Peripheral vascular remodeling in chronic heart failure: clinical relevance and new conceptualization of its mechanisms.

Increased peripheral vascular tone is a critical factor in the deterioration of clinical stage and symptoms in chronic congestive heart failure (CHF) because of increased cardiac afterload and decreased nutritive skeletal muscle blood flow. Endothelial function as represented by nitric oxide (NO) production shows significant attenuation with the progression of clinical severity of CHF as determined by New York Heart Association class and exercise capacity parameters. This endothelial dysfunction emerges in the early stages of CHF. In the advanced stage of the condition, both endothelium-dependent and endothelium-independent dilator mechanisms are impaired in limb resistance vessels. This occurs because vascular endothelial function, especially NO production, is an important factor in the regulation of vasodilatory function, as well as making an important contribution to vascular structure. Furthermore, although such vasodilatory circulating factors as natriuretic polypeptides and newly discovered adrenomedullin are increased in heart failure, the vasodilatory potency of these polypeptide hormones in the limb vascular bed is significantly blunted. These observations suggest that peripheral circulatory failure in CHF is caused not only by simple arterial muscle constriction, but also by structural and functional changes, including receptor and postreceptor levels in the vasculature. This vascular remodeling may be an important mechanism underlying vasodilatory failure in both limb conduit and intraskeletal muscle vessels and may contribute significantly to left ventricular dysfunction and exercise intolerance in patients with heart failure.     

The role of endogenous opioids in congestive heart failure: effects of nalmefene on systemic and regional hemodynamics in dogs

We studied the role of endogenous opiates and their interrelationships with the sympathetic nervous system in an experimental preparation of right-sided congestive heart failure (CHF) produced by surgical tricuspid avulsion and progressive pulmonary arterial constriction. Three groups of dogs with CHF and one group of sham-operated dogs were studied. One group of dogs with CHF was given normal saline as pretreatment, while the other two groups were pretreated with either propranolol alone (beta-blockade) or propranolol plus prazosin (alpha- plus beta-blockade). CHF was characterized by weight gain, ascites, elevated right atrial pressure, tachycardia, and reduced cardiac output. Compared with sham-operated animals, animals with CHF exhibited significantly higher baseline levels of plasma beta-endorphin and cortisol. Furthermore, only the animals with CHF responded to the opiate receptor-antagonist nalmefene with significant increases in plasma beta-endorphin, cortisol, and adrenocorticotropic hormone. Administration of nalmefene increased aortic blood pressure, cardiac output, left ventricular dP/dt and dP/dt/P, and blood flow to the myocardium, skeletal muscle, and kidneys in dogs with CHF, but had no appreciable effects in sham-operated dogs. beta-Receptor blockade abolished the increase in cardiac output, left ventricular performance, and blood flow produced by nalmefene, but had no effect on the pressor response to nalmefene. The increase in mean aortic pressure in the beta-blockade group was accompanied by an increase in skeletal muscle vascular resistance. Addition of prazosin in the alpha- plus beta-blockade group abolished the increases in mean aortic pressure and skeletal muscle vascular resistance, suggesting that the changes after propranolol probably resulted from unmasking of alpha-receptor-mediated vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Newer concepts in the medical management of patients with congestive heart failure

Congestive heart failure (CHF) remains a major cause of morbidity and mortality in the United States, especially among the elderly. Although an underlying disturbance in cardiac function can be identified in most patients, manifestations of the disease are greatly influenced by other factors, particularly neurohumoral and peripheral adaptive responses which occur secondary to impaired cardiac function. The renin-angiotensin system (RAS) is integrally involved in the pathophysiology of CHF. Originally considered a humoral system, the RAS is now known to exist and operate within cardiac and vascular tissues. The importance of tissue-specific renin-angiotensin systems in CHF is presently under investigation. Most patients with symptomatic CHF benefit from the administration of an ACE inhibitor. Certain asymptomatic patients, such as those with severe left ventricular (LV) dysfunction and those who are at high risk for LV remodeling after anterior wall myocardial infarction, may also benefit from ACE inhibitor therapy. Diuretics and nitrates improve symptoms and often cardiac output in many patients with CHF. Although many new inotropic agents have been tested in CHF patients, none appear clinically superior to digitalis glycosides. The efficacy of digitalis glycosides in CHF may in part result from sympathoinhibitory properties such as the activation of baroreceptor mechanisms. Despite the fact that many CHF patients die from arrhythmias, treatment of asymptomatic ventricular arrhythmias in these patients is not recommended. Patients with symptomatic or sustained ventricular arrhythmias are best treated by a physician experienced in cardiac electrophysiology. Therapy with beta-blocking drugs for CHF patients is controversial. Anticoagulants are recommended for selected patients with CHF. Finally, exercise therapy may improve functional capacity in some patients with CHF through its effects on peripheral blood vessels and skeletal muscle tissues.     

