Diabetic Cardiomyopathy, Insulin Resistance and Microangiopathy: Considerations on Treatment and Rehabilitation Part 3


In the treatment of the diabetic cardiomyopathy is of basic importance the control of the DM in accordance with the directives in force, the control of the physical weight, the healthy food and the physical regular activity, besides the rigorous control of associate diseases, principally arterial high blood pressure, coronary disease and cholesterol.

Many of the established therapies in heart failure are also known to improve insulin resistance, even in non heart failure populations. Standard lifestyle recommendations (exercise, smoking cessation, weight loss) are all associated with improvements in insulin sensitivity [93,94]. Exercise improves both outcomes and insulin sensitivity in the non-ischemic heart failure population [95]. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins all exert favorable effects on glucose metabolism [96,97]. Although beta-adrenergic blocking medications usually worsen insulin resistance, carvedilol has a neutral-to-slight insulin sensitizing effect [98]. Whether this difference contributes to the reported improvements in outcomes for patients treated with carvedilol, compared with metoprolol, remains unclear [99].

Glycemic control: Poor glycemic control has been associated with an increased risk of cardiovascular mortality, with an increase of 11% for every 1% rise in HbA1c levels [100], and other study has shown a link between HbA1c and heart failure [101]. Thus it has been assumed that improving glycemic control should have a beneficial effect on cardiovascular morbidity and mortality. Evidence suggests that good glycemic control is beneficial, at least in the early stages of myocardial dysfunction [102,103]. Evidence also suggests that diabetic cardiomyopathy does not develop in patients with tightly controlled type 1 diabetes, supporting an important role for hyperglycemia in the pathogenesis of diabetic cardiomyopathy [104]. Hyperglycemia is responsible for microvascular complications in diabetes, and because microvascular alterations are thought to contribute significantly to the pathogenesis of diabetic cardiomyopathy, good glycemic control is perhaps the most important component in the overall management of diabetic cardiomyopathy [74].

P-Blockers: Chronic stimulation of the sympathetic nervous system leads to increased heart rate and altered gene expression, resulting in cardiac remodeling in both heart failure and diabetes [105,106]. Traditionally, there has been a reluctance to use P-blockers in patients with diabetes for fear of adverse effects on insulin resistance and an unawareness of hypoglycemia. However, with the recent advances in the understanding of heart failure and the realization of the importance of the sympathetic nervous system in the release of vasoactive substances, they have become an essential treatment for heart failure. Thus P-blockers have been shown to prevent and even reverse cardiac remodeling, resulting in improved LV function and a reduction in mortality [107]. In summary, P-blockers should be given to all diabetic patients with any evidence of HF, unless specifically contra-indicated.

This will result in a relative risk reduction in mortality; however, the effect is not as pronounced as the introduction of P-blockers in non-diabetic patients, but both groups derive significant prognostic benefit [12].

Neurohormonal antagonism: ACE inhibitors form the cornerstone for treatment of heart failure. The captopril multi-centre study demonstrated a significant improvement in exercise capacity and symptoms of heart failure without an effect on mortality [108]. The CONSENSUS study group was the first to show a significant reduction in mortality with enalapril in patients with severe heart failure [109]. The SOLV-D investigators confirmed these findings and also showed that enalapril was able to prevent onset of new heart failure [110,111].

The important role of the renin-angiotensin-aldosterone system in the pathogenesis of complications in diabetic patients is well described. Evidence supports the use of angiotensin-converting enzyme inhibitors in preventing myocardial fibrosis, cardiac hypertrophy, and myocardial mechanical dysfunction associated with diabetic cardiomyopathy [112]. Angiotensin-converting enzyme inhibition and angiotensin- 1 receptor blockade also have been shown to prevent coronary perivascular fibrosis and collagen deposition [113].

ARBs (angiotensin II type 1 receptor blockers) have been proposed to have additive effects on haemodynamic measurements, neurohumoral activity and left ventricular remodeling when added to ACE inhibitors in patients with chronic heart failure.

Ca2+ channel antagonists: An early animal study demonstrated an improvement in diabetic cardiomyopathy with verapamil [114]; however, trials of verapamil, diltiazem and nifedipine have shown a detrimental effect in heart failure [115]. Amlodipine and felodipine were investigated in the PRAISE and Val-HeFT III trials respectively, and no significant benefit was observed over conventional treatment [116,117].

