CALIFORNIA MEDICAL ASSOCIATION

Any patient with so-called “refractory” heart failure should be looked upon as suboptimally handled. The patient should be studied for possible development of new disturbances, either inside or outside the vascular system, which, at the same time, have a bearing upon the heart failure.The entire therapeutic program should be reviewed to be sure that all aspects of therapy have been evaluated satisfactorily and established optimally. If diuretics, especially mercurial diuretics, have been given, the possible complications of such therapy, particularly in terms of electrolyte imbalance, should be considered. It is only through a general survey of the patient for an evaluation of these factors that they may be found and therapy instituted to minimize or eliminate them.     

Use of Loop Diuretics is Associated with Increased Mortality in Patients with Suspected Coronary Artery Disease,but without Systolic Heart Failure or Renal Impairment: An Observational Study Using Propensity Score Matching

Background

Loop diuretics are widely used in patients with heart and renal failure, as well as to treat hypertension and peripheral edema. However, there are no randomized, controlled trials (RCT) evaluating their long term safety, and several observational reports have indicated adverse effects. We sought to evaluate the impact of loop diuretics on long term survival in patients with suspected coronary artery disease, but without clinical heart failure, reduced left ventricular ejection fraction or impaired renal function.

Method and Findings

From 3101 patients undergoing coronary angiography for suspected stable angina pectoris, subjects taking loop diuretics (n=109) were matched with controls (n=198) in an attempted 1:2 ratio, using propensity scores based on 59 baseline variables. During median follow-up of 10.1 years, 37.6% in the loop diuretics group and 23.7% in the control group died (log-rank p-value 0.005). Treatment with loop diuretics was associated with a hazard ratio (95% confidence interval) of 1.82 (1.20, 2.76), and the number needed to harm was 7.2 (4.1, 30.3). Inclusion of all 3101 patients using propensity score weighting and adjustment for numerous covariates provided similar estimates. The main limitation is the potential of confounding from unmeasured patient characteristics.

Conclusions

The use of loop diuretics in patients with suspected coronary artery disease, but without systolic heart failure or renal impairment, is associated with increased risk of all-cause mortality. Considering the lack of randomized controlled trials to evaluate long term safety of loop diuretics, our data suggest caution when prescribing these drugs to patients without a clear indication.     

Metabolic Studies on Patients with Resistant Heart Failure Treated by Spironolactone

Metabolic balance studies were carried out on five patients with resistant heart failure treated with spironolactone and other diuretics. Spironolactone alone had little effect. When it was used in a daily dose of 400-600 mg. in combination with hydrochlorothiazide 100 mg. daily, the results were excellent in two patients. One of these was still free of failure after 12 months on combined therapy. In the other patient the serum potassium became elevated after a good diuresis, though on subsequent intermittent therapy with the drug the patient remained well for 12 months. In two other patients administration of spironolactone had to be discontinued because of elevation of the serum potassium before a good diuresis could take place. The fifth patient died.Spironolactone can be a useful adjunct to the therapy of resistant heart failure, but there appears to be a real danger of causing the serum potassium to rise to toxic levels in patients so treated.     

