The limited clinical value of a specific diabetic cardiomyopathy

Nutrition, Metabolism & Cardiovascular Diseases (2013) 23, 599e605

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/nmcd

REVIEW

The limited clinical value of a specific diabetic cardiomyopathy S. Vigili de Kreutzenberg a,*, A. Avogaro a,b a b

Department of Medicine DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy Venetian Institute of Molecular Medicine, Padova, Italy

Received 20 July 2012; received in revised form 29 January 2013; accepted 30 March 2013

KEYWORDS Diabetes; Cardiomyopathy; Heart failure

Abstract Aims: Diabetic patients show a higher likelihood of developing heart failure (HF), independently of the atherosclerotic process, than their nondiabetic counterparts. This suggests the presence of an intrinsic vulnerability of the heart in patients with diabetes mellitus. Data synthesis: A cardiomyopathy specific to the diabetic patient was first hypothesized by Rubler and co-workers, in 1972 and recognized as a nosologic entity by the World Health Organization (WHO) in 1995. All patients falling under Rubler’s definition had ascertained diabetic glomerusclerosis, but were unaffected by major coronary artery disease (CAD). Notably, the mean plasma glucose in those patients was 417
209 mg/dl. Since then, several studies conducted in both animals and in humans have focused on pathogenetic mechanisms, clinical manifestations, diagnostic as well as therapeutic approaches utilized for the treatment of diabetic cardiomyopathy (DCM). Despite the large body of literature available, the clinical entity and significance of this diabetic complication continue to be elusive. Conclusions: In the present report, recent pathophysiological findings and diagnostic strategies to treat DCM are reviewed. Particular attention is dedicated to the clinical manifestation of DCM, that is to heart failure (HF), and to the implications of co-morbidities and metabolic control on its evolution. ª 2013 Elsevier B.V. All rights reserved.

Introduction

* Corresponding author. Tel.: þ39 (0)49 8212183; fax: þ39 (0)49 8754179. E-mail address: [email protected] (S. Vigili de Kreutzenberg).

Diabetes and its chronic complications represent a challenging worldwide health problem both because of the alarming rise in the number of patients [1] and the incredible amount of economic and human resources invested in its management [2]. Cardiovascular disease

0939-4753/$ - see front matter ª 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.numecd.2013.03.008

600 (CVD) remains by far the first cause of disability and death in diabetic patients [3] as the heart appears to be the most involved target-organ of chronic diabetic damage. Due to the particular metabolic milieu of diabetes, the heart of diabetic patients can, in fact, be affected by different, interrelated pathologies, such as macroangiopathy, microangiopathy, cardiac neuropathy, and specific abnormalities of the myocardium. Those insults to the diabetic heart develop within the spectrum of a clinical picture which is, nevertheless, dominated by coronary heart disease and heart failure. As first observed by the Framingham Heart Study [4], diabetic patients show a higher likelihood of developing heart failure (HF) than coronary heart disease (CHD), which implies that e independently from the atherosclerotic process e the diabetic heart possesses an intrinsic vulnerability. Among different anatomo-clinical pictures affecting the heart in diabetes, DCM is a well defined pathological entity, first hypothesized by Rubler and co-workers in The American Journal of Cardiology in 1972. Those investigators described post-mortem anatomopathological findings in the heart of 4 (3 female and 1 male) out of 27 type 2 diabetic subjects who presented cardiomegaly and congestive heart failure of unknown origin [5]. All had confirmed diabetic glomerulosclerosis but were unaffected by major coronary artery disease. Despite the small number of cases studied, Rubler and colleagues hypothesized that there is a cardiomyopathy specifically linked to diabetes and DCM has existed since then. Diabetic microangiopathy was thought to be the main pathogenetic factor for the development of DCM, but even an abnormal myocardial metabolism, it has been hypothesized, could cause the disease. Notably, in that first report, the mean plasma glucose concentration in subjects affected by DCM was 491 mg/dl (range 1100e200 mg/dl). Galderisi et al. outlined the morphological and functional features of DCM for the first time [6]. DCM was recognized as a specific disease by the WHO in 1995 [7], when diabetes was listed for the first time among the causes of specific cardiomyopathies, defined as heart muscle diseases associated with specific cardiac or systemic disorders found under the metabolic cardiomyopathy subheading.