Resistance Versus Aerobic Exercise Training in Chronic Heart Failure

It is now accepted that exercise training is a safe and effective therapeutic intervention to improve clinical status, functional capacity, and quality of life in people with chronic heart failure (CHF). Nevertheless, this therapeutic modality remains underprescribed and underutilized. Both aerobic and resistance training improve exercise capacity and may partially reverse some of the cardiac, vascular, and skeletal muscle abnormalities in individuals with CHF. Aerobic training has more beneficial effects on aerobic power (peak oxygen consumption) and cardiac structure and function than resistance exercise training, while the latter is more effective for increasing muscle strength and endurance and promoting favorable arterial remodeling. Combined aerobic and resistance training is the preferred exercise intervention to reverse or attenuate the loss of muscle mass and improve exercise and functional capacity, muscle strength, and quality of life in individuals with CHF. The challenge now is to translate these research findings into clinical practice.     

Adaptations in autonomic function during exercise training in heart failure

Although neurohumoral excitation is the hallmark of heart failure (HF), the mechanisms underlying this alteration are not entirely known. Abnormalities in several systems contribute to neurohumoral excitation in HF, including arterial and cardiopulmonary baroreceptors, central and peripheral chemoreceptors, cardiac chemoreceptors, and central nervous system abnormalities. Exercise intolerance is characteristic of chronic HF, and growing evidence strongly suggests that exercise limitation in patients with chronic HF is not due to elevated filling pressures or inadequate cardiac output during exercise, but instead due to skeletal myopathy. Several lines of evidence suggest that sympathetic excitation contributes to the skeletal myopathy of HF, since sympathetic activity mediates vasoconstriction at rest and during exercise likely restrains muscle blood flow, arteriolar dilatation, and capillary recruitment, leading to underperfused areas of working muscle, and areas of muscle ischemia, release of reactive oxygen species (ROS), and inflammation. Although controversial, either unmyelinated, metabolite-sensitive afferent fibers, and/or myelinated, mechanosensitive afferent fibers in skeletal muscle underlie the exaggerated sympathetic activity in HF. Exercise training has emerged as a unique non-pharmacological strategy for the treatment of HF. Regular exercise improves functional capacity and quality of life, and perhaps prognosis in chronic HF patients. Recent studies have provided convincing evidence that these benefits in chronic HF patients are mediated by significant reduction in central sympathetic outflow as a consequence of improvement in arterial and chemoreflex controls, and correction of central nervous system abnormalities, and increase in peripheral blood flow with reduction in cytokines and increase in mass muscle.     

Nifedipine in congestive heart failure: effects on resting and exercise hemodynamics and regional blood flow

Ten patients with moderate to severe congestive heart failure (CHF) underwent central and regional hemodynamic measurements at rest and central hemodynamic measurements during exercise before and after the oral administration of nifedipine (0.2 mg/kg). Nifedipine significantly decreased systemic blood pressure, systemic vascular resistance, pulmonary artery pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure. Stroke volume and cardiac output increased after nifedipine. The measured parameters of left ventricular inotropy did not change significantly for this calcium channel blocker. While blood flow to renal, hepatic, and limb vascular beds increased (p less than 0.05 for renal and limb) after nifedipine, only limb blood flow increased in proportion to the increase in cardiac output, suggesting preferential dilatation of limb vasculature. Although initial-dose nifedipine did not increase exercise duration, it elicited an improvement in exercise hemodynamics by reducing systemic vascular resistance and pulmonary capillary wedge pressure and increasing stroke volume and cardiac output. The calcium channel blocker, nifedipine, can be administered safely in the setting of ventricular failure and appears to favorably alter resting and exercise hemodynamics. A select number of patients with CHF may benefit from its long-term administration.     

