Intrinsic skeletal muscle alterations in chronic heart failure patients: a disease-specific myopathy or a result of deconditioning?

Chronic heart failure (CHF) patients frequently experience impaired exercise tolerance due to skeletal muscle fatigue. Studies suggest that this in part is due to intrinsic alterations in skeletal muscle of CHF patients, often interpreted as a disease-specific myopathy. Knowledge about the mechanisms underlying these skeletal muscle alterations is of importance for the pathophysiological understanding of CHF, therapeutic approach and rehabilitation strategies. We here critically review the evidence for skeletal muscle alterations in CHF, the underlying mechanisms of such alterations and how skeletal muscle responds to training in this patient group. Skeletal muscle characteristics in CHF patients are very similar to what is reported in response to chronic obstructive pulmonary disease (COPD), detraining and deconditioning. Furthermore, skeletal muscle alterations observed in CHF patients are reversible by training, and skeletal muscle of CHF patients seems to be at least as trainable as that of matched controls. We argue that deconditioning is a major contributor to the skeletal muscle dysfunction in CHF patients and that further research is needed to determine whether, and to what extent, the intrinsic skeletal muscle alterations in CHF represent an integral part of the pathophysiology in this disease.

Preserved metabolic reserve capacity in skeletal muscle of post-infarction heart failure patients.

It has been proposed that exercise capacity during whole body exercise in post-infarction congestive heart failure (CHF) patients is limited by skeletal muscle function. We therefore investigated the balance between cardiopulmonary and muscular metabolic capacity. CHF patients (n=8) and healthy subjects (HS, n=12) were included. Patients with coronary artery disease (CAD, n=8) were included as a control for medication. All subjects performed a stepwise incremental load test during bicycling (∼24 kg muscle mass), two-legged knee extensor (2-KE) exercise (∼4 kg muscle mass) and one-legged knee extensor (1-KE) exercise (∼2 kg muscle mass). Peak power and peak pulmonary oxygen uptake (VO(2peak) ) increased and muscle-specific VO(2peak) decreased with an increasing muscle mass involved in the exercise. Peak power and VO(2peak) were lower for CHF patients than HS, with values for CAD patients falling between CHF patients and HS. During bicycling, all groups utilized 24-29% of the muscle-specific VO(2peak) as measured during 1-KE exercise, with no difference between the groups. Hence, the muscle metabolic reserve capacity during whole body exercise is not different between CHF patients and HS, indicating that appropriately medicated and stable post-infarction CHF patients are not more limited by intrinsic skeletal muscle properties during whole body exercise than HS.

Contraction and intracellular Ca(2+) handling in isolated skeletal muscle of rats with congestive heart failure.

A decreased exercise tolerance is a common symptom in patients with congestive heart failure (CHF). This decrease has been suggested to be partly due to altered skeletal muscle function. Therefore, we have studied contractile function and cytoplasmic free Ca(2+) concentration ([Ca(2+)](i), measured with the fluorescent dye indo 1) in isolated muscles from rats in which CHF was induced by ligation of the left coronary artery. The results show no major changes of the contractile function and [Ca(2+)](i) handling in unfatigued intact fast-twitch fibers isolated from flexor digitorum brevis muscles of CHF rats, but these fibers were markedly more susceptible to damage during microdissection. Furthermore, CHF fibers displayed a marked increase of baseline [Ca(2+)](i) during fatigue. Isolated slow-twitch soleus muscles of CHF rats displayed slower twitch contraction and tetanic relaxation than did muscles from sham-operated rats; the slowing of relaxation became more pronounced during fatigue in CHF muscles. Immunoblot analyses of sarcoplasmic reticulum proteins and sarcolemma Na(+),K(+)-ATPase showed no difference in flexor digitorum brevis muscles of sham-operated versus CHF rats. In conclusion, functional impairments can be observed in limb muscle isolated from rats with CHF. These impairments seem to mainly involve structures surrounding the muscle cells and sarcoplasmic reticulum Ca(2+) pumps, the dysfunction of which becomes obvious during fatigue.

Upregulation of the cardiac monocarboxylate transporter MCT1 in a rat model of congestive heart failure.