Pathophysiology and clinical features of diabetic cardiomyopathy DCM is characterized by specific metabolic and structural abnormalities linked to interrelated, multifactorial, complex mechanisms triggered by hyperglycaemia, insulin resistance and abnormal lipid metabolism. The diabetic heart shifts from glucose to free fatty acids (FFA) as its predominant energy suppliers [8,9] showing increased FFA uptake and enhanced beta-oxidation. To correct this imbalance and to ameliorate heart function, trimetazidine, a 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor, which favors glucose over FFA oxidation in cardiac myocytes, has been proposed as a therapeutic option [10], but its role in the treatment of DCM remains to be ascertained [11]. Other lipid metabolism abnormalities, described in animal models of DCM are increased fatty acid transporters [FATP/CD36 and FABPpm (membrane associated FA-binding

S. Vigili de Kreutzenberg, A. Avogaro protein)] and enhanced lipoprotein lipase activity [12], along with intramyocardial lipid accumulation and triglyceride deposition [13,14]. Myocardial steatosis is associated with diastolic dysfunction [15], but its role in the pathogenesis of DCM remains controversial [16,17]. Hyperglycaemia and high FFA levels determine an increased generation of mitochondrial and cytosolic reactive oxygen species (ROS) in the cardiomyocytes [18,19]. ROS directly impair cardiomyocyte proteins and DNA, alter gene expression and signal transduction pathways, such as PKC, ERK 1/2, growth factors, etc. [20], interfere with intracellular mediator activity and promote apoptosis [21,22]. Other intracellular mechanisms responsible for DCM are mitochondrial dysfunction, endoplasmic reticulum (ER) stress, increased collagen formation and deposition of advanced glycation end-products (AGE), abnormalities of contractile proteins, altered calcium transport/uptake, and endothelial dysfunction [23e25]. An important pathogenetic role in the development of DCM has recently been attributed to ER stress [26], which is involved in lipid synthesis, calcium homeostasis, protein folding and maturation, and regulation of apoptosis [27]. Experimental studies have demonstrated that hyperglycaemia-induced ROS hyperproduction determines ER stress, autophagy and cell death [28,29]. These events contribute to cardiac inflammation and myocardial remodeling. Oxidative stress also increases AGE and AGE receptors [30,31] that trigger a cascade of signaling, leading to modified protein and collagen deposition. Other important pathogenetic mechanisms causing DCM are dysregulation of cardiac innervation, chronic inflammation, and activation of the reninangiotensin system (RAS) [32]. Upregulation of RAS stimulates cardiac fibroblast proliferation and impairs collagen metabolism. Stem cell abnormalities [33], as well as environmental and epigenetic effects [34] have also been implicated as possible pathogenetic factors for DCM. Defective myocardial energy supply due to reduced adenosine triphosphate (ATP) production together with metabolic, neurohumoral and endothelial disturbances lead to myocyte hypertrophy, interstitial and perivascular fibrosis, impair myocyte contraction, promote cardiac stiffness, and ventricular myocardium rigidity. These histological alterations reduce myocardial compliance and induce early diastolic function disturbances and later systolic dysfunction. While wall thickness and left ventricular (LV) mass hypertrophy characterize DCM’s macroscopic alterations, HF is its overt clinical manifestation. It is interesting that similar mechanisms are working even in the presence of mechanical overload, and resulting in histological alterations, i.e., significant myocardial fibrosis and degeneration, areas of scarring, increased pericapillary basal lamina, etc., which consistently overlap with diabetes and hypertension [35]. Even if other possible cardiac outcomes such as CHD and sudden cardiac death can and do occur [36], the most particular clinical manifestation of DCM is HF which is indeed shared with several other pathological conditions. The prevalence of HF in diabetic patients can vary from 12% to 48% [37]; and its incidence in diabetic patients with respect to controls is 30.9 vs. 12.4 cases per 1000 personyears, rate ratio 2.5 [38]. Using a multivariate model, diabetes was found to be an independent contributor to LV