ATLAS OF ROENTGENOGRAPHIC POSITIONS

Mere diagnosis of a valvular heart lesion without circulatory incapacity is inconsequential in considering the prognosis for a pregnant woman.There are grave dangers of heart failure during pregnancy, labor or the postpartum period in women who have had congestive failure prior to pregnancy or during a previous pregnancy and delivery.Decisions as to whether or not to recommend avoidance of pregnancy or therapeutic abortion should depend not alone upon the prospect of death during gestation or at the time of delivery, but also upon the possibility of increased impairment of heart function and physical incapacity of the mother in the postpartum period.Because of the extensive surgical procedure there are few indications for interrupting pregnancy after the third lunar month; and because the major circulatory loads do not increase after the eighth month, rarely should labor be prematurely induced after that time.The exertion of labor, although generally inconsequential, in some cases may produce sustained oxygen debt. In cases in which labor in a previous pregnancy has been accompanied by heart failure, cesarean section should be considered as a means of lessening the possibility of serious failure or death, although this is not a frequent consideration.In the resemblance of circulatory changes that occur, during delivery and immediately postpartum, to those changes produced by the closure of an arteriovenous shunt or patent ductus arteriosus, lies a suggestion as to some of the causative factors in heart failure during or soon after delivery. Probably of great importance is the decrease in blood volume and hemoconcentration at delivery followed by the return of water to the circulatory system, with consequent transient increase in blood volume, in the postpartum period. Additionally, the rise of venous pressure after use of oxytocic drugs suggests that rapid infusion of blood from an engorged uterus may cause an abrupt and perhaps poorly tolerated hypervolemia.Death by heart failure in pregnancy and the puerperium has become extremely rare in recent years due to the frequent observations, meticulous diagnosis of impending failure and improved care of cardiac patients jointly by the obstetrician and the internist. In addition to digitalis therapy and sodium restriction, patients exhibiting evidence of impending heart failure may require bed rest through the entire third trimester of pregnancy. Oxygen should be administered during labor in such patients and anoxia guarded against during anesthesia.     

Heart disease as a complication of pregnancy; with emphasis on indications for recommending therapeutic abortion or avoidance of conception

Mere diagnosis of a valvular heart lesion without circulatory incapacity is inconsequential in considering the prognosis for a pregnant woman.There are grave dangers of heart failure during pregnancy, labor or the postpartum period in women who have had congestive failure prior to pregnancy or during a previous pregnancy and delivery. Decisions as to whether or not to recommend avoidance of pregnancy or therapeutic abortion should depend not alone upon the prospect of death during gestation or at the time of delivery, but also upon the possibility of increased impairment of heart function and physical incapacity of the mother in the postpartum period. Because of the extensive surgical procedure there are few indications for interrupting pregnancy after the third lunar month; and because the major circulatory loads do not increase after the eighth month, rarely should labor be prematurely induced after that time.The exertion of labor, although generally inconsequential, in some cases may produce sustained oxygen debt. In cases in which labor in a previous pregnancy has been accompanied by heart failure, cesarean section should be considered as a means of lessening the possibility of serious failure or death, although this is not a frequent consideration. In the resemblance of circulatory changes that occur, during delivery and immediately postpartum, to those changes produced by the closure of an arteriovenous shunt or patent ductus arteriosus, lies a suggestion as to some of the causative factors in heart failure during or soon after delivery. Probably of great importance is the decrease in blood volume and hemoconcentration at delivery followed by the return of water to the circulatory system, with consequent transient increase in blood volume, in the postpartum period. Additionally, the rise of venous pressure after use of oxytocic drugs suggests that rapid infusion of blood from an engorged uterus may cause an abrupt and perhaps poorly tolerated hypervolemia. Death by heart failure in pregnancy and the puerperium has become extremely rare in recent years due to the frequent observations, meticulous diagnosis of impending failure and improved care of cardiac patients jointly by the obstetrician and the internist. In addition to digitalis therapy and sodium restriction, patients exhibiting evidence of impending heart failure may require bed rest through the entire third trimester of pregnancy. Oxygen should be administered during labor in such patients and anoxia guarded against during anesthesia.     

The role of anemia in congestive heart failure and chronic kidney insufficiency: the cardio renal anemia syndrome

Anemia is a major problem in patients with chronic kidney insufficiency. The development of recombinant human erythropoietin has enabled physicians to correct this anemia. Although anemia has not been considered to be a common or important contributor to congestive heart failure, anemia of any cause can lead to cardiac damage and eventually congestive heart failure. Our joint renal-cardiac heart failure team found that anemia was indeed very common in congestive heart failure and was associated with severe, medication-resistant cardiac failure. Correction of the anemia with erythropoietin and intravenous iron led to a marked improvement in patients' functional status and their cardiac function, and to a marked fall in the need for hospitalization and for high-dose diuretics; renal function usually improved or at least stabilized. Subsequent investigations by others have confirmed many of our observations. We call this interrelationship between congestive heart failure, chronic kidney insufficiency, and anemia the Cardio-Renal Anemia syndrome. Treatment of the anemia in congestive heart failure may prove vital in preventing progression of both the heart failure and the associated renal disease.     

