. 1992;35(8):771-6. doi: 10.1007/BF00429099.

McVeigh

Brennan

Johnston

McDermott

McGrath

Henry

et al

Impaired Endothelium-Dependent and Independent Vasodilation in Patients with Type 2 (Non-Insulin-Dependent) Diabetes Mellitus

Diabetologia 1992 35 8 771 776

10.1007/BF00429099

33. Lambert J, Aarsen M, Donker AJ, Stehouwer CD. Endothelium-Dependent and -Independent Vasodilation of Large Arteries in Normoalbuminuric Insulin-Dependent Diabetes Mellitus. Arterioscler Thromb Vasc Biol. 1996;16(5):705-11. doi: 10.1161/01.atv.16.5.705.

Lambert

Aarsen

Donker

Stehouwer

Endothelium-Dependent and -Independent Vasodilation of Large Arteries in Normoalbuminuric Insulin-Dependent Diabetes Mellitus

Arterioscler Thromb Vasc Biol 1996 16 5 705 711

10.1161/01.atv.16.5.705

34. Chen S, Khan ZA, Cukiernik M, Chakrabarti S. Differential Activation of NF-Kappa B and AP-1 in Increased Fibronectin Synthesis in Target Organs of Diabetic Complications. Am J Physiol Endocrinol Metab. 2003;284(6):E1089-97. doi: 10.1152/ajpendo.00540.2002.

Chen

Khan

Cukiernik

Chakrabarti

Differential Activation of NF-Kappa B and AP-1 in Increased Fibronectin Synthesis in Target Organs of Diabetic Complications

Am J Physiol Endocrinol Metab 2003 284 6 E1089 E1097

10.1152/ajpendo.00540.2002

35. Mebazaa A, Mayoux E, Maeda K, Martin LD, Lakatta EG, Robotham JL, et al. Paracrine Effects of Endocardial Endothelial Cells on Myocyte Contraction Mediated via Endothelin. Am J Physiol. 1993;265(5 Pt 2):H1841-6. doi: 10.1152/ajpheart.1993.265.5.H1841.

Mebazaa

Mayoux

Maeda

Martin

Lakatta

Robotham

et al

Paracrine Effects of Endocardial Endothelial Cells on Myocyte Contraction Mediated via Endothelin

Am J Physiol 1993 265 5 Pt 2 H1841 H1846

10.1152/ajpheart.1993.265.5.H1841

36. Shimizu M, Umeda K, Sugihara N, Yoshio H, Ino H, Takeda R, et al. Collagen Remodelling in Myocardia of Patients with Diabetes. J Clin Pathol. 1993;46(1):32-6. doi: 10.1136/jcp.46.1.32.

Shimizu

Umeda

Sugihara

Yoshio

Ino

Takeda

et al

Collagen Remodelling in Myocardia of Patients with Diabetes

J Clin Pathol 1993 46 1 32 36

10.1136/jcp.46.1.32

37. Turkbey EB, Backlund JY, Genuth S, Jain A, Miao C, Cleary PA, et al. Myocardial Structure, Function, and Scar in Patients with Type 1 Diabetes Mellitus. Circulation. 2011;124(16):1737-46. doi: 10.1161/CIRCULATIONAHA.111.022327.

Turkbey

Backlund

Genuth

Jain

Miao

Cleary

et al

Myocardial Structure, Function, and Scar in Patients with Type 1 Diabetes Mellitus

Circulation 2011 124 16 1737 1746

10.1161/CIRCULATIONAHA.111.022327

38. Lorenzo-Almorós A, Tuñón J, Orejas M, Cortés M, Egido J, Lorenzo Ó. Diagnostic Approaches for Diabetic Cardiomyopathy. Cardiovasc Diabetol. 2017;16(1):28. doi: 10.1186/s12933-017-0506-x.

Lorenzo-Almorós

Tuñón

Orejas

Cortés

Egido

Lorenzo

Diagnostic Approaches for Diabetic Cardiomyopathy

Cardiovasc Diabetol 2017 16 1 28

10.1186/s12933-017-0506-x

39. Paiman EHM, van Eyk HJ, Bizino MB, Dekkers IA, de Heer P, Smit JWA, et al. Phenotyping Diabetic Cardiomyopathy in Europeans and South Asians. Cardiovasc Diabetol. 2019;18(1):133. doi: 10.1186/s12933-019-0940-z.

Paiman

EHM

van Eyk

Bizino

Dekkers

Heer

Smit

JWA

et al

Phenotyping Diabetic Cardiomyopathy in Europeans and South Asians

Cardiovasc Diabetol 2019 18 1 133

10.1186/s12933-019-0940-z

40. Kwong RY, Sattar H, Wu H, Vorobiof G, Gandla V, Steel K, et al. Incidence and Prognostic Implication of Unrecognized Myocardial Scar Characterized by Cardiac Magnetic Resonance in Diabetic Patients without Clinical Evidence of Myocardial Infarction. Circulation. 2008;118(10):1011-20. doi: 10.1161/CIRCULATIONAHA.107.727826.

Kwong

Sattar

Vorobiof

Gandla

Steel

et al

Incidence and Prognostic Implication of Unrecognized Myocardial Scar Characterized by Cardiac Magnetic Resonance in Diabetic Patients without Clinical Evidence of Myocardial Infarction

Circulation 2008 118 10 1011 1020

10.1161/CIRCULATIONAHA.107.727826

41. Seferović PM, Paulus WJ. Clinical Diabetic Cardiomyopathy: A Two-Faced Disease with Restrictive and Dilated Phenotypes. Eur Heart J. 2015;36(27):1718-27. doi: 10.1093/eurheartj/ehv134.

Seferović

Paulus

Clinical Diabetic Cardiomyopathy: A Two-Faced Disease with Restrictive and Dilated Phenotypes

Eur Heart J 2015 36 27 1718 1727

10.1093/eurheartj/ehv134

42. Bugger H, Abel ED. Molecular Mechanisms of Diabetic Cardiomyopathy. Diabetologia. 2014;57(4):660-71. doi: 10.1007/s00125-014-3171-6.

Bugger

Abel

Molecular Mechanisms of Diabetic Cardiomyopathy

Diabetologia 2014 57 4 660 671

10.1007/s00125-014-3171-6

43. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2016;17(12):1321-60. doi: 10.1093/ehjci/jew082.

Nagueh

Smiseth

Appleton

Byrd

3rd Dokainish

Edvardsen

et al

Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

Eur Heart J Cardiovasc Imaging 2016 17 12 1321 1360

10.1093/ehjci/jew082

44. Zabalgoitia M, Ismaeil MF, Anderson L, Maklady FA. Prevalence of Diastolic Dysfunction in Normotensive, Asymptomatic Patients with Well-Controlled Type 2 Diabetes Mellitus. Am J Cardiol. 2001;87(3):320-3. doi: 10.1016/s0002-9149(00)01366-7.

