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European Journal of Heart Failure 2005 7(3):309-316; doi:10.1016/j.ejheart.2005.01.008
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© 2005 European Society of Cardiology

Frequent non-cardiac comorbidities in patients with chronic heart failure

Ulf Dahlström

Department of Cardiology, Linköping University Hospital S-58185 Linköping, Sweden E-mail address: ulf.dahlstrom{at}lio.se


   Abstract
Top
 Abstract
1. Introduction
 2. Hypertension
 3. Diabetes
 4. Chronic obstructive pulmonary...
 5. Anemia
 6. In summary
 References
 
Heart failure (HF) in elderly patients is associated with more diffuse symptoms and signs due to the presence of other noncardiac comorbidities. This can cause difficulties in assessing the correct diagnosis and initiating appropriate therapy. The four most frequently occurring noncardiac comorbidities and therapies used to treat them are discussed in the present paper.

Hypertension is an important precursor of HF, and is still the most common risk factor for HF in the general population. About 50% of patients with untreated hypertension will develop HF. Pressure overload leads to the development of left ventricular hypertrophy (LVH) and diastolic dysfunction.

Diabetes, which occurs in about 20–30% of patients with HF, is an important comorbidity resulting in morphological and metabolic disturbances affecting myocardial blood flow and hormonal regulation leading to a poor outcome and necessitating aggressive conventional treatment.

Chronic obstructive pulmonary disease (COPD), occurs in approximately 20—30% of heart failure patients, and may complicate HF treatment, it is therefore important to recognize and treat it effectively.

Finally, the early detection of anemia, which occurs in 20–30% of HF patients, is important since it is associated with functional impairment and increased mortality and morbidity. Combined treatment with erythropoietin and intravenous iron has shown beneficial effects on clinical symptoms and morbidity.

In conclusion early detection of concomitant diseases in patients with HF is important and should be considered carefully when initiating therapy.

Key Words: Heart failure • Non-cardiac comorbidities • Prognosis

Received May 25, 2004; Revised October 25, 2004; Accepted January 13, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Hypertension
 3. Diabetes
 4. Chronic obstructive pulmonary...
 5. Anemia
 6. In summary
 References
 
Chronic heart failure (HF) is a leading and expanding cause of morbidity and mortality in the western world today. Most of the studies performed in patients with HF have a mean-age of included patients of around 65 years, while the mean age of HF patients in general exceeds 75 years. There are also gender differences, in controlled studies 60–70% of patients are men whereas in the heart failure population overall only 50% of patients or less are men. HF in elderly patients may also have more nonspecific symptoms and signs because they are masked by the presence of a number of comorbidities [1] thus there are diagnostic difficulties in elderly patients. Another relevant problem in elderly HF patients is polypharmacy and more frequent drug side effects [2]. Based on these difficulties, there is a lot of uncertainty today about how to manage elderly HF patients with several comorbidities [3]. Brown and coworkers [4] reported from a Scottish epidemiological study of 25,000 patients with a diagnosis of HF that concomitant diseases, which may be overlooked during routine management of HF, had a great impact on hospital admissions. In another study by Redelmeier et al. [5] it was clearly demonstrated that when one serious condition is the central focus of care, care for other chronic disorders is compromised. Recently, Braunstein and coworkers [6] presented the impact of noncardiac comorbidities on potentially preventable hospitalisations and mortality in elderly patients with HF. This was a cross-sectional study of 122,630 elderly patients (age ≥65 years) with HF identified through a 5% random sample of all US Medicare beneficiaries. The aim of the study was to assess the relationship between the 20 most common comorbidities and the total mortality and potentially preventable hospitalisations during 1 year. The authors found that 65% of the patients had at least one hospitalisation, of which 50% were potentially preventable. Moreover, 40% of the patients had ≥5 noncardiac comorbidities. The risk of hospitalisation was significantly related to the number of different chronic conditions. It was concluded that noncardiac comorbidities are frequent in elderly patients with HF and are strongly associated with adverse clinical outcomes. Therefore, if these comorbidities were recognized and managed better, although this may complicate conventional treatment, outcomes in these high-risk HF patients may be greatly improved. The 5 most common noncardiac comorbidities in this large study were essential hypertension (55%), diabetes mellitus (31%), chronic obstructive pulmonary diseases (26%), ocular disorders (24%) and hypercholesterolemia (21%). In the present paper we discuss in more detail the impact of co-existing hypertension, diabetes and chronic obstructive pulmonary disease in patients with heart failure. In addition, the effect of anemia, which has been recently identified as a major comorbidity in patients with HF, is also reviewed.