Hypokalaemia and diuretics: an analysis of publications.

Published data have been used to define the characteristics of the fall in serum potassium concentration after taking diuretics and the efficacy of the various treatments given to prevent or correct it. The average fall is less after the usual doses of frusemide (about 0.3 mmol/l) than after the usual doses of thiazides (about 0.6 mmol/l) and is little influenced by the dose or duration of treatment. The fall with a given drug is the same in heart failure and hypertension, but the initial serum potassium concentration is higher in heart failure, so that the final value is lower in hypertension. In standard doses potassium supplements are less effective than potassium-retaining diuretics in correcting the hypokalaemia. The relation between the average serum potassium value and the frequency of low values (hypokalaemia) is such that very low values after taking diuretics are unusual in patients with hypertension or heart failure. Hypokalaemia would almost disappear as an important complication of diuretic treatment if it was defined as a value less than 3.0 mmol/l rather than as a value less than 3.5 mmol/l.     

Nephrotic Syndrome with Heart Disease: A Reappraisal

The evidence that heart failure alone may cause a nephrotic syndrome is inconclusive. Mercurial diuretics, which have also been implicated as a cause of the nephrotic syndrome, had been given in 23 of the 24 well-documented cases.Two cases of heart disease and nephrotic syndrome are described. Glomerular lesions were minimal on light microscopy, but thickening of the glomerular tuft basement membrane and partial fusion of the epithelial cell foot processes were apparent on elecronmicroscopy. The response to prednisone was such as to justify a trial of corticosteroid therapy in such cases despite the presence of cardiac disease.     

Elderly heart failure patients and the role of beta-blocker therapy

In this article different aspects of chronic heart failure in old age are described. We mainly focus on the place of beta-blocker therapy in chronic heart failure. Beta-blockers are recommended for the treatment of stable chronic heart failure with left ventricular systolic dysfunction. There is additional information from recent studies that there is proven efficacy for beta-blocker therapy in patients with heart failure up to the age of 80 years. For patients with heart failure aged 80 and over the evidence to prescribe beta-blockers is limited. However, it is known that also in very elderly patients beta-blocker therapy is well tolerated. In patients with heart failure with preserved systolic ventricular function there is still no evidence that there is a beneficial effect of beta-blockers. It is still not clear if there are differences between beta-blocking agents. Of all beta-blockers, only bisoprolol, carvedilol, nebivolol and metoprolol CR are proven effective in stable chronic heart failure with impaired left ventricular systolic function and can be recommended in elderly patients on standard treatment with diuretics and ACE inhibition.     

Debate: does it matter how you lower blood pressure?

The evidence base for drug treatment of hypertension is strong. Early trials using thiazide diuretics suggested a shortfall in prevention of coronary heart disease. The superiority of newer drugs has been widely advocated but trial evidence does not support an advantage of beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or alpha-blockers for this outcome. Even meta-analyses have failed to clarify matters. If this issue is to be settled, bigger and better trials of longer duration in high-risk patients are needed. Meanwhile, the importance of rigorous blood pressure control using multiple drugs has been established. This should be the focus of our attention rather than agonising over differences in cause-specific outcomes that may not be generalisable to all patient populations.     

Metabolic modulation and cellular therapy of cardiac dysfunction and failure

At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.     

Statin therapy in heart failure

PURPOSE OF REVIEW: The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure. RECENT FINDINGS: This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way. SUMMARY: Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.     