Zabalgoitia

Ismaeil

Anderson

Maklady

Prevalence of Diastolic Dysfunction in Normotensive, Asymptomatic Patients with Well-Controlled Type 2 Diabetes Mellitus

Am J Cardiol 2001 87 3 320 323

10.1016/s0002-9149(00)01366-7

45. Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic Cardiomyopathy: Mechanisms and New Treatment Strategies Targeting Antioxidant Signaling Pathways. Pharmacol Ther. 2014;142(3):375-415. doi: 10.1016/j.pharmthera.2014.01.003.

Huynh

Bernardo

McMullen

Ritchie

Diabetic Cardiomyopathy: Mechanisms and New Treatment Strategies Targeting Antioxidant Signaling Pathways

Pharmacol Ther 2014 142 3 375 415

10.1016/j.pharmthera.2014.01.003

46. Dogdus M, Dindas F, Akhan O, Yenercag M, Yildirim A, Abacioglu OO, et al. Impaired Left Atrial Strain in the Presence of Interatrial Block in Patients with Type 2 Diabetes Mellitus. Int J Cardiovasc Imaging. 2021;37(7):2127-34. doi: 10.1007/s10554-021-02278-0.

Dogdus

Dindas

Akhan

Yenercag

Yildirim

Abacioglu

et al

Impaired Left Atrial Strain in the Presence of Interatrial Block in Patients with Type 2 Diabetes Mellitus

Int J Cardiovasc Imaging 2021 37 7 2127 2134

10.1007/s10554-021-02278-0

47. Murtaza G, Virk HUH, Khalid M, Lavie CJ, Ventura H, Mukherjee D, et al. Diabetic Cardiomyopathy - A Comprehensive Updated Review. Prog Cardiovasc Dis. 2019;62(4):315-26. doi: 10.1016/j.pcad.2019.03.003.

Murtaza

Virk

HUH

Khalid

Lavie

Ventura

Mukherjee

et al

Diabetic Cardiomyopathy - A Comprehensive Updated Review

Prog Cardiovasc Dis 2019 62 4 315 326

10.1016/j.pcad.2019.03.003

48. Dunlay SM, Roger VL, Redfield MM. Epidemiology of Heart Failure with Preserved Ejection Fraction. Nat Rev Cardiol. 2017;14(10):591-602. doi: 10.1038/nrcardio.2017.65.

Dunlay

Roger

Redfield

Epidemiology of Heart Failure with Preserved Ejection Fraction

Nat Rev Cardiol 2017 14 10 591 602

10.1038/nrcardio.2017.65

49. Shah SJ. Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview. J Cardiovasc Transl Res. 2017;10(3):233-44. doi: 10.1007/s12265-017-9756-y.

Shah

Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview

J Cardiovasc Transl Res 2017 10 3 233 244

10.1007/s12265-017-9756-y

50. Jorge AL, Rosa ML, Martins WA, Correia DM, Fernandes LC, Costa JA, et al. The Prevalence of Stages of Heart Failure in Primary Care: A Population-Based Study. J Card Fail. 2016;22(2):153-7. doi: 10.1016/j.cardfail.2015.10.017.

Jorge

Rosa

Martins

Correia

Fernandes

Costa

et al

The Prevalence of Stages of Heart Failure in Primary Care: A Population-Based Study

J Card Fail 2016 22 2 153 157

10.1016/j.cardfail.2015.10.017

51. Redfield MM. Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2016;375(19):1868-77. doi: 10.1056/NEJMcp1511175.

Redfield

Heart Failure with Preserved Ejection Fraction

N Engl J Med 2016 375 19 1868 1877

10.1056/NEJMcp1511175

52. Beale AL, Nanayakkara S, Segan L, Mariani JA, Maeder MT, van Empel V, et al. Sex Differences in Heart Failure with Preserved Ejection Fraction Pathophysiology: A Detailed Invasive Hemodynamic and Echocardiographic Analysis. JACC Heart Fail. 2019;7(3):239-49. doi: 10.1016/j.jchf.2019.01.004.

Beale

Nanayakkara

Segan

Mariani

Maeder

van Empel

et al

Sex Differences in Heart Failure with Preserved Ejection Fraction Pathophysiology: A Detailed Invasive Hemodynamic and Echocardiographic Analysis

JACC Heart Fail 2019 7 3 239 249

10.1016/j.jchf.2019.01.004

53. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure with Preserved Ejection Fraction. Circulation. 2017;136(1):6-19. doi: 10.1161/CIRCULATIONAHA.116.026807.

Obokata

Reddy

YNV

Pislaru

Melenovsky

Borlaug

Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure with Preserved Ejection Fraction

Circulation 2017 136 1 6 19

10.1161/CIRCULATIONAHA.116.026807

54. Unger ED, Dubin RF, Deo R, Daruwalla V, Friedman JL, Medina C, et al. Association of Chronic Kidney Disease with Abnormal Cardiac Mechanics and Adverse Outcomes in Patients with Heart Failure and Preserved Ejection Fraction. Eur J Heart Fail. 2016;18(1):103-12. doi: 10.1002/ejhf.445.

Unger

Dubin

Deo

Daruwalla

Friedman

Medina

et al

Association of Chronic Kidney Disease with Abnormal Cardiac Mechanics and Adverse Outcomes in Patients with Heart Failure and Preserved Ejection Fraction

Eur J Heart Fail 2016 18 1 103 112

10.1002/ejhf.445

55. Tromp J, Lim SL, Tay WT, Teng TK, Chandramouli C, Ouwerkerk W, et al. Microvascular Disease in Patients with Diabetes with Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction. Diabetes Care. 2019;42(9):1792-99. doi: 10.2337/dc18-2515.

Tromp

Lim

Tay

Teng

Chandramouli

Ouwerkerk

et al

Microvascular Disease in Patients with Diabetes with Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction

Diabetes Care 2019 42 9 1792 1799

10.2337/dc18-2515

56. Figtree GA, Rådholm K, Barrett TD, Perkovic V, Mahaffey KW, de Zeeuw D, et al. Effects of Canagliflozin on Heart Failure Outcomes Associated with Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus. Circulation. 2019;139(22):2591-3. doi: 10.1161/CIRCULATIONAHA.119.040057.