Diabetic cardiomyopathy mass and wall thickness in women, evaluating 1986 men and 2529 women without cardiovascular disease, participating in the original Framingham Study cohort and the Framingham Offspring Study [6]. Male and female diabetic subjects participating in the Strong Heart Study had higher LV mass and wall thicknesses and lower LV fractional shortening, midwall shortening, and stress-corrected midwall shortening [39]. While it is problematic to assign echocardiographic abnormalities to DCM, de Simone et al. demonstrated that some parameters, such as greater LV mass index, larger left atrium, lower systolic function, and greater left atrial systolic force can identify subjects who are particularly prone to develop HF [40]. On the other hand, with regard to type 1 diabetic patients, who are specifically exposed to hyperglycemia, Konduracka et al. reported no significant differences in myocardial dysfunction or post-mortem histological findings in diabetic and non-diabetic subjects [41].

Testing for a specific diabetic cardiomyopathy On the basis of its progressive anatomical, structural and functional characteristics, Fang et al. [23] suggested staging DCM, whose progression is characterized by earlier diastolic and later systolic dysfunction. While other authors have indeed attempted to address DCM staging [42], the outcome has remained theoretical, since it is difficult to reach a definite diagnosis of DCM. To establish the diagnosis of DCM, CHD and arterial hypertension must first be ruled out. Cardiac function evaluation is mandatory to investigate DCM, and diastolic dysfunction has long been considered the first marker of DCM. Diastolic dysfunction, which has been described in more than 70% of asymptomatic diabetic patients, can be diagnosed by doppler cardiography by calculating the ratio of peak blood flow velocities during LV rapid filling (E wave) and atrial systolic contraction (A wave) [43]. The measurement can, however, be influenced by several variables, such age, hypertension, LV hypertrophy, heart rate and rhythm, PR interval, cardiac output, mitral annular size, left atrium function [44], thus limiting its diagnostic value. The role of diastolic dysfunction as the first marker of DCM has recently been questioned [45], since an early systolic dysfunction, assessed by systolic strain, has been demonstrated in type 2 diabetes mellitus (T2DM) even with normal diastolic function [46,47]. Systolic strain alteration seems to be more specific to DCM because it is determined only by diabetes and gender and is considered the first marker of DCM by some [45,47]. By applying more sophisticated methods to conventional echocardiography, the Left ventricular dysfunction in diabetes (DYDA) Study found that left ventricular dysfunction (LVD), both systolic and/or diastolic, is present in more than half of diabetic patients without clinically detectable cardiac disease [48]; LVD was characterized by higher LV mass, relative wall thickness, prevalence of concentric geometry, and LV hypertrophy. As highlighted by a number of previously cited manuscripts, LV hypertrophy (often concentric) is a critical feature of DCM. New technologies such as cardiac RMI and PET and new cardiac indexes, such as coronary flow reserve and ventricular torsion, have improved the identification of DCM [49e52]. Rijzewijk et al. who evaluated myocardial

601 substrate and high-energy phosphate (HEP) metabolism in asymptomatic males with well-controlled, uncomplicated T2DM and confirmed absence of cardiac ischemia were unable to show any direct relation between cardiac diastolic function and parameters of myocardial metabolism [53]. The detection of myocardial steatosis by proton magnetic resonance spectroscopy appears useful in identifying diabetic patients at risk for diastolic dysfunction [14]. There is, however, no single diagnostic approach for the identification of DCM and its diagnosis often results unreliable in clinical practice. No laboratory test appears to be useful for diagnostic purposes. Brain natriuretic peptide (BNP), which is secreted in response to ventricular volume and pressure overload, has been hypothesized as a possible marker. BNP concentrations have been found to be higher with a marked association to diastolic dysfunction in middle-aged diabetic patients without HF compared to non-diabetic subjects [54]. As reported by Fang et al., BNP determination has not been included in the guidelines for DCM diagnosis [55] as screening parameters, including BNP, do not appear to be sufficiently sensitive to identify subclinical dysfunction, which instead requires more sophisticated echocardiographic analysis.