BACKGROUND: Cardiac metabolism becomes more dependent on carbohydrates in congestive heart failure (CHF), and lactate may be used as an important respiratory substrate. Monocarboxylate transporter 1 (MCT1) promotes cotransport of lactate and protons into and out of heart cells and conceivably flux of lactate between cells, because it is abundantly present in the intercalated disk. METHODS AND RESULTS: Six weeks after induction of myocardial infarction (MI) in Wistar rats, left ventricular end-diastolic pressures were >15 mm Hg, signifying CHF. MCT1 and connexin43 protein levels in CHF were 260% and 20%, respectively, of those in sham-operated animals (Sham), and the corresponding mRNA signals were 181% and not significantly changed, respectively. Confocal laserscan immunohistochemistry and quantitative immunogold cytochemistry showed that MCT1 density was much higher in CHF than in Sham both at the surface membrane and in the intercalated disk. In CHF, a novel intracellular pool of MCT1 appeared to be associated with cisternae, some close to the T tubules. In contrast, connexin43 particles, seen exclusively at gap junctions, were substantially fewer. Maximum lactate uptake was 107+/-15 mmol. L(-1). min(-1) in CHF and 42+/-6 mmol. L(-1). min(-1) in Sham cells (P<0.05). The K(m) values were between 7 and 9 mmol/L (P=NS). CONCLUSIONS: In cardiomyocytes from CHF rats, (1) the amount of functional MCT1 in the sarcolemma, including in the intercalated disk, is increased several-fold; (2) a new intracellular pool of MCT1 appears; (3) another disk protein, connexin43, is much reduced; and (4) increased reliance on lactate and other monocarboxylates (eg, pyruvate) could provide tight metabolic control of high-energy phosphates.

Temperature-dependent skeletal muscle dysfunction in rats with congestive heart failure.

Abnormalities in the excitation-contraction coupling of slow-twitch muscle seem to explain the slowing and increased fatigue observed in congestive heart failure (CHF). However, it is not known which elements of the excitation-contraction coupling might be affected. We hypothesize that the temperature sensitivity of contractile properties of the soleus muscle might be altered in CHF possibly because of alterations of the temperature sensitivity of intracellular Ca(2+) handling. We electrically stimulated the in situ soleus muscle of anesthetised rats that had 6-wk postinfarction CHF using 1 and 50 Hz and using a fatigue protocol (5-Hz stimulation for 30 min) at 35, 37, and 40 degrees C. Ca(2+) uptake and release were measured in sarcoplasmic reticulum vesicles at various temperatures. Contraction and relaxation rates of the soleus muscle were slower in CHF than in sham at 35 degrees C, but the difference was almost absent at 40 degrees C. The fatigue protocol revealed that force development was more temperature sensitive in CHF, whereas contraction and relaxation rates were less temperature sensitive in CHF than in sham. The Ca(2+) uptake and release rates did not correlate to the difference between CHF and sham regarding contractile properties or temperature sensitivity. In conclusion, the discrepant results regarding altered temperature sensitivity of contraction and relaxation rates in the soleus muscle of CHF rats compared with Ca(2+) release and uptake rates in vesicles indicate that the molecular cause of slow-twitch muscle dysfunction in CHF is not linked to the intracellular Ca(2+) cycling.

Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin-1 mRNA and endothelin peptide.

OBJECTIVES: Recent reports indicate that endothelin (ET) plays an important pathophysiological role in congestive heart failure (CHF). However, existing data on local cardiopulmonary ET production are few. No studies have hitherto examined the specific anatomic localization of cardiopulmonary ET synthesis in CHF. Thus, the aims of the present study were to examine whether cardiopulmonary preproET-1 mRNA synthesis is upregulated in CHF and to determine the anatomic localization of preproET-1 mRNA and the mature peptide. METHODS: CHF was induced in rats by occluding the left coronary artery. Only animals with a left ventricular end-diastolic pressure above 15 mmHg after one week were included (n = 28). Sham-operated animals served as controls (n = 24). Hearts and lungs were examined by mRNA slot blot analyses, in situ hybridization (ISH) and immunohistochemistry (IHC). RESULTS: In CHF-rats, slot blot analyses revealed a 3.5 +/- 1.1-fold and a 6.4 +/- 0.8-fold upregulation of preproET-1 mRNA in the noninfarcted and the infarcted area of the left ventricles, respectively (p < 0.05 for both). ISH revealed that the preproET-1 mRNA was localized predominantly over the granulation tissue in the infarcted region. The ET peptide was predominantly localized to inflammatory cells and remaining cardiomyocytes in the infarcted region as determined by IHC. Lungs from CHF-rats showed a 1.5 +/- 0.1-fold upregulation of preproET-1 mRNA (p = 0.01). The most abundant preproET-1 mRNA and ET-1-like-immunoreactivity (ET-1-ir) was seen over inflammatory cells and over airway epithelial cells. Some ET-1-ir was also located to bronchial and vascular smooth muscle cells. CONCLUSION: Increased cardiopulmonary ET synthesis strongly suggest a pathophysiological role for ET in CHF.

Significance of lipoproteins in serum binding variations of amitriptyline, nortriptyline, and quinidine.

