Long-QT syndrome-associated caveolin-3 mutations differentially regulate the hyperpolarization-activated cyclic nucleotide gated channel 4.

Background Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current If. It associates with cav-3 and both form a macromolecular complex. Methods To examine the effects of human LQTS-associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole-cell patch-clamp technique. Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics. Conclusions Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.

[Dialysis and ultrafiltration therapy in patients with cardio-renal syndrome: recommendations of the working group "heart-kidney" of the German Cardiac Society and the German Society of Nephrology]. / Dialyse- und Ultrafiltrationsverfahren bei kardio-renalem Syndrom. Empfehlung der Arbeitsgemeinschaft "Herz--Niere" der Deutschen Gesellschaft für Kardiologie--Herz- und Kreislaufforschung e.V. und der Deutschen Gesellschaft für Nephrologie e.V.

Renal failure is common in patients with severe heart failure. This complex pathophysiological interaction has been classified as cardio-renal syndrome. In these patients hydropic decompensation is the main cause of hospitalization. In patients with refractory heart failure, characterized by diuretic resistance and congestion due to volume overload, ultrafiltration has to be considered. In acute decompensated heart failure with worsening of renal function, extracorporeal ultrafiltration is the preferred treatment modality. On the other hand, patients suffering from chronic decompensated heart failure, particularly patients with ascites, will profit from the treatment specific advantages of peritoneal ultrafiltration. Prerequisite for an optimized care of patients with cardio-renal syndrome is the close collaboration among intensive care doctors, cardiologists and nephrologists.

[Heart failure and anemia]. / Herzinsuffizienz und Anämie.

Chronic heart failure has an age-dependent prevalence of 2% and is therefore one of the most frequent diseases in western societies. A reduced hemoglobin concentration according to the definition of the World Health Organization is a common comorbidity affecting more than half of all heart failure patients. Elderly patients, patients suffering from renal impairment and women are more likely to develop anemia but a definitive etiology of anemia is only identified in the minority of cases. Anemia is associated with a poor clinical status and a greater risk of hospitalization and is a predictive factor for increased mortality. The incidence of anemia appears to increase with a poorer functional class. Intravenous iron therapy improves the exercise capacity in patients with systolic heart failure and iron deficiency and is currently being recommended for patients with persistent symptoms despite optimal medical and device therapy. However, erythropoietin-stimulating agents as a treatment for anemia in chronic heart failure have failed to improve clinical outcome in a large randomized trial. In patients with heart failure but with maintained ejection fraction, anemia is also associated with a poor prognosis. Specific therapeutic recommendations for these patients are still not available.

[Why rheumatoid arthritis needs cardiologists]. / Warum die rheumatoide Arthritis den Kardiologen braucht.

Rheumatoid arthritis (RA) is associated with a shortened life expectancy. Most premature deaths are caused by cardiovascular (CV) events; therefore it is of importance to consider the increased CV risk when treating RA patients. Traditional CV risk factors cannot fully explain the increased risk but the common understanding is that inflammation significantly contributes to the excess risk observed. Without the use of correction factors commonly used risk calculators underestimate the true CV risk in RA patients. Methotrexate and TNF inhibitors appear to be beneficial with regard to the CV risk. To date there are only few recommendations for interventions in the CV system of RA patients which go beyond those formulated for the general population. The present manuscript summarizes the published evidence concerning the increased CV risk in RA patients.

[Diagnostics and therapy of heart failure]. / Diagnostik und Therapie der Herzinsuffizienz.

Heart failure represents one of the most common diseases in the western world with an estimated prevalence of 0.4-2% in Europe. The frequency and incidence is very age-dependant and chronic cardiac insufficiency has a high stage-dependant mortality. Aging of the population and prolongation of the lives of cardiac patients has led to an increasing prevalence of heart failure. However, average survival remains poor after hospitalization for a first episode of heart failure. Diagnostics and therapy of heart failure are subject to constant change due to ongoing progress in research and new randomized controlled trials. This review will focus on new developments and current guidelines for diagnosis and treatment of heart failure. Findings on natriuretic peptides and echocardiography in patients with preserved ejection fraction will be presented and innovative therapeutic measures, such as ivabradine will be discussed. Besides new drug developments insight into device therapy, such as MitraClip® and operative approaches for heart failure will be presented.

[The German National Disease Management Guideline "Chronic Heart Failure"]. / Nationale VersorgungsLeitlinie Chronische Herzinsuffizienz.