Heart failure in diabetes: dissecting the role of hypertension, coronary heart disease, and obesity One of the reasons that makes diagnosis of DCM so difficult is that diabetes is often associated with co-morbidities which can themselves affect the heart, and the clinician faces the frustrating prospect of unraveling the role played by diabetes from that of other co-morbidities. Hypertension is a frequent co-morbidity in patients with T2DM, and its presence enhances the risk of HF in diabetic patients [56]. High blood pressure was found to be a predictor of HF according the United Kingdom Prospective Diabetes Study (UKPDS), which found that good blood pressure control significantly reduced the incidence of fatal and non-fatal stroke by 44% (P Z 0.013) and heart failure by 56% (P Z 0.0043) [57]. According to the Losartan Intervention for Endpoint reduction in hypertension (LIFE) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) studies, losartan significantly reduced the incidence of first hospitalization for HF versus placebo (hazard ratio 0.74, p Z 0.037) in the latter study and versus atenolol in the former one (hazard ratio 0.57, p Z 0.019) [58]. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme reported that candesartan treatment significantly reduced cardiovascular deaths and hospital admission for heart failure [59]. In the Irbesartan Diabetic Nephropathy Trial (IDNT) study, patients receiving irbesartan had a significantly lower incidence of congestive heart failure (CHF) compared to placebo recipients [60]. Furthermore, Nichols and colleagues demonstrated that the reduction in systolic blood pressure was an independent predictor of incident CHF in patients with type 2 diabetes [61]. With regard to high blood pressure, CHD has been recognized as an important cause of HF in patients with T2DM [62,63]. When Nichols and colleagues attempted to isolate

602 independent predictors of prevalent CHF, they reported that CHD (4.44, 3.74e5.26) and hypertension (1.69, 1.40e2.05) were important predictors of prevalent CHF [61]. In the Type 2 Diabetes, Hypertension, Cardiovascular Events and Ramipril (DIABHYCAR) study, history of cardiovascular disease was an independent predictor of incident HF [62], while in the Atherosclerosis Risk in Communities (ARIC) study, the crude HF incidence rates per 1000 person-years were lower in the absence of CHD (incidence rate 15.5 for CHD-negative vs 56.4 for CHD-positive, p < 0.001) [62]. In a study that examined the association of DM and death among subjects with advanced symptomatic as well unsymptomatic systolic HF, the adverse impact of DM on survival was observed only in the HF patients with an ischemic etiology [37]. By definition, HF due to DCM is independent of CHD, therefore DCM may lead to HF without the intermediate step of myocardial infarction (MI). This has also been highlighted by some population-based studies: the Cardiovascular Health Study focusing on a community-based elderly population reported that intact LV systolic function preceded the onset of CHF incident [64]. In that cohort of elderly individuals, the incidence of HF was approximately twofold in diabetic men and women with respect to their non-diabetic counterparts, underscoring that T2DM is a potent, independent risk factor for HF. However, as already mentioned, the risk of HF in diabetic subjects cannot be fully explained by incident MI and coexisting CV risk factors. In the Strong Heart Study, de Simone et al. demonstrated that diabetes remains a predictor of incident HF, independent of MI and concomitant risk factors, such as subclinical systolic dysfunction and abnormal LV parameters. On the other hand, HF is influenced by poor metabolic control [40,65]. Echocardiographic LV wall motion abnormalities, assessed in the same study population, were associated with a significantly higher (2.4- to 3.4fold) risk of cardiovascular morbidity and mortality, independently of established risk factors and in the absence of overt CVD [66]. Although high blood pressure and CHD have been considered two of the most important risk factors for the development of HF, several studies have also underlined the importance of obesity. According to the Framingham Heart Study, there was an increase in the risk of HF of 5% for men and 7% for women, for each increment of 1 in BMI, even after adjustment for myocardial infarction, diabetes, hypertension, and cholesterol [67]. In the ARIC study, parameters of adipose tissue distribution, such as waist circumference, were independently associated to incident HF [68]. The presence of insulin resistance, subclinical inflammation and activation of the renin angiotensin axis may be the link between obesity and HF [69]. Several studies have underlined that obesity seems to confer a survival benefit in patients with established HF, a phenomenon termed the ‘obesity paradox’ [70]. Nonetheless, as observed by Adamopoulos and colleagues, the obesity paradox reported in HF may not be present when obesity coexists with diabetes mellitus [71].