Figtree

Rådholm

Barrett

Perkovic

Mahaffey

Zeeuw

et al

Effects of Canagliflozin on Heart Failure Outcomes Associated with Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus

Circulation 2019 139 22 2591 2593

10.1161/CIRCULATIONAHA.119.040057

57. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure with Preserved Ejection Fraction. Circulation. 2015;131(6):550-9. doi: 10.1161/CIRCULATIONAHA.114.009625.

Mohammed

Hussain

Mirzoyev

Edwards

Maleszewski

Redfield

Coronary Microvascular Rarefaction and Myocardial Fibrosis in Heart Failure with Preserved Ejection Fraction

Circulation 2015 131 6 550 559

10.1161/CIRCULATIONAHA.114.009625

58. Pieske B, Tschöpe C, de Boer RA, Fraser AG, Anker SD, Donal E, et al. How to Diagnose Heart Failure with Preserved Ejection Fraction: The HFA-PEFF Diagnostic Algorithm: A Consensus Recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297-317. doi: 10.1093/eurheartj/ehz641.

Pieske

Tschöpe

Boer

Fraser

Anker

Donal

et al

How to Diagnose Heart Failure with Preserved Ejection Fraction: The HFA-PEFF Diagnostic Algorithm: A Consensus Recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

Eur Heart J 2019 40 40 3297 3317

10.1093/eurheartj/ehz641

59. Durgan DJ, Pat BM, Laczy B, Bradley JA, Tsai JY, Grenett MH, et al. O-GlcNAcylation, Novel Post-Translational Modification Linking Myocardial Metabolism and Cardiomyocyte Circadian Clock. J Biol Chem. 2011;286(52):44606-19. doi: 10.1074/jbc.M111.278903.

Durgan

Pat

Laczy

Bradley

Tsai

Grenett

et al

O-GlcNAcylation, Novel Post-Translational Modification Linking Myocardial Metabolism and Cardiomyocyte Circadian Clock

J Biol Chem 2011 286 52 44606 44619

10.1074/jbc.M111.278903

60. Marcondes-Braga FG, Moura LAZ, Issa VS, Vieira JL, Rohde LE, Simões MV, et al. Emerging Topics Update of the Brazilian Heart Failure Guideline - 2021. Arq Bras Cardiol. 2021;116(6):1174-212. doi: 10.36660/abc.20210367.

Marcondes-Braga

Moura

LAZ

Issa

Vieira

Rohde

Simões

et al

Emerging Topics Update of the Brazilian Heart Failure Guideline - 2021

Arq Bras Cardiol 2021 116 6 1174 1212

10.36660/abc.20210367.

61. Lind M, Bounias I, Olsson M, Gudbjörnsdottir 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(9786):140-6. doi: 10.1016/S0140-6736(11)60471-6.

Lind

Bounias

Olsson

Gudbjörnsdottir

Svensson

Rosengren

Glycaemic Control and Incidence of Heart Failure in 20,985 Patients with Type 1 Diabetes: An Observational Study

Lancet 2011 378 9786 140 146

10.1016/S0140-6736(11)60471-6

62. Hippisley-Cox J, Coupland C. Diabetes Treatments and Risk of Heart Failure, Cardiovascular Disease, and All Cause Mortality: Cohort Study in Primary Care. BMJ. 2016;354:i3477. doi: 10.1136/bmj.i3477.

Hippisley-Cox

Coupland

Diabetes Treatments and Risk of Heart Failure, Cardiovascular Disease, and All Cause Mortality: Cohort Study in Primary Care

BMJ 2016 354 i3477

10.1136/bmj.i3477

63. Seferović PM, Coats AJS, Ponikowski P, Filippatos G, Huelsmann M, Jhund PS, et al. European Society of Cardiology/Heart Failure Association position Paper on the Role and Safety of New Glucose-Lowering Drugs in Patients with Heart Failure. Eur J Heart Fail. 2020;22(2):196-213. doi: 10.1002/ejhf.1673.

Seferović

Coats

AJS

Ponikowski

Filippatos

Huelsmann

Jhund

et al

European Society of Cardiology/Heart Failure Association position Paper on the Role and Safety of New Glucose-Lowering Drugs in Patients with Heart Failure

Eur J Heart Fail 2020 22 2 196 213

10.1002/ejhf.1673

64. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): a Double-Blind, Randomised Placebo-Controlled Trial. Lancet. 2019;394(10193):121-30. doi: 10.1016/S0140-6736(19)31149-3.

Gerstein

Colhoun

Dagenais

Diaz

Lakshmanan

Pais

et al

Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND): a Double-Blind, Randomised Placebo-Controlled Trial

Lancet 2019 394 10193 121 130

10.1016/S0140-6736(19)31149-3.

65. Cefalu WT, Kaul S, Gerstein HC, Holman RR, Zinman B, Skyler JS, et al. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where do we Go from Here? Reflections from a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2018;41(1):14-31. doi: 10.2337/dci17-0057.

Cefalu

Kaul

Gerstein

Holman

Zinman

Skyler

et al

Cardiovascular Outcomes Trials in Type 2 Diabetes: Where do we Go from Here? Reflections from a Diabetes Care Editors’ Expert Forum

Diabetes Care 2018 41 1 14 31

10.2337/dci17-0057

66. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-28. doi: 10.1056/NEJMoa1504720.

Zinman

Wanner

Lachin

Fitchett

Bluhmki

Hantel

et al

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

N Engl J Med 2015 373 22 2117 2128

10.1056/NEJMoa1504720

67. Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, et al. Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation. 2019;139(11):1384-95. doi: 10.1161/CIRCULATIONAHA.118.037778.

Fitchett

Inzucchi

Cannon

McGuire

Scirica

Johansen

et al

Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial

Circulation 2019 139 11 1384 1395

10.1161/CIRCULATIONAHA.118.037778

68. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-57. doi: 10.1056/NEJMoa1611925.

Neal

Perkovic

Mahaffey

Zeeuw

Fulcher

Erondu

et al

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

N Engl J Med 2017 377 7 644 657

10.1056/NEJMoa1611925

69. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-306. doi: 10.1056/NEJMoa1811744.

Perkovic

Jardine

Neal

Bompoint

Heerspink

HJL

Charytan

et al

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

N Engl J Med 2019 380 24 2295 2306

10.1056/NEJMoa1811744

70. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136(3):249-59. doi: 10.1161/CIRCULATIONAHA.117.029190.

Kosiborod

Cavender

Wilding

Khunti

Holl

et al

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

Circulation 2017 136 3 249 259

10.1161/CIRCULATIONAHA.117.029190

71. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-57. doi: 10.1056/NEJMoa1812389.