   2. Hypertension
Top
 Abstract
 1. Introduction
 2. Hypertension
3. Diabetes
 4. Chronic obstructive pulmonary...
 5. Anemia
 6. In summary
 References
 
2.1. Epidemiology
Papers showing the prevalence of hypertension in patients with HF are listed in Table 1 [6–10]. Many reports today conclude that the most important etiology of HF is ischemic heart disease. However, many of the patients developing an ischemic heart disease (angina pectoris or myocardial infarction) have had hypertension previously. Detailed examination of the patient documentation shows that many of these patients have had untreated hypertension. Based on these reports it is more correct to conclude that the most common etiology of HF is ischemic heart disease and/or hypertension.


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  		Table 1 Epidemiological data on the prevalence of hypertension (HT), diabetes (DM), chronic obstructive pulmonary disease (COPD) and anemia in patients with heart failure (HF)

 
2.2. Mechanisms linking hypertension to heart failure
Arterial hypertension represents the most common cause of pressure overload of the left ventricle and the principal structural adaptation to an increased load is development of left ventricular hypertrophy (LVH). In the Framingham study it was reported that hypertensive patients with definitive signs of LVH on electrocardiography had a 10-fold greater risk of developing HF than hypertensive patients without LVH [11]. LVH produces an increase in wall thickness at the expense of chamber volume, due to hypertrophy of the myocytes and by a parallel alignment of the sarcomeres [12]. It has been proposed that LVH is associated with a specific hypertensive cardiomyopathy [13,14]. This cardiomyopathy is divided into four different stages, where stage one is hypertension with diastolic relaxation abnormalities and grade four is a dilated cardiomyopathy with reduced ejection fraction. Programmed cell death–apoptosis–might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from compensated hypertrophy to HF [15].

Traditionally, HF has been attributed to a decreased systolic left ventricular function, usually accompanied by an increase in left ventricular filling pressure and/or volume [16]. However, over the past 10 years it has become clear, that in 20–30% of patients, systolic function is normal and diastolic left ventricular dysfunction with impairment of the filling and relaxation properties of the heart might have led to the clinical manifestation of HF, particularly in elderly patients with hypertension or ischemic heart disease [17]. There is no doubt today that diastolic heart failure is a pathophysiological clinical condition distinct from or concomitant with systolic HF [18].

Usually, left ventricular diastolic dysfunction precedes systolic dysfunction and therefore diastolic dysfunction is the more common mechanism of HF in hypertensive patients [14].

Several explanations have been proposed to explain the relationship between LVH and HF. One theory is based on alterations in the coronary microcirculation, leading to poor perfusion of the myocardium, resulting in impaired cardiac function and loss of contractile proteins and thus decreased contractility [19]. Another theory suggests that the increased pressure load on the heart, partly compensated by development of LVH over time, becomes insufficient leading to further reduced cardiac output and ventricular dilatation and thus HF [20]. Brilla favours the hypothesis that the hypertrophy of the myocytes is governed by different ventricular loading conditions involving hormonal and paracrine factors such as the renin–angiotensin–aldosterone system and the sympathetic system [21].

2.3. Prognosis
Although hypertension is one of the most important risk factors for the development of HF, it was found repeatedly in overt HF that higher blood pressure was associated with a lower mortality rate than ischemic heart disease [22].