Diabetic cardiomyopathy, heart failure and metabolic control The role of metabolic control on the clinical evolution of DCM and the development of HF is unclear. Several studies

S. Vigili de Kreutzenberg, A. Avogaro focusing on a specific DCM did not assess levels of metabolic control [39,72e74]. Nonetheless, the link between glycemia and HF seems relevant as not only diabetes but also impaired fasting glucose and impaired glucose tolerance are strongly associated with HF [75]. Iribarren et al.’s cohort study showed that degree of glycemic control parallels the risk for HF: a 1% increase in HbA1c is associated with an 8% increased risk of HF hospitalization or HF death [76]. The age-adjusted rate per 1000 person-years was 4.5 for a value of HbA1c less than 7% and 5.8 for HbA1c between 7.0 and 7.9% for the entire cohort. In view of recent intervention trials, it is nevertheless difficult to weed out the specific role of metabolic control in HF onset from that of hypertension, CHD, and obesity. One of the reasons might be that HF has also been included as one of the combined primary or secondary end-points. The number of HF events was significantly higher according to the BARI2D study [77], whose eligibility criteria included diagnosis of both T2DM and CHD. No relationship has been observed in intervention trials between HF events, BMI and target HbA1c values. Ray et al. evaluated whether intensive glucose control reduces macrovascular events and all-cause mortality in type 2 diabetic subjects, selecting five prospective randomized controlled trials, concerning a total of 33,040 participants [78]. The conclusion was that the intensive glucose-lowering treatment studied did not significantly affect heart failure (OR 1.08; 95% CI 0.90e1.31). While the authors underlined that there was a marked heterogeneity in the studies examined, they reported that intensive therapy was associated to a significantly beneficial effect on ischemic heart disease. Similar findings were reported by Zhang et al. [79] (RR with regard to heart failure 1.09; 95% CI 0.90e1.32; P Z 0.37), and, more recently, by Castagno and coll. [80] with regard to 37,229 type 2 diabetic patients participating in selected randomized trials. In that metanalysis, the reported overall risk of HF-related events was 1.20 (95% CI 0.96e1.48). In all the studies included in the analysis (VA-CSDM Feasibility trial, UKPDS, PROactive, ACCORD, ADVANCE, VADT, RECORD), intensive glucose control seemed ineffective in reducing HF events in T2DM, when compared to standard therapy, except for those trials in which patients were treated with glitazone in which case there was an excessive risk of HF events [81]. In an analysis of high quality studies, Boussageon and coll. were unable to find any benefit in HF in patients receiving intensive glucose lowering treatment, but paradoxically noted a significantly higher risk of congestive HF in those patients [82]. The reasons behind these finding remain speculative; among these, insulin therapy could have a causal role or represent a marker of more serious disease [83].

Final remarks In the light of literature data, it is difficult to make affirmations about a cardiomyopathy specifically linked to the diabetic condition but independent of hypertension, CHD, and obesity. The presence of co-morbidities parallels or probably prevails over the contribution of hyperglycaemia in the pathogenesis of heart disease in diabetics. The clinical manifestations of DCM do not differ from those

Diabetic cardiomyopathy associated to HF of other origins; similarly, when routine diagnostic tests are utilized, these do not help to identify DCM, unless very sophisticated tools are employed. In the end, proven therapeutic interventions beyond, needless to say, maintenance of a good metabolic control are still unavailable for DCM. How HF is related to metabolic control and DCM have yet to be defined, and DCM’s clinical entity and significance likewise continue to be elusive.

Disclosures None.

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