Assessment of exercise tolerance in chronic congestive heart failure

In patients with chronic heart failure, exercise capacity is poorly related to cardiac hemodynamics, and peripheral circulation is an important determinant of exercise tolerance. The ability of the muscle vasculature to dilate is markedly impaired, in part, because of exaggerated neurohumoral activity increasing vascular wall stiffness. For this reason, increasing cardiac output is not sufficient to increase exercise capacity if not accompanied by improving vascular reactivity. The poor reliability and reproducibility of exercise tolerance assessed by maximal exercise duration or maximal attained work load (particularly on a treadmill) has led to widespread measurement of respiratory gas during exercise. Peak oxygen consumption (peak VO2), even if it is symptom-limited, has been shown to be a very reproducible criterion of exercise tolerance; moreover, because VO2 is the product of cardiac output and arteriovenous oxygen difference, it also has a qualitative hemodynamic significance. Ventilatory threshold can be determined before maximal exercise; however, problems of determination limit the practical value of this criterion. Unfortunately, peak VO2 lacks sensitivity to detect minor improvement or impairment of symptoms during daily life, although these are significant to the patient. Submaximal exercises have been proposed for this purpose and are currently being evaluated.     

Physical training as an adjunct therapy in patients with congestive heart failure: Patient selection, training protocols, results, and future directions

Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF: reduced endothelium-dependent vasodilation and altered skeletal muscle metabolism. Physical exercise training has evolved as an important therapeutic approach to influence these noncardiac causes of exercise intolerance. It has been shown to enhance the oxidative capacity of the working skeletal muscle, to attenuate ergoreflex activity, to correct endothelial dysfunction, and to improve ventilation. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 mL/kg.min^-1. Uncertainty remains concerning optimal patient selection, training protocol, and long-term effects on cardiac function. For patients experiencing stable CHF while on optimal cardiac medication, a combination of inhospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potential as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

Renal and hormonal effects of phosphodiesterase III inhibition in congestive heart failure

Evaluation of the impact of therapeutic interventions in congestive heart failure (CHF) with compounds such as the phosphodiesterase (PDE) III inhibitors must include the determination of regional blood flow and functional changes. Thus, whereas PDE III inhibitors produce a significant increase in cardiac output and reduction of systemic vascular resistance, it is necessary to understand their effects on the kidney and neurohormonal parameters. The evaluation of these effects must take into consideration both the baseline renal and neurohormonal abnormalities in CHF, and the cellular actions of PDE III inhibition, which include an increase in cyclic adenosine monophosphate and cytosolic calcium. In a group of 13 patients with CHF, milrinone therapy for 1 month did not increase renal blood flow or glomerular filtration rate, or favorably affect neurohormonal parameters. However, forearm blood flow increased proportionately with cardiac output. Therefore PDE III inhibition produces a preferential increase in skeletal muscle blood flow, which may be a relative shunting of blood from the kidney. Alternatively, PDE III inhibition may activate renal cellular mechanisms that offset the anticipated favorable response to the increase of cardiac output produced by milrinone.     

Aging and heart failure--similar syndromes of exercise intolerance? Implications for exercise-based interventions