Wiviott

Raz

Bonaca

Mosenzon

Kato

Cahn

et al

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

N Engl J Med 2019 380 4 347 357

10.1056/NEJMoa1812389

72. Cahn A, Mosenzon O, Wiviott SD, Rozenberg A, Yanuv I, Goodrich EL, et al. Efficacy and Safety of Dapagliflozin in the Elderly: Analysis from the DECLARE-TIMI 58 Study. Diabetes Care. 2020;43(2):468-75. doi: 10.2337/dc19-1476.

Cahn

Mosenzon

Wiviott

Rozenberg

Yanuv

Goodrich

et al

Efficacy and Safety of Dapagliflozin in the Elderly: Analysis from the DECLARE-TIMI 58 Study

Diabetes Care 2020 43 2 468 475

10.2337/dc19-1476

73. Kluger AY, Tecson KM, Lee AY, Lerma EV, Rangaswami J, Lepor NE, et al. Class Effects of SGLT2 Inhibitors on Cardiorenal Outcomes. Cardiovasc Diabetol. 2019;18(1):99. doi: 10.1186/s12933-019-0903-4.

Kluger

Tecson

Lee

Lerma

Rangaswami

Lepor

et al

Class Effects of SGLT2 Inhibitors on Cardiorenal Outcomes

Cardiovasc Diabetol 2019 18 1 99

10.1186/s12933-019-0903-4

74. Scheen AJ. Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors. Circ Res. 2018;122(10):1439-59. doi: 10.1161/CIRCRESAHA.117.311588.

Scheen

Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors

Circ Res 2018 122 10 1439 1459

10.1161/CIRCRESAHA.117.311588

75. Kramer CK, Zinman B. Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes. Annu Rev Med. 2019;70:323-34. doi: 10.1146/annurev-med-042017-094221.

Kramer

Zinman

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes

Annu Rev Med 2019 70 323 334

10.1146/annurev-med-042017-094221

76. van Steenbergen A, Balteau M, Ginion A, Ferté L, Battault S, Ravenstein CM, et al. Sodium-Myoinositol Cotransporter-1, SMIT1, Mediates the Production of Reactive Oxygen Species Induced by Hyperglycemia in the Heart. Sci Rep. 2017;7:41166. doi: 10.1038/srep41166.

van Steenbergen

Balteau

Ginion

Ferté

Battault

Ravenstein

et al

Sodium-Myoinositol Cotransporter-1, SMIT1, Mediates the Production of Reactive Oxygen Species Induced by Hyperglycemia in the Heart

Sci Rep 2017 7 41166

10.1038/srep41166

77. Vrhovac I, Eror DB, Klessen D, Burger C, Breljak D, Kraus O, et al. Localizations of Na(+)-D-glucose Cotransporters SGLT1 and SGLT2 in Human Kidney and of SGLT1 in Human Small Intestine, Liver, Lung, and Heart. Pflugers Arch. 2015;467(9):1881-98. doi: 10.1007/s00424-014-1619-7.

Vrhovac

Eror

Klessen

Burger

Breljak

Kraus

et al

Localizations of Na(+)-D-glucose Cotransporters SGLT1 and SGLT2 in Human Kidney and of SGLT1 in Human Small Intestine, Liver, Lung, and Heart

Pflugers Arch 2015 467 9 1881 1898

10.1007/s00424-014-1619-7

78. McMurray JJV, Solomon SD, Docherty KF, Jhund PS. The Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial (DAPA-HF) in Context. Eur Heart J. 2021;42(13):1199-202. doi: 10.1093/eurheartj/ehz916.

McMurray

JJV

Solomon

Docherty

Jhund

The Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial (DAPA-HF) in Context

Eur Heart J 2021 42 13 1199 1202

10.1093/eurheartj/ehz916

79. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi: 10.1056/NEJMoa1911303.

McMurray

JJV

Solomon

Inzucchi

Køber

Kosiborod

Martinez

et al

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

N Engl J Med 2019 381 21 1995 2008

10.1056/NEJMoa1911303

Study association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of funding: There were no external funding sources for this study.

Artigo de Revisão

Miocardiopatia Diabética e Insuficiência Cardíaca

0000-0003-0034-4981

Jorge

Antonio José Lagoeiro

Concepção e desenho da pesquisa Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo intelectual importante ¹ ² Carvalho

Marcio Roberto Moraes de

Concepção e desenho da pesquisa Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo intelectual importante ²

1 Brasil Programa de Pós-graduação em Ciências Cardiovasculares – Universidade Federal Fluminense (UFF), Niterói, RJ – Brasil 2 Brasil Faculdade de Medicina, Universidade Federal Fluminense (UFF), Niterói, RJ – Brasil

Correspondência: Antonio José Lagoeiro Jorge • Avenida Marques do Paraná, 303, 6º andar. CEP 24030-215, Centro, Niterói, RJ – Brasil E-mail: antoniolagoeiro@id.uff.br

Potencial conflito de interesse

Não há conflito com o presente artigo

Diabetes Mellitus Cardiomiopatias Insuficiência Cardíaca

Introdução

A prevalência global de diabetes, principalmente de diabetes tipo 2 (DM2), tem aumentado progressivamente ao longo dos anos de maneira preocupante.¹ As estimativas mais recentes do Atlas de Diabetes da Federação Internacional de Diabetes consideram mais de 450 milhões de adultos com diabetes em todo o mundo, sendo que a projeção para 2045 é de 693 milhões de indivíduos com DM2² . Essa pandemia de diabetes irá impor um fardo significativo à sociedade, tanto em termos de custos substanciais ao sistema de saúde quanto de resultados ruins para a saúde dos pacientes com DM2.²

O estudo de Framingham estabeleceu as ligações epidemiológicas entre diabetes e aumento do risco de insuficiência cardíaca (IC).³ É bastante estudado que o diabetes não apenas aumenta o risco de IC, mas também aumenta sua incidência em aproximadamente 2,5 vezes, independentemente da idade ou de comorbidades concomitantes.¹ Os pacientes diabéticos representam hoje até um terço dos pacientes em estudos clínicos de IC, sendo o diabetes um preditor independente de desfecho ruim^{4 , 5} e que levou a uma epidemia mundial de IC.⁶