Statins: The safety and efficacy of statin therapy in patients with moderate to severe heart failure has been demonstrated [118]. There is a significant reduction in mortality in patients with a non-ischemic heart failure, adding further support to the additional effects of statins beyond their reduction in cholesterol and prevention of progression of CAD [118]. There is a need for a large randomized, blinded, placebo-controlled trial to evaluate further the benefits in patients with heart failure.

Modulators of free fatty acid metabolism, such as trimetazidine, have proven useful in the management of angina, but their efficacy on diabetic cardiomyopathy is unknown [74].

Thiazolidinediones (TZDs): TZDs are a class of compounds for treating patients with Type II diabetes mellitus, which act by increasing insulin sensitivity in skeletal muscle and adipose tissue through binding and activation of PPAR-S, a nuclear receptor that has a regulatory role in differentiation of cells. Additionally they also act on PPAR-a and increase serum HDL (high-density lipoprotein)-cholesterol, decrease serum triacylglycerols (triglycerides) and increase LDL cholesterol levels marginally (pioglitazone to a lesser extent) [119]. The TZDs, apart from insulin-sensitizing fat and skeletal muscle, increase the expression and function of glucose transporters in the heart, leading to improved glucose metabolism, and reduce FFA utilization by the myocardium [120]. Unfortunately, their clinical utility in the HF population is limited, owing to their promotion of fluid retention/edema, an effect mediated via activation of amiloride-sensitive sodium channels in the collecting duct [130]. Recent controversy has also arisen over a possible association between rosiglitazone (1 of 2 TZDs approved in the U.S.) and increased rates of myocardial infarction [131].

Currently, the most promising potential medical therapies can be divided into 2 broad categories—metabolic modulators and diabetic medications [25].

Metabolic modulators: The agents in this group increase myocardial efficiency by increasing glucose metabolism and decreasing FFA metabolism. Interestingly, 3 of the agents are used as antianginals; it is by increasing energy efficiency that these agents are believed to produce their antianginal effect. One of the most promising potential treatment agents is trimetazidine. This medication—currently available in Europe but not in the U.S.—works by inhibiting the final enzyme in beta-oxidation of FFA. Trimetazidine administration results in improved myocardial ATP/phosphocreatine levels, a marker for myocardial energy stores [25,121].

A second agent that works by inhibiting FFA metabolism is perhexiline. Like trimetazidine, perhexiline is also used as an antianginal agent in other countries but is not approved in the U.S. Unfortunately, clinical use of this agent might be limited, owing to risks of hepatotoxicity and peripheral neuropathy [25,122].

Ranolazine is a third antianginal agent with potential as a metabolic modulator and is approved in the U.S. Unfortunately, it might not be an ideal choice for 2 reasons: 1. Although ranolazine does cause a switch from FFA to glucose, the degree of this effect is relatively limited at physiologic levels. Its main mechanism of action involves lowering intracellular calcium levels via inhibition of a slow-inactivating sodium current. 2. Ranolazine is associated with QT prolongation, although increased rates of ventricular arrhythmias have not been observed [123,124].

L-carnitine is an essential cofactor of fatty acid metabolism, shuttling the end-products of peroxisomal fatty acid oxidation into the mitochondria and modulating the intramitochondrial acyl-coenzyme A/coenzyme A ratio. Although its main role is enhancement of FFA metabolism, experimental evidence also supports an enhancement of glucose metabolism. Several human and animal studies support a modest benefit in left ventricular energetics and function with L-carnitine administration [125,126].

Diabetic medications: If insulin resistance—the fundamental feature of most cases of type II diabetes mellitus— plays a principal role in the pathogenesis of dilated cardiomyopathy in many patients, then agents used to treat patients with diabetes mellitus might also be useful for the insulin-resistant cardiomyopathy population [25].

Metformin, the only biguanide approved in the U.S., prevents worsened glucose metabolism in a non-HF, insulin-resistant population and can improve calcium handling in myocytes [127,128]. However, its use in heart failure patients is limited by the possible potential for lactic acidosis, and a myocardial imaging study showed no improvement in myocardial glucose uptake with metformin administration. The same study did show increased myocardial glucose uptake with the administration of a TZD [129]. These agents work by activating PPAR-, a transcription factor that promotes insulin sensitivity and decreases circulating FFAs. Interestingly, TZDs seem to affect the myocardium, despite the near-complete lack of PPAR-receptors in the myocardium, indicating that the effects on the myocardium are due to decreased circulating FFA [25,26].