A classic hallmark of chronic heart failure (CHF) is exercise intolerance; however, the extent of exercise limitation is not correlated with the degree of left ventricular dysfunction. Over the past 2 decades it has become more and more evident that peripheral factors, such as skeletal muscle dysfunction, ventilatory abnormalities, and endothelial dysfunction, contribute the greater part to the limitation of exercise capacity. The molecular and pathophysiological changes observed in these organ systems are not always specific to the underlying CHF but rather represent a common pathway that is activated in several chronic disease processes, including severe chronic obstructive pulmonary disease, cancer, and in the normal aging process. A major contributing factor for skeletal muscle catabolism (i.e. elevated cytokine expression in the skeletal muscle) can be found in both normal healthy aging and in heart failure patients. It is reasonable to assume that the overlap of aging and CHF-associated changes in the skeletal muscle partially explains the disabling consequences of the CHF syndrome among elderly patients (nearly 80% of all patients hospitalized for CHF are >65 years old). Peripheral alterations in CHF are often not adequately treated in routine clinical care since standard pharmacological therapy is still focused on the cardiac function and neurohormonal alteration. Exercise training is a guideline-oriented adjuvant therapy with well-documented beneficial effects on exercise tolerance, skeletal muscle function, endothelial function, and respiration. In this review, the effects of exercise in aging and in CHF are compared and the parallel mechanisms are explored.     

Stellenwert von trainingsbedingten Rückwirkungen am arteriellen Gef??system und der Skelettmuskulatur in der Therapie der Herzinsuffizienz NYHA II/III

Dynamic muscular exercise performed by healthy subjects leads to a rise in the left ventricular blood ejection with an acute increase in the local wall shear stress on the endothelium of the arterial vessels. These hemodynamic changes results in a release of endothelium-dependent relaxing factors, one of them concerns nitric oxide (NO). Therefore an arterial vasodilatation with an acute increase in the blood flow volume to the exercising muscle groups occurs. If more than 1/6 of the skeletal musculature is involved in exercise and if training duration exceeds 3-5 hours a week the chronically increased blood flow volume in the cardiovascular system triggers structural and functional changes of the heart and the arterial vessels. It develops a functional intact excentric hypertrophy of the myocardium; within the arterial vessels an increase in the diameter of the muscular arteries supplying the trained muscle groups occurs. These training-induced adaptations of the cardiovascular system are adjusted to improve the aerobic skeletal muscle metabolism. In congestive heart failure a pathological excentric myocardial hypertrophy is found. In this case the systolic myocardial function is impaired and the left ventricular ejection fraction is reduced already in early stages, so that the cardiac output can not be sufficiently increased during exercise. In addition a dysfunction of the endothelium of the arterial vessels occurs. As a consequence the endothelium-dependent arterial vasodilation is reduced, so that the peripheral arteries could not supply the muscle groups involved in exercise with enough blood flow volume. Therefore, the acute delivery of the working musculature with oxygen and energy substrates is insufficient, so that premature muscular fatigue occurs. The reduced exercise resistance of the patients leads chronically to a generalized skeletal muscle atrophy. Ultrastructural analysis revealed a decrease of oxidative type 1 muscle fibers with a relative increase of more glycolytic type 2 fibers. In addition, the volume density and the surface area of the cristae of mitochondria are reduced. All these changes results in a decrease of aerobic skeletal muscle metabolism independent of the blood flow volume, so that the physical fitness of the patients progressively decline. On the basis of the training-induced physiological adaptations of the cardiovascular system, a special exercise therapy supervised by a physician was developed for patients with congestive heart failure NYHA II/III. It have been shown that various exercise programs, which are adjusted to the degree of cardiac function impairment are suitable to restore the endothelial dysfunction of the arterial vessels as well as to cure the disturbed skeletal muscle metabolism in these patients independent of an improvement of cardiac function. Therefore in patients with congestive heart failure NYHA II/III who underwent regularly such an exercise therapy, the secondary impaired physical fitness could be rebuild without an excessive risk for an acute exercise-induced cardiovascular emergency.     