A miocardiopatia diabética pode ser definida pela existência de alterações estruturais e funcionais do miocárdio na ausência de outros fatores de risco cardíaco, como doença arterial coronariana, hipertensão e doença valvular significativa em indivíduos com diabetes.⁷ O termo miocardiopatia diabética foi descrito pela primeira vez por Rubler em 1972, em uma pequena coorte de quatro pacientes. O autor demonstrou que não havia evidência de doença arterial coronariana nos resultados da autópsia dos quatro pacientes do estudo com glomeruloesclerose diabética e insuficiência cardíaca.⁷ Hipertrofia e fibrose miocárdica foram observadas no coração desses pacientes, sugerindo que o metabolismo seria o responsável pelos achados. O estudo de Rubler atende à definição contemporânea de miocardiopatia da European Society of Cardiology.⁸ As observações de Rubler foram apoiadas pelos resultados de Regan⁹ em 1977, que realizou autópsia de 11 pacientes diabéticos não complicados, mostrando que 9 não tinham doença arterial coronariana e que a maioria morreu de IC. Múltiplas amostras do ventrículo esquerdo (VE) e do septo revelaram níveis aumentados de triglicerídeos e colesterol em comparação com os controles. Portanto, foi sugerida a presença de uma anormalidade extravascular difusa, que é a base para miocardiopatia diabética.⁹

Aspectos clínicos da miocardiopatia associada a diabetes

Estudos mostram que a prevalência de IC em pacientes diabéticos varia de 19 a 26%, sendo que essa associação foi independente de obesidade, hipertensão, dislipidemia e doença coronariana.³ Um estudo mostrou que a incidência de IC foi maior em diabéticos (39%) em comparação com não diabéticos (23%), com risco relativo de 1,3 para o desenvolvimento de IC após 43 meses de observação.¹⁰ Dados adicionais derivados de estudos observacionais de base populacional, como o Cardiovascular Health Study (CHS),¹¹ o Strong Heart Study (SHS)¹² e o Multi-Ethnic Study of Atherosclerosis (MESA),¹³ demonstraram diferenças na massa e espessura da parede do VE e aumento da disfunção diastólica e sistólica entre pacientes diabéticos e indivíduos normais. Em pacientes com DM2, cada aumento de 1% nos níveis de hemoglobina glicada foi associado a um aumento de 8% do risco de IC, independentemente de outros fatores de risco como obesidade, tabagismo, hipertensão, dislipidemia e doença coronariana, sugerindo que aumentos graduais na glicemia são um poderoso promotor de IC em pacientes diabéticos.¹⁴

A hiperglicemia e a resistência sistêmica à insulina são as principais anormalidades clínicas no diabetes, e todas estão envolvidas na patogênese da miocardiopatia diabética.¹⁵ A miocardiopatia diabética costuma ser assintomática nos estágios iniciais de sua evolução. Uma das primeiras manifestações é a hipertrofia do VE e/ou diminuição da complacência do VE, caracterizada por enchimento diastólico precoce prejudicado, enchimento atrial aumentado e prolongamento do relaxamento isovolumétrico. A dilatação do VE e a IC sintomática ocorrem após o desenvolvimento da disfunção sistólica.¹⁵ A rigidez e hipertrofia dos cardiomiócitos, bem como a fibrose miocárdica, contribuem para essa anormalidade cardíaca ( Figura 1 ). O CHS constatou que, em uma coorte de 5.201 homens e mulheres, as espessuras do septo ventricular e da parede miocárdica posterior esquerda eram maiores em pacientes diabéticos do que em indivíduos não diabéticos e que isso estava associado ao comprometimento da função sistólica e/ou diastólica.¹¹

Figura 1 – Os mecanismos fisiopatológicos da cardiomiopatia diabética. Hiperglicemia, resistência à insulina e alterações metabólicas no cardiomiócito induzem resistência à insulina e distúrbios metabólicos que aumentam a disfunção mitocondrial, inflamação, neuropatia autonômica, estresse oxidativo, ativação de sistema renina-angiotensina-aldosterona (SRAA) e produção de produtos finais de glicação avançada (AGEs), levando à morte dos cardiomiócitos, bem como à disfunção microvascular. Essas anormalidades fisiopatológicas promovem rigidez cardíaca, hipertrofia e fibrose, resultando em disfunção cardíaca diastólica, disfunção sistólica e insuficiência cardíaca. Adaptado de Jia et al. <xref ref-type="bibr" rid="B14">14</xref>

A evolução clínica da miocardiopatia diabética pode ser dividida em duas fases. A primeira fase é clinicamente assintomática e caracterizada por aumento da fibrose e rigidez; há redução do enchimento diastólico precoce, remodelamento dos volumes atriais e elevação da pressão diastólica final do VE.¹⁶ Fatores patológicos subjacentes incluem hiperglicemia, resistência sistêmica e cardíaca à insulina, aumento dos níveis de ácidos graxos livres (FFA), inflamação sistêmica e tecidual e estresse oxidativo ( Figura 1 ). A atividade reduzida da bomba de cálcio (Ca2+), que se manifesta pelo sequestro ineficiente do Ca2+ pelo retículo sarcoplasmático, é considerada como importante contribuinte para o desenvolvimento da disfunção diastólica cardíaca nesses pacientes.¹⁷

O segundo estágio da miocardiopatia diabética se caracteriza pela hipertrofia do VE, remodelamento cardíaco, agravo da disfunção diastólica e consequente surgimento de manifestações clínicas da presença de IC com fração de ejeção preservada (ICFEp). Com a progressão da miocardiopatia diabética, disfunção diastólica e redução da complacência cardíaca, podem coexistir com disfunção sistólica levando ao fenótipo de fração de ejeção reduzida.¹⁵

A fisiopatologia da miocardiopatia associada ao diabetes

Anormalidades tais como fibrose, hipertrofia e piora da perfusão microvascular coronariana têm sofrido avaliações. São, portanto, características do coração diabético, tanto em cenários clínicos como experimentais. São registradas variações desde índices de remodelamento cardíaco até comprometimento da perfusão microvascular coronariana. Esses defeitos morfológicos podem contribuir para as deficiências funcionais identificadas no coração humano diabético.

Outros mecanismos para a constituição da miocardiopatia induzida por diabetes ( Figura 2 ) são mediadores já bem estabelecidos como a inflamação, estresse oxidativo, alterações metabólicas, sinalização de insulina, regulação gênica, estresse, ativação neuro-humoral e morte celular cardíaca.^{18 , 19}

Figura 2 – Mecanismos protetores do SGLT2 na insuficiência cardíaca. Existem diversos mecanismos pelos quais os inibidores de cotransportador de sódio e glicose 2 (SGLT2) previnem e melhoram a insuficiência cardíaca. Os mecanismos envolvidos têm efeitos metabólicos, hemodinâmicos e outros mecanismos envolvendo a diminuição da atividade do sistema simpático e também o componente tardio da corrente do canal de sódio cardíaco. Late-INa, componente tardio da corrente do canal de sódio cardíaco. Adaptado de Nakamura et al. <xref ref-type="bibr" rid="B19">19</xref>