Using isotope technique, the serum binding of amitriptyline (AT), nortriptyline (NT), and quinidine (Q) was measured by equilibrium dialysis in sera containing varying amounts of lipoproteins. Sera were obtained from 10 fasting subjects with normal to grossly elevated levels of cholesterol, triglycerides, or both. When the lipoproteins were removed from eight of the sera by a standard ultracentrifugation technique, the ratio bound/unbound (B/F) AT decreased an average of 47% (range 30% to 68%), NT an average of 54% (range 39% to 67%), and Q an average of 6% (range 0 to 16%). This decrease in the ratio B/F correlated linearly with the sum of serum concentrations of cholesterol and triglycerides for AT (r = 0.88) and NT (r = 0.82), but not for Q (r = 0.15). In three lipoprotein-depleted sera resuspended with lipoproteins at eight different concentrations ranging from 0 to 100% of the original content, there was a linear correlation between the ratio B/F for AT and NT and the lipoproteins, as evidence by cholesterol or triglycerides concentrations (r = 0.97 to 0.99), but not for Q (r = -0.17 to 0.36). Finally, in the original 10 serum samples, there was a linear correlation between the ratio B/F and the serum lipoproteins (sum of cholesterol and triglycerides) for AT (r = 0.89) and NT (r = 0.68), whereas there was no such relationship for Q (r = -0.15). These data indicate that basic drugs differ in binding characteristics (probably depending on lipophility).

Binding and displacement of basic, acidic and neutral drugs in normal and orosomucoid-deficient plasma.

The binding of the basic drugs quinidine, propranolol and amitriptyline, the neutral drug digitoxin and the acidic drug phenytoin to heparinised normal plasma, to orosomucoid (alpha 1-acid glycoprotein)-deficient plasma and to purified orosomucoid and albumin was studied in both the presence and absence of tris (2-butoxyethyl)-phosphate (TBEP) and de-(2-ethylhexyl)-phthalate (DEHP). The addition of TBEP and DEHP to heparinised plasma in concentrations up to 2.5 mmol/L markedly increased the unbound fractions of quinidine and propranolol, but the increase was less for amitiriptyline, TBEP being the most potent displacer. In orosomucoid-deficient plasma, which was prepared by immunoprecipitation, the free fraction of quinidine was similar to that of normal plasma in which maximal displacement with TBEP was obtained. The addition of the displacers to orosomucoid-deficient plasma caused no further reduction in the binding, nor was the plasma binding of digitoxin and phenytoin significantly affected. When combining purified albumin and orosomucoid in concentrations found in normal plasma, quinidine binding approached that of heparinised normal plasma. This study confirms the dominant role of orosomucoid in the variable plasma binding of basic drugs, and underlines the value of using immunologically prepared orosomucoid-deficient plasma and TBEP or DEHP as model displacers.

Effects of N-acetylprocainamide as compared with procainamide in isolated rat atria.

The actions of procainamide and its major metabolite N-acetylprocainamide were tested and compared on isolated rat atria. While procainamide exerted a negative chronotropic and iontropic effect, N-acetylprocainamide had the opposite effect. It is suggested that a N-acetylprocainamide-induced increase in myocardial work can counteract the negative inotropic action of procainamide and thus to some extent explain the variable results with the latter compound on myocardial performance reported from in vivo experiments. Procainamide increased the refractory period and reduced the excitability of isolated rat atria. N-acetylprocainamide, on the other hand, caused negligible effects on these parameters.

The regulatory challenge.

The concepts of drug regulation should ideally be derived from an appropriately defined and broadly agreed national drug and health policy, according to health needs, relevant criteria and the local circumstances. The major long term challenge emerging from these concepts is how to establish a sufficiently comprehensive and functional drug and therapeutic audit as a basis for regulatory and other decisions within the health chain that strike a balance between sociomedical and economic requirements. Such an audit involves three sequential phases: collection and compilation of all relevant facts and premises; data organisation and analyses by competent auditors and decision, implementation, and re-evaluation with subsequent adjustments. Despite extensive international and national efforts during recent years, only fragmentary solutions exist, and only in a few countries. Thus, another major challenge still remains: how to weight and integrate the sometimes quite conflicting interests and scopes of politicians, administrators, the teaching institutions, the health professions, the pharmaceutical manufacturers--and the consumers. All the partners involved have to emphasise that the problems behind the present miseries of global drug use are basically of political and economic nature, although there are considerable limitations imposed by widely varying attitudes and deficient knowledge and criteria. Thus there is a need for joint action and a strengthening of collaboration and communication combined with the best possible elements of professional skills and common sense.