Exercise reduces persistent ductus arteriosus shunting in piglets

To determine the effects of dynamic exercise on ductal left to right shunting and skeletal and myocardial blood flow distribution, a persistent ductus arteriosus was created by balloon catheters in neonatal piglets. At 8-10 weeks of age, aortic, pulmonary artery, and left atrial catheters were placed and radiolabelled microspheres injected for measuring left ventricular output, organ blood flows, and ductus left to right shunting at rest and during treadmill exercise (1.6 mph). At rest, effective left ventricular output and myocardial and skeletal muscle blood flows were similar in the study group and controls. Exercise increased skeletal muscle and left ventricular blood flows similarly in the control and study group and did not accentuate the exercise induced small reduction in the left ventricular subendocardial to subepicardial blood flow ratio. This was due to a significant reduction in the ductus left to right shunt during exercise (mean(SD) 34(15) vs 18(7)%, p less than 0.02) and maintenance of effective left ventricular output in the study group (447(144) vs 446(98) ml.min-1.kg-1 in controls). The reduction in ductus shunting during exercise was due to a significant decrease in systemic vascular resistance and a small increase in pulmonary vascular and ductus resistance. Thus, reduced persistent ductus arteriosus shunting and maintenance of effective left ventricular output prevents myocardial perfusion abnormalities during dynamic exercise in swine with a persistent ductus and small to moderate left to right shunts.     

Why does chronic heart failure cause breathlessness and fatigue?

Traditional explanations for the symptoms of fatigue and breathlessness experienced by patients with chronic heart failure (CHF) focus on how reduced cardiac output on exercise leads to impaired skeletal muscle blood supply, thus causing fatigue, and on how the requirement for a raised left ventricular filling pressure to maintain cardiac output results in reduced pulmonary diffusion owing to interstitial edema, thus causing breathlessness. However, indices of left ventricular function relate poorly to exercise capacity and symptoms, suggesting that the origin of symptoms may lie elsewhere. There is a specific heart failure myopathy that is present early in the condition which may contribute largely to the sensation of fatigue. Receptors present in skeletal muscle sensitive to work (ergoreceptors) are overactive in patients with CHF, presumably as a consequence of the myopathy, and their activity is related both to the ventilatory response to exercise and breathlessness, and to the sympathetic overactivity of CHF. In the present paper, we review the systemic consequences of left ventricular dysfunction to understand how they relate to the symptoms of heart failure.     

Trainingstherapie bei kardiologischen Patienten (Sportkardiologie)

Clinical application of physical exercise has developed into an evidence-based therapeutic option for cardiovascular diseases, especially coronary artery disease (CAD) and chronic heart failure (CHF). In CAD regular physical exercise training partially corrects endothelial dysfunction and leads to an economization of left ventricular function. Meta-analyses have shown a reduction of angina pectoris symptoms and a decrease of total and cardiovascular mortality by regular aerobic exercise training. Endurance training for CHF reduces cardiac afterload by correcting peripheral endothelial dysfunction und leads to a better left ventricular function. In addition exercise training reduces the adrenergic tone and the stimulation of the renin-angiotensin-aldosterone system in CHF. Exercise training provides positive effects on the metabolism and function of skeletal muscle (e.g. reduced inflammation and oxidative stress). Supervised regular physical exercise training in CHF is safe and has improved the morbidity in clinical studies. Thus aerobic exercise training is an important component of therapeutic management of stable CAD and CHF with a class 1a recommendation in the current guidelines.     

Exercise physiology in cardiovascular diseases

Exercise testing protocols and training regimens are well established for patients recovering from myocardial infarction or coronary artery bypass surgery. However, exercise rehabilitation programs for patients with peripheral arterial disease or left ventricular dysfunction with congestive heart failure have not been well developed. Several recent reports have established reproducible exercise testing protocols with objective measures of performance for patients with peripheral arterial disease and congestive heart failure. Using these testing methods to define changes in exercise capacity, exercise training programs have been shown to result in a significant increase in exercise performance and community-based quality of life. The mechanism of improvement appears to involve peripheral adaptations in skeletal muscle metabolism rather than increases in cardiac output or peripheral blood flow.     