Insulin or insulin-secretagogues represent a potential class of antidiabetic agents that could be used to treat an insulin-resistant cardiomyopathy population. A beneficial impact of these agents could theoretically be gleaned by directly promoting glucose metabolism and decreasing circulating FFA. However, therapy with such agents has generally failed to inhibit insulin-resistant cardiomyopathy in animal models and is less attractive than the insulin-sensitizing agents, because it fails to address the underlying physiologic problem of insulin resistance and exposes the patient to the potential negative effects of hyperinsulinemia [25].

Recently, a new class of antidiabetic medications has been developed that acts on the glucagon-like peptide (GLP)-1 pathway. Glucagon-like peptide-1 is 1 of 2 main "incretins" in the body—hormones that promote post-prandial insulin secretion and improved insulin sensitivity [132]. Unfortunately, GLP-1 is impractical as a pharmacological therapy, because it is rapidly degraded in vivo by dipeptidyl peptidase (DPP)-IV, resulting in a 1- to 2-min half-life. Another option, exenatide, shares 53% homology with GLP-1 and works as a partial agonist of the GLP-1 receptor [132]. An alternative to administering a GLP-1 agonist is administering a DPP-IV antagonist. The first agent in this class, sitagliptin, was approved in the U.S. in October 2006, and several others are in development.

Cardiac Rehabilitation

Cardiac rehabilitation program is defined as a long-term program involving medical evaluation, prescribed exercise, cardiac risk factor modification, education and counseling. These programs are designed to limit the physiological and psychological effect of cardiac illness, reduce the risk of sudden death or recurrent ischemia, control cardiac symptoms, stabilize or reverse the atherosclerotic process, and enhance the psychosocial and vocational status of selected patients. Cardiac rehabilitation programs are prescribed for patients who have had a myocardial infarction, have had coronary bypass surgery, or have chronic stable angina pectoris [134].

The European Society of Cardiology defines cardiac rehabilitation program as the sum of interventions required to ensure the best physical, psychological and social conditions so that patients with chronic or post acute cardiac disease may, by their own efforts, preserve or assume their proper place in society [135].

The words "chronic" and "preserve" were added to the previous definition of the World Health Organization (WHO) in order to stress the concept of the importance of rehabilitation in the long term care of patients with chronic disease, including those who had not had recent acute events.

Cardiovascular health is achieved through interventions to enhance vascular protection. The use of these interventions can only be effective when patients and health professionals are able to know the risk of recurrent vascular events, the treatment targets, the therapies needed and lifestyle modifications, reaching thus success in goal [136].

The promise of cardiac rehabilitation is that interventions such as exercise and risk factor reduction can achieve reduced cardiac events and mortality, likelihood of hospitalizations and need for invasive procedure [137,138]. Rehabilitation has improved cardiac mortality in patients with cardiovascular disease and has proved that the addiction of exercise to the standard pharmacological interventions currently recommended and prescribed can still produce additional patient benefits, notably after acute coronary events [138]. Several trials have shown significant improvements in cardiovascular risk factors and cardiovascular outcomes and have also documented benefits of cardiac rehabilitation in populations over the age 70 years [136,139].

Table 1. Core elements of the Canadian guideline of cardiac rehabilitation [136]

Patient referral process

- Patient assessment

- Risk stratification

- Exercise stress testing

- Risk factor assessment

Lifestyle and risk factor modification

Nutritional counseling

- Risk factor counseling and management

- Lipids

- Hypertension

- Smoking cessation

- Diabetes

- Psychosocial issues

- Weight management, particularly abdominal obesity

- Psychosocial management

- Physical activity counseling and exercise training

Patient education programs

- Lifestyle adherence strategies

- Medication adherence strategies

Outcomes assessment programs

- Health outcomes

- Educational outcomes

- Behavioral outcomes

- Service outcomes

Continuous quality improvement programs

Continuous professional development programs

Cardiovascular rehabilitation showed positive results in reducing inflammatory cytokines, plasma fibrinogen concentrations, platelet aggregation, glucose intolerance, serum LDL, serum triglycerides and systolic blood pressure [136,140,141]. Besides, beneficial effects of cardiac rehabilitation may also be attributed to the comprehensive, proactive chronic disease management with respect to improved cardiovascular disease risk factor management, and improved patient adherence to lifestyle interventions and prescribed medications [142].