2.4. Treatment
Treatment of hypertension with a number of different drugs has been shown to dramatically reduce the incidence of HF and also to reduce LVH [23]. Treatment recommendations are shown in Table 2. Moreover, many studies have shown that calcium channel blockers are effective in patients with hypertension and also reduce LVH. However, calcium channel blockers have so far not been shown to have beneficial effects on mortality and morbidity in controlled studies of HF patients, this class of drugs are therefore not included in the conventional treatment of HF.


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  		Table 2 Treatment recommendations in patients with heart failure and concomitant hypertension, diabetes, chronic obstructive pulmonary disease or anemia

 

   3. Diabetes
Top
 Abstract
 1. Introduction
 2. Hypertension
 3. Diabetes
4. Chronic obstructive pulmonary...
 5. Anemia
 6. In summary
 References
 
3.1. Epidemiology
Papers showing the prevalence of diabetes in patients with HF in different studies are listed in Table 1 [6,24–33]. However, since the reported figures are from selected study populations, it is questionable whether this is a true picture of the prevalence of diabetes in the HF population. Therefore, we have also included in Table 1 data from registries with more unselected patients, since this is perhaps a better estimate of the true prevalence of diabetes in the HF population. When interpreting data from large registries there are always a number of limitations. However, to date there are several studies supporting the conclusion that poor glycemic control may be an independent risk factor for developing HF. Heart failure is also associated with alterations in peripheral perfusion [34,35] and glucose metabolism [36]. Moreover, decreased insulin sensitivity is associated with the progression and severity of heart failure [37].

3.2. Mechanisms linking diabetes to heart failure
Based on data from several different studies it has been suggested that there is a specific diabetic cardiomyopathy [38–40]. Morphological alterations have been found in the diabetic heart such as intramyocardial microangiopathy, interstitial fibrosis and myocyte hypertrophy. This intramyocardial microangiopathy may explain the reduced coronary blood flow found in diabetic patients [41]. There are also reports demonstrating that there is an accumulation of collagen and other glycation end-products in the myocardium of the diabetic patient, leading to an increased myocardial stiffness and resulting in abnormal diastolic function [42,43]. There is also evidence to suggest that metabolic factors are important players in the development of cardiac dysfunction in diabetic patients. In addition to hyperglycemia, increased turnover of free fatty acids and impaired uptake of glucose in the myocardium are all important factors leading to a disturbed cardiac function. The increased free fatty acids lead to several negative effects, such as decreased glucose oxidation, lactic acid accumulation, increased myocardial oxygen consumption and development of insulin resistance. The metabolic disturbances result in decreased contractility due to an increased intracellular calcium concentration, conduction disturbances promoting development of arrhythmias and finally abnormal energy supply. In conclusion there are morphological as well as metabolic disturbances found in the diabetic heart which may support the hypothesis of a specific diabetic cardiomyopathy which may partly explain the increased prevalence of HF in diabetic patients.

However, there may be other explanations for the increased risk of HF in diabetic patients. In the Framingham study [44] and the SOLVD studies [23,45] it was found that diabetic patients had more hypertension, higher lipid values and were more obese. Furthermore, in the Framingham study it was also found that coronary artery disease was more common among diabetic patients. This increased risk of coronary artery disease has been linked to different mechanisms such as altered platelet function, increased levels of fibrinogen and impaired endothelial dependent vasodilation. Recently, Aronson et al. discussed the molecular mechanisms behind hyperglycemia and atherosclerosis in a review [46]. It is also well-known, but not fully understood, that the ordinary compensatory response in the noninfarcted area after a myocardial infarction is blunted in diabetic patients [47]. In summary, we can conclude that several reports support the occurrence of a diabetic cardiomyopathy, and that comorbidities such as hypertension and the increased rate of coronary artery disease in diabetic patients may also be important underlining explanations to the increased risk of developing HF.

3.3. Prognosis
Diabetes has been shown to be an independent predictor of morbidity and mortality. This was first shown in the SOLVD studies and was recently confirmed after further analysis in the same study. Similar results have been found in the RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction) trial [48].