O endotélio é o maior órgão do corpo, sendo responsável pelo funcionamento normal dos vasos. O endotélio atua regulando a liberação de fatores secretores em resposta a estímulos mecânicos. O principal papel do endotélio é garantir o fluxo sanguíneo adequado, que depende do equilíbrio entre agentes vasodilatadores e vasoconstritores. Os vasodilatadores incluem a prostaciclina I2 (PGI2) e o óxido nítrico (NO), e os vasoconstritores incluem endotelina 1 (ET1) e tromboxano A2 (TXA2), que contrabalançam a vasodilatação excessiva e mantêm o tônus vascular. A resistência à insulina e o diabetes foram descritos como associados à disfunção endotelial, que também é encontrada em situações como obesidade, sedentarismo e tabagismo. Essas observações sugerem que a complexa fisiopatologia da disfunção endotelial envolve múltiplos mecanismos e participa de várias doenças, entre elas o desenvolvimento da miocardiopatia diabética.²⁰

A sinalização prejudicada do NO está intimamente relacionada com danos no diabetes melito, caracterizados pela desregulação da geração de NO e sua biodisponibilidade.²¹ Estudos²² indicam anormalidades cardíacas observadas em ratos diabéticos, sugerindo o papel central do NO na fisiopatologia da miocardiopatia diabética. Além disso, a inibição da síntese do NO (NOS) reduziu os níveis de NO, nitrotirosina e espécies reativas de oxigênio (ROS), indicando desacoplamento da NOS endotelial em corações diabéticos.²³ A oxidação da tetrahidrobiopterina induzida por ROS e o aumento do conteúdo de dimetilarginina assimétrica (ADMA) contribuem para o desacoplamento da NOS endotelial no DM2.^{23 , 24}

A NOS é catalisada por L-arginina e fosfato de dinucleotídeo de adenina-nicotinamida (NADPH) na presença de oxigênio. Entretanto, em vasos diabéticos, a NOS é afetada. Alguns estudos sugeriram que a causa da inativação do NO e, portanto, sua deficiência se deva ao aumento dos radicais livres, e não à regulação negativa da atividade ou expressão da NOS endotelial.^{25 , 26}

O metabolismo anormal e a disfunção das mitocôndrias estão relacionados às alterações metabólicas na miocardiopatia diabética. Foi relatado que a hiperglicemia causa dano oxidativo do DNA mitocondrial nas células endoteliais, aumentando as ROS mitocondriais.²⁷

A inflamação é um mecanismo importante na miocardiopatia diabética. Para lidar com os fatores que causam danos, as células endoteliais são ativadas e produzem interleucinas, quimosinas, interferons, monócitos proteína quimioatraente-1 (MCP-1) e outros fatores inflamatórios.²⁸ Monócitos e neutrófilos são recrutados para o endotélio ativado após a liberação dessas substâncias e iniciam a inflamação. Fatores pró-inflamatórios elevados estimulam as células endoteliais a secretar mais fatores pró-inflamatórios, que induzem a secreção de diversos reagentes de fase aguda e modulam a inflamação crônica.²⁰

Além disso, os níveis inflamatórios se elevam quando células endoteliais são expostas a soro hiperinsulinêmico, sendo que a disfunção mitocondrial induz disfunção endotelial e promove inflamação pela produção excessiva de ROS.^{29 , 30} O estado inflamatório desencadeado pela ativação endotelial pode, então, ser consequência de um desequilíbrio entre excesso de ROS e insuficiência de antioxidantes, resultando em estresse oxidativo e dano celular.²⁰

As células endoteliais vasculares são propensas a serem danificadas pela hiperglicemia devido a suas características e localização. Células endoteliais danificadas causam aumento da permeabilidade, disfunção da barreira e comprometimento da vasodilatação.³¹ Estudos hemodinâmicos sugerem que a resposta vasodilatadora dependente do endotélio no diabetes esteja alterada.^{32 , 33} Na miocardiopatia diabética, se observa liberação excessiva de vários vasoconstritores pelas células endoteliais, interferindo na estrutura vascular coronariana e garantindo a normalidade do fluxo sanguíneo. Nesse cenário, há perda do equilíbrio entre os vasoconstritores e os vasodilatadores.²⁰

Na miocardiopatia diabética, observamos níveis elevados de vasodilatadores, como NO e PGI2, e também de vasoconstritores, como ET1 e TXA2. A ET1 é regulada positivamente nos órgãos-alvo do DM2, incluindo o coração e os rins.³⁴ A ET1 é predominantemente expressa em células endoteliais cardíacas em comparação com cardiomiócitos no tecido cardíaco adulto normal, destacando, portanto, o importante papel das células endoteliais na miocardiopatia diabética.³⁵ Além disso, o aumento da produção de endotelina no coração diabético pode levar à hipertrofia dos vasos e ao aumento da fibrose miocárdica, ambos característicos da miocardiopatia diabética.²⁶

As primeiras evidências de fibrose cardíaca associada ao diabetes no coração humano foram amplamente derivadas de análises pós-morte ou de biópsia.³⁶ O aumento da deposição de colágeno intersticial tipos I e III é evidente em biópsias miocárdicas humanas diabéticas em comparação com não diabéticas.³⁶ Abordagens recentes usando mapeamento T1 derivado de ressonância magnética cardíaca (RMC) e imagem de realce tardio de gadolínio (LGE) provaram ser úteis na detecção não invasiva de fibrose cardíaca em humanos.^{37 , 38} Elas revelam que o diabetes está associado ao aumento da fibrose cardíaca, mesmo na ausência de lesão isquêmica prévia,^{5 , 39 , 40} mas algumas observações sugerem que a fibrose pode surgir mais tarde na progressão da doença, mesmo após os déficits na função cardíaca terem se manifestado.⁴

O DM2 leva à disfunção diastólica do VE, ao remodelamento restritivo do VE e à ICFEp, devido à indução de um estado pró-inflamatório acompanhado por piora da função endotelial da microvasculatura coronariana. Em pacientes com ICFEp, a inflamação endotelial microvascular coronariana e os cardiomiócitos expostos à sinalização endotelial parácrina alterada contribuem principalmente para o remodelamento concêntrico do VE.⁴¹

Um outro estágio da miocardiopatia diabética é caracterizado por hipertrofia do VE, remodelamento cardíaco, agravo da disfunção diastólica cardíaca e consequente surgimento de ICFEp.¹⁵ A progressão da miocardiopatia diabética e da disfunção diastólica e a redução da complacência cardíaca podem coexistir com disfunção sistólica, levando a fração de ejeção reduzida, aumento do VE e redução do tempo de ejeção, como consequência à redução da complacência ventricular esquerda. Anormalidades na expressão de proteínas contráteis e reguladoras são responsáveis pelos defeitos mecânicos na contração cardíaca.¹⁵