Thus, both exercise and comprehensive, target-driven risk factor reduction can have significant benefits on patient outcomes, and the combination of the two is fully developed and completely expressed within contemporary cardiac rehabilitation programs [136].

Cardiac rehabilitation is a disease intervention whose success is derived not only from what interventions or therapies are prescribed but equally fro the process of how those interventions or therapies are delivered to patients.

The Canadian guideline of cardiac rehabilitation [136] proposes the following core elements of these programs:

• Patient referral process: to make easy the identification and inclusion of the patients in the program of cardiac rehabilitation. The use of algorithms and the commitment of health professional is necessary.

• Patient assessment: this include the welcome of the patient, being carried out a focused history and physical examination with particular emphasis on cardiovascular symptoms, exercise limitations, psychosocial problems and evidence of significant valvular heart disease or heart failure. Besides, accurate risk stratification is necessary, with the inclusion of exercise stress testing if necessary.

• Lifestyle and risk factor modification: any patient debit to receive a personalized exercise prescription and lifestyle recommendations focusing specifically on those risk factors relevant for each patient.

• Nutritional counseling: health professional should recommend a healthy diet bases on characteristics of each patient. A specialized professional can be necessary.

• Risk factor counseling and management: eliminate modifiable risk factors like smoking and dietary errors are a challenge. Cardiac rehabilitation staff should have a basic working familiarity with the principles of the model of behavior change, social cognitive theory and motivational interviewing techniques.

Persons with predominant abdominal adiposity (waist circumference larger than 102 cm in men and 88cm in women) are much more likely to have the metabolic syndrome, and cardiac rehabilitation professionals are reminded to measure the wais girth o all patients [143].

Physical inactivity and sedentary lifestyle are the most important, and seemingly the most prevalent, fundamental causes of atherosclerotic vascular disease. Physical inactivity worsens and potentiates the adverse effects of other cardiovascular risk factors such as hypertension, diabetes and dyslipidemia [144].

Depression and anxiety often complicate cardiovascular events and cause distress in their own right. Besides, depression reduces participation in cardiac rehabilitation programs [145,146].

• Patient education programs: to help patients to understand cardiovascular disease and improve lifestyle modifications and adherence to the program.

There are three recognized phases of cardiac rehabilitation [133].

Inpatient rehabilitation (Phase 1): Inpatient rehabilitation is now mostly limited to early mobilization, so that self care is possible by discharge, and brief counseling to explain the nature of the illness or intervention, to increase the patient’s awareness of his or her risk factors and to reassure the patient about future progress and follow-up.

Ambulatory outpatient rehabilitation (Phase 2): Most cardiac rehabilitation is based upon supervised ambulatory outpatient programs conducted during convalescence. Attendance begins soon after discharge from hospital, ideally within the first few days.

Formal outpatient cardiac rehabilitation programs vary widely in content. Almost all contain an element of group exercise which is conducted by allied health professionals. Therefore, an educational and supportive element is inevitably delivered together with the exercise. Psychological and social support may be given on an individual basis, as required, or may be provided to groups of patients and family members.

Maintenance (Phase 3): A lifetime, maintenance stage follows the ambulatory program in which physical fitness and risk factor control are supported in a minimally supervised or unsupervised setting. They may consist of regular recall and review by physician or nurse. Patients may receive additional medication, further education, social support, exercise classes and behavioral intervention, as required. Some patients may be enrolled in special groups for specific reasons (for example, diabetes, obesity, smoking, lipid disorder, hypertension, heart failure) if clinics are established for the management of these particular risk factors or conditions. In other programs, patients may be enrolled in an ongoing exercise class.

The World Health Organization Expert Committee report "Rehabilitation after Cardiovascular Diseases, with Special Emphasis on Developing Countries" of 1993 [147] made the following recommendations:

1. Cardiac rehabilitation should be an integral component of the long-term, comprehensive care of cardiac patients.

2. Cardiac rehabilitation programs or services should be available to all patients with cardiovascular disease, both children and adults.

3. Rehabilitation services should be provided by any trained health professional caring for cardiac patients, since no sophisticated equipment or facilities are required. Both patients and their families should participate.

4. Rehabilitation programs should be integrated into the existing health care system; this can be done at modest cost. The major requirement is for health professionals to be trained in prescribing appropriate exercise and providing health education and vocational guidance.