Belastung und Belastbarkeit bei chronischer Herzinsuffizienz

BACKGROUND: Exercise intolerance in patients with chronic heart failure (CHF) shows no correlation to the degree of left ventricular dysfunction. This surprising finding has directed attention to peripheral changes in CHF. During the last years several different peripheral factors as determinants of exercise intolerance have been defined, i.e. abnormalities in ventilation, reduced endothelium-dependent vasodilatation of peripheral conduit and resistance vessels, and altered skeletal muscle metabolism. Skeletal muscle alterations are characterized by a reduced oxidative capacity, a catabolic state with reduced local IGF-I expression and muscle atrophy, chronic inflammation with local expression of the inducible isoform of nitric oxide synthase (iNOS) and an accelerated rate of programmed cell death (apoptosis). EFFECTS OF PHYSICAL EXERCISE: Physical exercise training has evolved as an important therapeutic approach to influence these non-cardiac causes of exercise intolerance. After the first studies documenting the effect of aerobic training on the peripheral causes of exercise intolerance in CHF the question was asked: Should we treat the heart or the periphery to improve exercise intolerance in CHF? Today, we have come closer to the answer: It is now clear that these two systems are not mutually exclusive. Exercise training in CHF has been shown to improve skeletal muscle metabolism and function, to avert muscle catabolism, to reduce neurohumoral overactivation, to reverse endothelial dysfunction and to contribute to the prevention of pathologic left ventricular remodeling. After 6 months of regular exercise training oxidative capacity of the working skeletal muscle increases by approximately 40%. Regular exercise training leads to a significant improvement of endothelium-dependent vasodilatory capacity of peripheral resistance vessels, thereby reducting peripheral resistance in particular during exercise. These beneficial training effects result in a small, but significant improvement of stroke volume and reduction in cardiomegaly. CONCLUSION: Although several questions regarding patient selection, optimal training protocol and training intensity remain unanswered, exercise training can been seen as an established adjunct to pharmacotherapy in CHF. We may soon reach the conclusion that by treating the periphery with exercise programs we are in fact treating the heart, as well. All exercise-induced adaptations converge to increase peak oxygen uptake by up to 2 ml/kg.min. For patients in stable CHF on optimal cardiac medication a combination of in-hospital and home-based aerobic endurance training in combination with local muscle strength training seems most promising. Although exercise training offers no causal treatment of CHF, it has great potentials as an adjunct therapy directed at improving exercise tolerance and expanding the physical limits of CHF patients.     

31P-nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with chronic lung disease and congestive heart failure.

The development of 31P-nuclear magnetic resonance (NMR) has enabled direct and non-invasive measurements of muscle metabolism. Serial measurements of the phosphocreatine/inorganic phosphate (PCr/Pi) ratio, which is closely related to the adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio and pH during and after forearm exercise were performed in 11 patients with chronic lung disease (CLD), nine patients with chronic heart failure (CHF) and eight control subjects. As compared with control subjects, the PCr/Pi ratio in the patients with CLD or CHF was lower during the recovery period and significantly lower at three and 4 min exercise. The pH values after exercise were lower in patients with CLD or CHF compared to control subjects. The PCr/Pi ratio at 4 min after exercise in the patients with CLD or CHF did not correlate with parameters of cardiac function or arterial and mixed venous oxygen tension. The arterial oxygen content and output in patients with CLD and CHF were significantly lower than that of control subjects. Nutritional parameters were not statistically different among the three groups. These observations suggest that metabolic abnormalities may be present in the skeletal muscles of patients with CLD and CHF that are not due to under-nutrition. These may result from reduced arterial oxygen output and, partially, from physical detraining.     

The pulmonary circulation and exercise responses in the elderly

Aging is associated with a progressive deterioration in the structure and function of the pulmonary circulation. Remodeling of the pulmonary vasculature occurs from maturity to senescence that is characterized by an increase in pulmonary vascular stiffness, pulmonary vascular pressures, and pulmonary vascular resistance along with increased heterogeneity of alveolar ventilation and pulmonary perfusion and decreased pulmonary capillary blood volume and membrane diffusing capacity that is consistent with a reduction in alveolar-capillary surface area. In theory, the aforementioned age-related changes in the pulmonary circulation may conspire to make elderly individuals more susceptible to gas exchange abnormalities during exercise. However, despite the erosion in ventilatory reserve with aging, the healthy older adult appears able to maintain alveolar ventilation at a level that allows maintenance of arterial blood gases within normal limits, even during heavy exercise. This ability to maintain adequate gas exchange likely occurs because age-related reductions in the maximal metabolic demand of exercise occur at a rate equal to or greater than the rate of deterioration in ventilatory reserve. A more prominent aspect of aging is the loss of lung elastic recoil that is associated with a modest reduction in the expiratory boundary of the maximal flow-volume envelope. This in turn increases the severity of expiratory airflow limitation and induces dynamic lung hyperinflation during exercise. The consequences of this age-associated decrease in elastic recoil on the pulmonary circulation are speculative, but an age-associated decline in elastic recoil may influence pulmonary vascular resistance and cardiac output, in addition to its impact on the work and oxygen cost of breathing.     