3.4. Treatment
Since it now has been documented that diabetes is more prevalent in the HF population and is associated with a worse outcome, effective treatment is very important. The first question is whether the response to conventional HF treatment such as diuretics, beta-receptor blockers and ACE-inhibitors is the same in diabetic as in nondiabetic patients (Table 2) [25,28,49–51].

Since there is some relationship between poor metabolic control and development of heart failure, it would be interesting to evaluate whether aggressive treatment with insulin, addressing the metabolic consequences of diabetes such as decreased glucose utilization and increased free fatty acid turnover, would improve outcome in diabetic patients with HF. Such studies have not been undertaken in patients with HF but are recommended. Interestingly, this theory has been addressed in patients with myocardial infarction, with a favourable effect on long-term prognosis [52].

In conclusion, diabetes is an important comorbidity in patients with HF resulting in morphological and metabolic disturbances affecting myocardial blood flow, hormonal regulation and leading to a poor outcome necessitating aggressive conventional treatment.


   4. Chronic obstructive pulmonary disease
Top
 Abstract
 1. Introduction
 2. Hypertension
 3. Diabetes
 4. Chronic obstructive pulmonary...
5. Anemia
 6. In summary
 References
 
4.1. Epidemiology
Papers showing the prevalence of chronic obstructive pulmonary disease (COPD) in patients with HF are listed in Table 1 [6,9,53,54]. The presence of COPD may complicate the treatment of patients with HF. Moreover, it is common for patients with severe HF to have respiratory abnormalities of restrictive origin, airway obstruction and inspiratory muscle weakness, which further contributes to the dyspnoea experienced by these patients. Thus, it is relatively common to have restrictive as well as obstructive pulmonary abnormalities in the early course of HF [55].

4.2. Mechanisms linking COPD to heart failure
Although about 20% of patients with HF also have COPD, the relationship between these two etiologically distinct conditions is not fully understood. Reversible obstructive defects have been described in patients with acute HF, while restrictive defects with reduced carbon monoxide diffusion capacity are more typical for patients with chronic HF. A range of different mechanisms has been proposed for the restrictive pattern such as reduced lung volume due to cardiomegaly and alveolar and interstitial fluid, development of interstitial fibrosis, changes in lung compliance and finally weakness of the respiratory muscles [55]. COPD and HF have similar symptoms, such as low exercise tolerance and dyspnoea due to muscular alterations as well as obstructively or restrictively reduced pulmonary function, although they are two completely different conditions [56].

4.3. Treatment
In the conventional treatment of HF, beta-receptor blockers are one of the cornerstones of therapy. However, this creates a dilemma for the physician responsible for HF treatment since this type of drug is contraindicated in patients with COPD and asthma. This is an even greater problem in elderly patients. It has been suggested that bisoprolol might be used since it is highly beta-1-receptor selective. This is further supported by a meta-analysis from Salpeter et al., confirming the role of cardioselective beta-blockers in patients with COPD [57]. In a study by Kotlyar et al. [58] the tolerability of carvedilol (unselective beta-receptor blocker with vasodilatory alpha-receptor mediated properties) was tested in patients with COPD and HF and no significant influence of airflow was noted. However, in patients with asthma and HF evaluated in the same study, there was marked limitation of the airflow with development of bronchoconstriction and symptoms such as wheezing. In conclusion beta-receptor blockers may be used in patients with COPD and HF. Treatment recommendations are shown in Table 2.


   5. Anemia
Top
 Abstract
 1. Introduction
 2. Hypertension
 3. Diabetes
 4. Chronic obstructive pulmonary...
 5. Anemia
6. In summary
 References
 
5.1. Epidemiology
It has recently been found that anemia is a common comorbidity in patients with HF and that it has prognostic importance. Papers reporting the prevalence of anemia in patients with HF are shown in Table 1 [59–62]. The prevalence of anemia in different studies varies since an exact definition for anemia (cut-off value of hemoglobin) is still lacking. The most frequently used definition is a hemoglobin value less than 120 g/l, or more correctly a value of <130 g/l in men and less than 120 g/l in women. As mentioned previously, anemia has a prognostic importance and is associated with increased mortality and morbidity in patients with severe HF [63–65]. Effective treatment is therefore very important [66].