Beta blockers in heart failure haemodynamics,clinical effects and modes of action

Treatment for heart failure may be directed at relieving symptoms and/or improving prognosis. One of the primary aims of research in heart failure is to alter the progressive decline in pump function and thereby improve prognosis.For many years, diuretics have been known as therapeutics in heart failure and they are very effective in symptom relief. Vasodilators and inotropes also have beneficial effects on symptom relief especially in the acute phase through changes in cardiac output, filling pressures and renal perfusion. However, although these treatments produce short-term relief, none have been shown to influence the disease process and thereby improve mortality. Indeed, many of these drugs may even lead to untoward long-term clinical outcomes as has been shown for example for milrinone and ibopamine.There is overwhelming evidence that drugs interfering with the neurohormonal activation in heart failure not only produce symptomatic relief but are also capable of attenuating disease progression with concomitant reductions in both morbidity and mortality. About a decade ago, convincing and large-scale evidence showed that ACE inhibitors produced favourable effects by antagonising the activated renin-angiotensin system. More recently, β-blockers, which antagonise the activated sympathetic system, were shown to be beneficial in the long term in moderate severe heart failure in terms of significant improvements in both morbidity and mortality. The RALES study further amplified the concept that drugs that interact in the neurohormonal system have beneficial effects. In this study, spironolactone, a weak, potassium-sparing diuretic counteracting aldosterone showed a reduction in mortality in more severe forms of heart failure.     

ACUTE MYOCARDIAL INFARCTION—A Discussion of Certain Controversial Issues

As a general rule, it is not believed possible to classify patients with acute myocardial infarction as to the future severity of their illness at the time of the initial examination. However, classifications are possible from complete clinical data of the first few days with regard to the predicted mortality rates. Whether to manage the patient in the hospital or at home depends on the community facilities. The patient should be in bed for a period of two to three weeks if unquestioned infarction has occurred.The main avenue of investigation as to lowering of mortality needs to be directed toward the prevention of heart failure or sudden unexpected death probably related to arrhythmia. If the patient is hospitalized and laboratory facilities are available, anticoagulant therapy can be safely and effectively carried out without undue risk or prohibitive increase in the cost of management. The experience of the author and his colleagues has led to the belief that anticoagulants given routinely to patients with myocardial infarction are effective in decreasing the incidence of thromboembolic complications.     

Relation of trauma to disease; aspects of correlation in cases involving compensation

As a general rule, it is not believed possible to classify patients with acute myocardial infarction as to the future severity of their illness at the time of the initial examination. However, classifications are possible from complete clinical data of the first few days with regard to the predicted mortality rates. Whether to manage the patient in the hospital or at home depends on the community facilities. The patient should be in bed for a period of two to three weeks if unquestioned infarction has occurred. The main avenue of investigation as to lowering of mortality needs to be directed toward the prevention of heart failure or sudden unexpected death probably related to arrhythmia. If the patient is hospitalized and laboratory facilities are available, anticoagulant therapy can be safely and effectively carried out without undue risk or prohibitive increase in the cost of management. The experience of the author and his colleagues has led to the belief that anticoagulants given routinely to patients with myocardial infarction are effective in decreasing the incidence of thromboembolic complications.     

Classification of implants with reference to safety considerations

Implants are listed both in the German Drug Law (Arzneimittelgesetz) and in the Regulations of the Safety of Medical Technical Equipment (Medizinger?teverordnung). In recent time, various guidelines concerning implants have been under discussion in Europe. It is surprising to note that more than one set of guidelines has been thought to be necessary. The present article discusses possible definitions of some of the terms employed in connection with implants, and attempts to identify the differences and common features of implants under aspects of safety, thus providing a broader base for public discussions. An analysis of the implants presently available has shown that it is useful to establish a hierarchy of possible hazards that takes into account the danger to the patient under worst-case conditions. A survey has demonstrated that in the worst case, most implants are associated with only an impairment or inconvenience for the patient, but no threat to life. In contrast, a minority of implants are of such a nature that in the case of severe failure, a life-threatening situation can develop for the patient. Such a hazard is not dependent upon whether the implant has a driving energy source or not. These findings indicate that within the framework of safery considerations, more attention need to be paid to "passive" implants than has been the case so far.     