Age-related Changes in Venticular–Arterial Coupling: Pathophysiologic Implications

The interaction of the heart with the systemic vasculature, termed ventricular–arterial coupling, is a central determinant of net cardiovascular performance. The capacity of the body to augment cardiac output, regulate systemic blood pressure, and respond appropriately to elevations in heart rate and venous filling volume is related as much to the properties of the heart as it is the vasculature into which the heart ejects. With aging, changes in the arterial system associated with vascular stiffening and a reduction in peripheral vasomotor regulation can profoundly affect this coupling by imposing far greater pulsatile and late-systolic loads on the heart. This is accompanied by tandem increases in left ventricular end-systolic stiffness (end-systolic chamber elastance) and reduced diastolic compliance. Altered coupling related to combined ventricular–vascular stiffening increases blood pressure lability for a given change in hemodynamic loading and heart rate (i.e. under stress demands), as well as reduces the capacity to enhance cardiac output without greatly increasing cardiac wall stress. Furthermore, such coupling influences myocardial perfusion by elevating the proportion of coronary flow during the systolic time period. This more closely links ventricular systolic function with myocardial flow, and can compromise flow reserve and exacerbate ischemic dysfunction when ventricular systolic function declines, such as with concomitant heart failure or acute regional ischemia. This article reviews the theory behind ventricular–arterial coupling analysis, the changes in coupling that occur with age and their impact on normal reserve mechanisms, and the likely role of these changes have on heart failure and ischemic heart disease and disease therapy in the elderly.     

Origins of Symptoms in Heart Failure

Chronic heart failure is accompanied by disabling symptoms, poor quality of life, and marked exercise limitation. Despite being initiated by a reduction in left ventricular pump function, the syndrome that develops in treated heart failure is one in which a vast array of noncardiac abnormalities develop, many of which may limit exercise in their own right, and some of which may lead to progressive deterioration in left ventricular performance and prognosis. The conventional explanations for the development of symptoms and exercise limitation in heart failure are now seen as being inadequate in many respects. Exercise is usually limited by either dyspnea or muscular fatigue, and it was originally thought the former reflected elevated pulmonary capillary wedge pressures producing pulmonary congestion and edema, whereas the latter was due to inadequate cardiac output, leading to poor muscular perfusion. Recent evidence has shown, however, that there is little correlation between left ventricular function and exercise limitation; that the limiting symptoms can be changed by relatively minor alterations in the exercise test procedure; and that the hemodynamic characteristics of patients do not predict whether fatigue or dyspnea is the predominant symptom. Abnormal peripheral blood flow, endothelial dysfunction, abnormal skeletal muscle structure and function, and skeletal muscle wasting all appear better correlated with symptom generation in heart failure than hemodynamic status. An early metabolic change in skeletal muscle, due in part to abnormal muscle metabolism, activates work-sensitive neural afferents (ergoreceptors) in the muscle, which reflexly increase sympathetic drive, ventilation, and generalized vasoconstriction as well as being prime candidates for carrying the fatigue signal to the cortical centers. Treatments that correct skeletal muscle abnormalities in chronic heart failure, such as ACE inhibitors and physical training, have been shown to improve exercise tolerance and to reduce both fatigue and dyspnea. In addition, such treatments, in particular exercise training of muscle, reduce the overactivity of the work-sensitive ergoreceptors, giving a possible mechanism for both the generation of symptoms and the beneficial response to treatments that improve either muscle blood flow or metabolism in heart failure. The importance of peripheral factors in chronic heart failure stresses the multiorgan nature of this syndrome.