5.2. Mechanisms linking anemia to heart failure
We know that anemia may cause HF but why should HF patients develop anemia? There are several explanations and the most important are discussed below:

Firstly there may be a reduced iron uptake due to poor intake, malabsorption or chronic blood loss due to heavy menstruation or ongoing medication with aspirin or warfarin. The increased plasma volume usually seen in HF patients may cause a reduced hemoglobin value due to hemodilution. Neurohormonal activation (the renin–angiotensin–aldosterone system) and vasopressin induce sodium and water retention and thus a hemodilution. Reduced renal function is frequently seen in HF patients (vasoconstriction resulting in impaired renal perfusion) with consequent anemia probably due to impaired production of erythropoietin in the kidney [67].

HF is an inflammatory state resulting in increased levels of circulating cytokines and especially tumour necrosis alpha and interleukin-6. There is a close association between the development of anemia and high levels of cytokines, probably due to depression of the bone marrow thus interfering with the production of erythropoietin in the kidney, the erythropoetic response to EPO in the bone marrow and finally also with the release and utility of the iron from the reticuloendothelial system [68].

Angiotensin converting enzyme inhibitors, regarded as one of the most important drugs in the treatment of patients with HF have been shown to depress erythropoietin production in the kidney as well as in the bone marrow, which may lead to an anemia [69,70]. Elevated plasma levels of erythropoietin are of prognostic value for mortality in patients with HF independent of hemoglobin values [71].

5.3. Correction of anemia
Studies using blood-transfusions to correct the developed anemia in patients with HF have shown beneficial effects in terms of clinical improvement [72]. Moreover, it is important to correct the anemia in order to improve the prognosis of the patients. Anemia is very common in patients undergoing treatment with hemodialysis due to impaired production of erythropoietin by the kidney due to renal insufficiency. Nephrologists have for many years treated this anemia with administration of human erythropoietin with consecutive beneficial unloading effects on the heart [73,74]. Silverberg et al., in a study published in the year 2000 showed that combination treatment with subcutaneous erythropoietin and intravenous iron, improved cardiac and renal function, NYHA functional class and morbidity by greatly reducing the number of hospitalisations [66] in patients with severe HF and anemia. A combined treatment has been shown to reduce the need for high erythropoietin doses, since if the iron-deficiency is not corrected it will lead to resistance to treatment with erythropoietin, thus increasing the need for higher doses [75] resulting in more side-effects such as hypertension and the risk of developing thrombosis [76]. Treatment recommendations for HF patients with anemia are shown in Table 2.

In conclusion it is important to detect anemia as early as possible in patients with HF, since it is associated with great functional impairment, and increased mortality and morbidity. Studies are needed to achieve a better understanding of the mechanisms and interaction between hemoglobin levels and HF progression. Treatment of anemia with a combination of human erythropoietin and intravenous iron has shown promising results. However, there is a great need for large, randomised, placebo-controlled studies to assess whether treatment of anemia really has an impact on HF survival and morbidity as well as clinical improvement. Such studies are ongoing.


   6. In summary
Top
 Abstract
 1. Introduction
 2. Hypertension
 3. Diabetes
 4. Chronic obstructive pulmonary...
 5. Anemia
 6. In summary
References
 
This review of the literature clearly demonstrates that noncardiac comorbidities are common in patients with HF and that it is important to recognize these conditions and take them into consideration when selecting treatment for these patients. Appropriate treatment of the HF as well as the concomitant diseases will improve the prognosis of these patients. In the present paper we have only touched upon the problem of comorbidities and only discussed four of the most frequent noncardiac comorbidities. There are several other comorbidities which play a role in the management of HF which are not discussed in this paper.


   References
Top
 Abstract
 1. Introduction
 2. Hypertension
 3. Diabetes
 4. Chronic obstructive pulmonary...
 5. Anemia
 6. In summary
 References
 

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