A associação entre a diminuição da biodisponibilidade de NO na microcirculação coronariana e piora da função diastólica é complexa, envolvendo múltiplos caminhos. A hipofosforilação dependente da proteína quinase G é responsável pelo retardo do relaxamento ativo e menor distensibilidade passiva do VE. A reserva de fluxo coronariano (CFR) deprimida também é um importante contribuinte para disfunção diastólica.²⁰

O diagnóstico da miocardiopatia associada ao diabetes

A disfunção cardíaca geralmente é clinicamente silenciosa no diabetes e frequentemente não é detectada até os estágios avançados da doença. Mesmo em pacientes assintomáticos e normotensos com diabetes bem controlado, considera-se que cerca de 50% apresentam algum grau de disfunção cardíaca. É amplamente aceito que uma das características do coração diabético é a disfunção diastólica do VE, sendo, de fato, um dos primeiros sinais de miocardiopatia diabética, muitas vezes detectável antes da disfunção sistólica do VE clinicamente significativa.^{14 , 42}

A existência de disfunção diastólica isolada como um indicador de miocardiopatia diabética foi até recentemente contestada, uma vez que os pacientes nos estágios iniciais do diabetes não eram rotineiramente sujeitos a uma avaliação cuidadosa da função diastólica. As complicações cardíacas do diabetes geralmente só eram investigadas depois que os sintomas evidentes de IC se tornavam evidentes. Com o advento de técnicas de imagem mais sensíveis e reconhecimento mais frequente de IC em pessoas afetadas pelo diabetes, essa abordagem pode ser alterada. Independentemente de ser avaliada no contexto clínico ou pré-clínico/laboratorial, a RMC é amplamente considerada a abordagem padrão-ouro para avaliação da função cardíaca.⁵

No entanto, embora o diabetes esteja associado a parâmetros da função diastólica do VE derivados da RMC, a RMC nem sempre está prontamente disponível, tendo acesso limitado em circunstâncias regionais e/ou de baixo nível socioeconômico. O avanço nas abordagens de imagem de ecocardiografia nos últimos anos, em contextos clínicos e experimentais, agora permite uma avaliação serial da função cardíaca de resolução relativamente alta, detalhada e não invasiva, sem o consumo de tempo ou as restrições de disponibilidade/acesso geralmente impostas pela RMC, e, como tal, é a abordagem de imagem de escolha para a maioria da rotina cardíaca clínica e pré-clínica e estudos de pesquisa intervencionista.⁴³

As alterações iniciais na função diastólica do VE que são consideradas características da miocardiopatia induzida por diabetes incluem alterações no enchimento e relaxamento do VE, muitas vezes na ausência de alterações na função sistólica do VE.^{5 , 44} Conforme detalhado pelas diretrizes mais recentes publicadas pela American Society of Echocardiography (ASC) e pela European Association of Cardiovascular Imaging, uma variedade de sinais baseados em Doppler pode ser usada para a avaliação da função diastólica, com vários parâmetros da função diastólica avaliada. Esses parâmetros incluem aqueles determinados no final da diástole (que se correlacionam com a pressão diastólica final do VE), que são obtidos medindo a velocidade do fluxo sanguíneo através da válvula mitral (via Doppler) ou a velocidade análoga de movimento do tecido miocárdico adjacente (via Doppler tecidual).¹

A avaliação ecocardiográfica produz duas fases principais de movimento, uma fase inicial, denominada como a onda E no fluxo Doppler e e’ no Doppler tecidual, e uma fase atrial posterior, denominada como a onda A no fluxo Doppler e a’ no Doppler tecidual.⁴⁵ A velocidade da onda A do pico mitral e a velocidade da onda a’ do anel mitral derivada do Doppler tecidual, bem como aquelas que são medidas no início da diástole, como a relação E/A mitral, o tempo de desaceleração da onda E e a relação E/e’, são parâmetros comuns derivados do ecocardiograma. E/e’ é um dos parâmetros mais reprodutíveis e confiáveis desses exemplos.⁴³ O tempo de relaxamento ventricular isovolumétrico (IVRT) também tem sido amplamente utilizado para avaliar a função diastólica, mas é altamente dependente da frequência cardíaca e da pós-carga.⁴³ Uma abordagem adicional incluiu a avaliação do strain atrial. A miocardiopatia atrial é um dos aspectos da miocardiopatia do diabetes. Dogdus et al. descreveram comprometimento da função atrial tanto de reservatório como contrátil em pacientes obesos e diabéticos.⁴⁶ Também apontaram que a presença de bloqueio interatrial nestes pacientes é um marcador de doença ainda em estágio pré-clínico de IC. A disfunção cardíaca em corações diabéticos progride de anormalidades cardíacas subclínicas, como fibrose do VE, para disfunção diastólica e eventualmente disfunção sistólica acompanhada por fração de ejeção reduzida. Várias técnicas não invasivas, incluindo ecocardiografia, tomografia computadorizada e RMC, podem ser utilizadas para detectar alterações na estrutura e função cardíacas (principalmente fibrose).⁴⁷ Além disso, níveis elevados de peptídeo natriurético atrial, peptídeo natriurético do tipo B (BNP) e N-acetilglucosamina (O-GlcNAc), entre outros, também podem servir como marcadores de miocardiopatia diabética e insuficiência cardíaca.¹⁵

A insuficiência cardíaca com fração de ejeção preservada e o coração diabético

O fenótipo ICFEp é mais prevalente que o fenótipo IC com fração de ejeção reduzida (ICFEr), com uma prevalência aumentada secundária ao aumento da prevalência global de diabetes, obesidade e hipertensão em uma população envelhecida.^{48 - 50} A ICFEp representa um espectro de várias etiologias, como a hipertensão arterial sistêmica, obesidade e envelhecimento, além de outros fatores de risco e comorbidades. Tanto mulheres, em particular as idosas, quanto pessoas diabéticas são mais comuns na população com ICFEp em comparação com ICFEr.^{49 , 51 , 52}

No entanto, considerar a ICFEp como um único fenótipo é um equívoco, pois o distúrbio é particularmente heterogêneo, com pelo menos três grupos distintos.⁵¹ Isso inclui o fenótipo obesidade-cardiometabólico, que tem sido classicamente associado à ICFEp, pacientes com alto índice de massa corporal, disfunção diastólica acentuada e comumente acompanhados por diabetes e/ou hipertensão. Outros subgrupos incluem a síndrome de deficiência de BNP –pacientes obesos com baixo BNP que muitas vezes também são hipertensos – e, por fim, o fenótipo cardiorrenal com insuficiência ventricular direita.^{53 , 54} Desses três grupos, a sobrevida livre de eventos é maior para aqueles no grupo de deficiência de peptídeo natriurético e pior no grupo de insuficiência cardiorrenal.⁴⁹ A interseção entre esses grupos de fenótipos também parece ser evidente.⁴⁸