Designer natriuretic peptides: a vision for the future of heart failure therapeutics

Despite recent pharmacological advances in heart failure therapy, mortality from acute decompensated heart failure remains high. Conventional therapies are often insufficient to address the complex interplay between structural, functional, neurohumoral, and renal mechanisms involved in the heart failure syndrome. The natriuretic peptide system, however, offers a unique pleiotropic strategy which could bridge this gap in heart failure therapy. Exogenous administration of native A-type and B-type natriuretic peptides has been met with both success and limitations, and despite the limitations, remains a worthwhile endeavor. Alternatively, synthetic modification to create "designer" chimeric peptides holds the possibility to extend both the application and therapeutic benefits possible with a natriuretic peptide based approach. Herein we describe the development of natriuretic peptide based heart failure therapies, including the design, rationale, and preliminary studies of the novel chimeric peptides CD-NP and CU-NP.     

Central sleep apnoea syndrome in chronic heart failure: an underestimated and treatable comorbidity

Chronic heart failure is a clinical syndrome with a high mortality and morbidity. Despite optimal therapy, five-year survival is still only 50%. Central sleep apnoea syndrome is seen in approximately 40% of patients with congestive heart failure. Sleep apnoea syndrome can be divided into two forms in these patients: obstructive sleep apnoea syndrome (OSAS) and central sleep apnoea syndrome (CSAS, Cheyne-Stokes respiration), of which CSAS is the most common. CSAS is a form of sleep apnoea in congestive heart failure which is driven by changes in pCO₂. As a consequence of apnoea-hypopnoea an imbalance in myocardial oxygen delivery/consumption ratio will develop, sympathetic and other neurohormonal systems will be activated and right and left ventricular afterload will be increased. Sleep apnoea is associated with an increased mortality in patients with systolic heart failure. Treatment of sleep apnoea increases left ventricular ejection fraction and transplant-free survival. Because of its high prevalence, poor quality of life, poor outcome, and the beneficial effects of treatment, physicians treating patients with heart failure should be aware of central sleep apnoea. There are different treatment options, but the exact effects and indications of each option have not yet been fully determined. Further studies should be done to further investigate its prevalence, and to establish the most adequate therapy for the individual patient. (Neth Heart J 2010;18:260-3.)     

Congestive heart failure. New frontiers.

Congestive heart failure is a common syndrome with high mortality in its advanced stages. Current therapy includes the use of vasodilator drugs, which have been shown to prolong life. Despite current therapy, mortality remains high in patients with severe heart failure. Potent new inotropic vasodilators have improved ventricular performance but have not prolonged life in patients with end-stage heart failure. Serious arrhythmias are implicated in the sudden deaths of 30% to 40% of patients with severe heart failure, but the benefits of antiarrhythmic therapy have not been established. Upcoming trials will address this question. Ventricular remodeling and progressive dilatation after myocardial infarction commonly lead to congestive heart failure; early unloading of the ventricle with an angiotensin-converting enzyme inhibitor may attenuate these events. These findings support the concept that angiotensin-converting enzyme inhibitors may be useful in managing heart failure of all degrees of severity, including left ventricular dysfunction and end-stage heart failure. Part of the damage that may occur with acute myocardial infarction, particularly in this era of thrombolysis therapy, is reperfusion injury, which may be mediated by oxygen-derived free radicals. Better knowledge of the mechanisms and treatment of myocardial infarction, the leading cause of congestive heart failure, may help prevent or attenuate the development of this syndrome.     

Pulmonary arterial hypertension in a patient treated with dasatinib: a case report

Background

There have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in the form of pleural effusions, which we speculate led only to partial reversion of the disease.

Case presentation

A 67-year-old white man with chronic myelogenous leukemia was treated with the dual Src and BCR-ABL tyrosine kinase inhibitor dasatinib. After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg. Computed tomography ruled out a possible pulmonary embolism; laboratory specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed.A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units.

Conclusions

Patients should always be closely monitored when using dasatinib for a prolonged time. Dasatinib-induced pulmonary hypertension may be fully reversible after the therapy is suspended, but the key factors involved are still unclear and need to be further studied.