5 Responsibility for the implementation of cardiac rehabilitation should be given to a designated health professional at the local level, trained as a coordinator. This individual should, in turn, be responsible to an appropriate physician or to a department, hospital, or other health care facility, which may operate under the auspices of the government or a nongovernmental organization or other agency.

6 All plans for the implementation of rehabilitative programs should include provision for evaluating the efficacy of the programs

The conclusion from the guidelines and policy statements is that cardiac rehabilitation services should be available to all patients with cardiac and vascular disease. There is uniformity of opinion to support the view that cardiac rehabilitation should include exercise, education, social support, behavioral change, follow-up of patients and program evaluation. However, there are significant differences between regions regarding specific aspects of the content of these programs; that is "how much of what and for whom?" and in methods of delivering programs [133].

Exercise in cardiac rehabilitation: Widely accepted recommendations regarding exercise training have come from many authoritative sources based upon literature review and consensus [133,135,148]. It is also well recognized that physical performance spontaneously recovers through resumption of normal activities after a period of physical inactivity following acute myocardial infarction or other illnesses. However, trials have demonstrated that exercise training produces a significantly more rapid recovery of physical function. Although previously thought to have been hazardous, progressive resistive exercise training is now recommended, particularly for those who have become inactive and weakened by muscle wasting [133]. There are clinical trials demonstrating improvement in psychological functioning (anxiety, depression and other measures) from exercise training alone, compared with standard medical care [149,150]. The benefit is more apparent with multifactorial rehabilitation.

Exercise training is recommended to improve subsequent exercise habits. However, programs should be followed by long-term availability of support and facilities for maintenance of activity. Exercise training extending beyond convalescence, with a maintenance or follow-up (phase 3) program is recommended to reduce morbidity, recurrent events, hospital readmissions and mortality. The evidence for these claims for secondary prevention comes from some studies with long-term follow-up support and from meta-analyses [151,152]. As suggested earlier, it may be that some benefits arise not from the exercise training itself, but from the comprehensive nature of the interventions.

Low to moderate intensity exercise training is recommended for all cardiac rehabilitation programs. Exercise training at low to moderate intensity has effects similar to those of moderate to high intensity exercise training. From these trials, it appears that a higher level of supervised exercise training has a small, positive relationship to maximal physical working capacity at the completion of the exercise program, but no significant difference is achieved in the long term. Thus, while the process of reconditioning appears to be accelerated through high intensity exercise, it is not associated with any recognizable or demonstrable other benefit. It is therefore reasonable to conclude that low to moderate intensity exercise is, with the single exception of physical working capacity, as effective as high intensity exercise, provided that home activity (particularly walking) is encouraged and undertaken [133,153].

Until recently, it was recommended that high risk patients should not be enrolled in exercise training programs (based upon moderate to high intensity exercise). Several trials and observational studies have now shown, however, that low levels of exercise lead to improvement in physical functioning and quality of life. This applies to patients with impaired ventricular function, with controlled cardiac failure and with symptomatic or asymptomatic residual ischemia.

Exclusion factors are serious conditions requiring attention before exercise is commenced. These are [148]:

• Significant hypertension or hypotension

• Severe aortic stenosis

• Uncontrolled arrhythmias

• Uncontrolled congestive heart failure

• Uncontrolled diabetes or metabolic disturbance

• High grade atrioventricular block without a pacemaker

• Current pericarditis or myocarditis

• Recent pulmonary or other embolism

• Recent stroke or transient ischemic attack

• Recent major surgery

• Terminal illness or severe disabling concurrent illness

• Acute febrile or systemic illness

• Physical or psychological disability preventing participation An additional reason for exclusion is physician or patient refusal

Clinical risk stratification based upon history, examination and resting electrocardiogram is usually sufficient. Technological investigation of patients should be limited to specific tests to answer specific clinical questions applicable to individuals [133]. When necessary, complementary investigation must be performed before the onset of an exercise program.


Diabetic cardiomyopathy became a concrete reality after investigations performed in the last three decades. Diverse pathophysiologic mechanisms have been proposed to explain this condition, but hyperglycemia is the main candidate to be the process initiator. Research in the field of metabolic and structural changes has reached the development of therapeutic options and new medication must be used in the future.

Despite the absence of clear instruments for the diagnosis, diabetic cardiomyopathy should not be ignored by the clinicians and the rigorous control of diabetes is probably the better tool against the disease at the moment.

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