O crescente surgimento e conscientização da ICFEp no campo de pesquisa da IC pode levar alguns a considerar a miocardiopatia diabética simplesmente a manifestação da ICFEp coexistente com o diabetes, uma vez que ambos compartilham várias características comuns. De fato, pacientes diabéticos podem apresentar ICFEp ou ICFEr.^{55 , 56} Se esses pacientes diabéticos também apresentarem complicações microvasculares, então um fenótipo ICFEp, em vez de ICFEr, é mais prevalente, assim como um prognóstico pior.⁵⁵ As características post-mortem do miocárdio humano com ICFEp incluem evidências claras de aumentos tanto na massa cardíaca quanto da fibrose, com redução da densidade microvascular.⁵⁷ Essas observações também podem ser evidenciadas pela ecocardiografia.⁴⁸ É provável que um grande componente do aumento da massa cardíaca seja atribuível à fibrose e não à hipertrofia per se , já que a hipertrofia clinicamente significativa pode ser evidente apenas em aproximadamente 50% dos pacientes com ICFEp.⁵⁷ Além da fibrose cardíaca e disfunção microvascular, inflamação e rigidez cardíaca também são evidentes.⁵¹ Em contraste com as coortes de ICFEp,⁵⁸ a miocardiopatia diabética não parece “favorecer” um gênero em detrimento do outro.⁵⁹ Assim, embora a miocardiopatia diabética seja mais complexa do que simplesmente a manifestação de ICFEp coexistente com o diabetes, fica claro que o fenótipo da ICFEp é enriquecido no diabetes.

O tratamento da miocardiopatia associada ao diabetes

O tratamento da IC é semelhante para pacientes com e sem diabetes. No entanto, as drogas antidiabéticas têm efeitos diferentes em pacientes com IC, sendo necessário priorizar drogas que sejam seguras e que reduzam os eventos relacionados à IC.⁶⁰

Não há dúvidas de que o mau controle glicêmico contribui para o aumento do risco de IC em pacientes com diabetes, sendo o risco de IC correlacionado com os níveis de hemoglobina glicada (HbA1c).⁶¹ Antes da era atual, as terapias intensas de redução da glicose falharam amplamente em reduzir o risco de IC incidente e podiam até exacerbar o risco de IC, como por exemplo as tiazolidinedionas, sulfonilureias, certos inibidores da dipeptidil peptidase-4 (DPP-4) e potencialmente o uso de insulina e agonistas do glucagon (GLP-1).^{62 , 63} Embora o agonista de GLP-1 tenha se mostrado seguro e tolerável em pacientes com DM2 no estudo REWIND, com evidência de redução sustentada da glicose (redução na HbA1c de 0,61 unidades percentuais ao longo de 5 meses), em comparação com placebo ao longo de 5 anos, não foram observadas diferenças na incidência cumulativa de desfechos cardiovasculares.⁶⁴

A chegada dos inibidores do cotransportador de sódio-glicose-2 (SGLT2i) ( Figura 2 ) trouxe uma mudança importante no tratamento desses pacientes.^{65 , 66} O estudo EMPA-REG OUTCOME⁶⁷ forneceu a primeira observação de que o SGLT2i representava ações cardioprotetoras robustas para uma terapia eficaz de redução da glicose. O risco de hospitalização por IC e mortalidade cardiovascular foi reduzido em 35–50% com empagliflozina em comparação com placebo em pacientes com DM2.⁶⁶ Descobertas semelhantes com relação aos benefícios no nível de hospitalização por ICFEr e mortalidade cardiovascular foram subsequentemente observadas em estudos clínicos em DM2 com canagliflozina^{68 - 70} (CANVAS, CREDENCE, CVD-REAL) e dapagliflozina^{71 , 72} (DECLARE-TIMI 58). A redução das hospitalizações por IC surgiu, assim como um efeito de classe.⁷³ Além disso, o SGLT2i parece igualmente benéfico em pacientes com DM2 afetados por ICFEp ou ICFEr.⁶³

Os mecanismos que contribuem para a cardioproteção do SGLT2i, particularmente no que diz respeito ao benefício na IC no contexto do diabetes, ainda precisam ser esclarecidos, com uma infinidade de mecanismos putativos relatados na literatura.⁷⁴ Se efeitos benéficos ao nível da remodelação e/ou disfunção cardíaca são evidentes neste momento no coração diabético ainda precisa ser melhor estabelecido. Embora tenha sido sugerido que os benefícios do SGLT2i simplesmente refletem mecanismos como aumento da glicosúria, natriurese e redução da PA,⁷⁵ o consenso sobre o mecanismo de cardioproteção do SGLT2i ainda não foi alcançado. O SGLT2 não é detectado no coração,^{76 , 77} portanto, o mecanismo de cardioproteção é provavelmente de natureza extracardíaca; além disso, mais de um mecanismo pode contribuir. Embora glicosúria aumentada e natriurese provavelmente ajudem na renoproteção, provavelmente não são suficientes para explicar completamente o benefício cardíaco, particularmente em relação à IC.^{76 , 77}

Apesar dessa falta de consenso sobre o mecanismo responsável pelo benefício do SGLT2i, esse benefício tem sido aceito com certeza e entusiasmo. De fato, ensaios clínicos estão em andamento para SGLT2i em IC, mesmo na ausência de diabetes, e as evidências já mostram que os SGLT2i são eficazes no contexto da IC em pacientes não diabéticos.⁷⁸ Por exemplo, o estudo randomizado de fase 3 DAPA-HF com o uso de dapagliflozina ou placebo (além do tratamento padrão) em mais de 4.700 pacientes com IC com FEVE < 40% revelou um risco acentuadamente reduzido de agravamento da IC ou morte cardiovascular, tanto em diabéticos como em não diabéticos.⁷⁹

Conclusão

As principais características da miocardiopatia diabética incluem rigidez cardíaca, fibrose e hipertrofia ventricular com disfunção diastólica e progressão para disfunção sistólica e IC. A disfunção endotelial tem sido considerada um elo crucial no desenvolvimento da miocardiopatia diabética. É importante ressaltar que a hiperglicemia e a resistência à insulina sistêmica estão independentemente associadas ao desenvolvimento e à progressão da disfunção cardíaca e IC no diabetes. O tratamento com um SGLT2i é atualmente um dos tratamentos mais eficazes para a miocardiopatia associada ao diabetes. Porém, um tratamento eficaz para a lipotoxicidade do miocárdio ainda não foi bem estabelecido.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.