Chronic heart failure (CHF) is an illness mostly affecting elderly people. In Germany CHF is one of the most common causes of death and at the same time one of the most common diagnosis in inpatient care. Due to the expected increase in life expectancy in the next few years experts predict a further step-up of the incidence. Against this background development of a national guideline on chronic heart failure was prioritised and accordingly the National Disease Management Guideline (NDMG) Chronic Heart Failure was developed by a multi- and interdisciplinary group. The guideline group comprised experts from all relevant scientific medical societies as well as a patient expert. The National Disease Management Guideline (NDMG) on Chronic Heart Failure aims at supporting patients and health care providers with respect to decisions on a specific health care problem by giving recommendations for actions. Recommendations are informed by the best available scientific evidence on this topic.Patients with CHF often suffer from multiple conditions. Due to this fact and the old age patients do have very complex and demanding health care needs. Thus accounting for co-morbidities is paramount in planning and providing health care for theses patients and communication between doctor and patient but also between all health care providers is crucial.Basic treatment strategies in chronic heart failure comprise management of risk factors and prognostic factors as well as appropriate consideration of co-morbidities accompanied by measures empowering patients in establishing a healthy life style and a self-dependant management of their illness.Psycho-social aspects have a very strong influence on patients' acceptance of the disease and their self-management. In addition they have a strong influence on therapy management of the treating physician thus they have to be addressed adequately during the consultation.The National Disease Management Guideline (NDMG) Chronic Heart Failure (CHF) is an interdisciplinary guideline putting particular emphasis on giving recommendations for health care management at the interfaces of the health care system. The NDMG CHF provides a collection of evidence-based and consensus-based recommendations for diagnostics and therapy of patients with CHF. This CPG is meant to improve health care for all affected patients regardless of stage of disease or health care setting. Quality improvement though can only happen when the NDMG CHF is adopted into daily routine. To support implementation a patient version of the guideline was developed. The article compiles the most relevant recommendations and algorithms of the National Disease Management Guideline (NDMG) Chronic Heart Failure (CHF).

[Expert consensus statement on interventional renal sympathetic denervation for hypertension treatment]. / Interventionelle renale Sympathikusdenervation zur Behandlung der therapieresistenten Hypertonie.

This commentary summarizes the expert consensus and recommendations of the working group 'Herz und Niere' of the German Society of Cardiology (DGK), the German Society of Nephrology (DGfN) and the German Hypertension League (DHL) on renal denervation for antihypertensive treatment. Renal denervation is a new, interventional approach to selectively denervate renal afferent and efferent sympathetic fibers. Renal denervation has been demonstrated to reduce office systolic and diastolic blood pressure in patients with resistant hypertension, defined as systolic office blood pressure ≥ 160 mm Hg and ≥ 150 mm Hg in patients with diabetes type 2, which should currently be used as blood pressure thresholds for undergoing the procedure. Exclusion of secondary hypertension causes and optimized antihypertensive drug treatment is mandatory in every patient with resistant hypertension. In order to exclude pseudoresistance, 24-hour blood pressure measurements should be performed. Preserved renal function was an inclusion criterion in the Symplicity studies, therefore, renal denervation should be only considered in patients with a glomerular filtration rate > 45 ml/min. Adequate centre qualification in both, treatment of hypertension and interventional expertise are essential to ensure correct patient selection and procedural safety. Long-term follow-up after renal denervation and participation in the German Renal Denervation (GREAT) Registry are recommended to assess safety and efficacy after renal denervation over time.

[New tyrosine kinase and EGFR inhibitors in cancer therapy. Cardiac and skin toxicity as relevant side effects. Part A: heart]. / Neue Tyrosinkinase- und EGFR-Inhibitoren in der Tumortherapie. Herz und Haut als wichtige Schädigungsorgane. Teil A: Herz.

Cardiotoxicity is a serious side effect of targeted molecular therapies in cancer treatment. Monoclonal antibodies and tyrosine kinase inhibitors are known to be potent therapies in various neoplastic diseases due to inhibition of specific signal transduction pathways. Although targeted therapies are considered to be less toxic and better tolerated than common chemotherapies certain cardiac side effects have been observed. Cardiac toxicity may range from asymptomatic reduction of left ventricular function to life-threatening events like heart failure and acute coronary syndrome. Further side effects are arterial hypertension, thrombosis and arrhythmias. Cardiovascular side effects are common for anti-HER2 therapy in combination with anthracyclines and for inhibitors of angiogenesis. In these patients careful cardiac monitoring is warranted. Because of missing randomized long-term follow-ups, information about cardiac side effects is limited in newly developed targeted molecular therapies. In case of cardiac side effects or preexisting cardiac disease before therapy initiation, assessments by a cardiologist throughout the course of treatment are important. For patients with severe cardiac side effects, discontinuation of treatment is warranted; in case of asymptomatic cardiac side effects symptom-specific therapy should be performed.

[Mitochondrial calcium channels - a new pharmacological target?]. / Mitochondriale Kalzium-Ionenkanäle - eine neue pharmakologische Zielstruktur?

Calcium is of vital importance to cardiac cell function and plays an important role in heart failure. The mechanism of calcium regulation by mitochondria is still not fully resolved. This review is focused on the function, regulation, and possible therapeutic potential of cardiac mitochondrial Ca(2+) channels.

[New therapeutic approaches in heart failure]. / Neue Therapieansätze bei Herzinsuffizienz.

Chronic heart failure is one of the most common causes of death in western countries. For heart failure with preserved systolic function thus far no reduction of mortality or morbidity could be demonstrated in clinical trials. Conversely, prognosis of systolic heart failure has been improved by the introduction of various drugs and devices in recent years. Since the publication of the latest heart failure guidelines, additional results from clinical studies have been obtained, which should be considered in patient treatment. In patients with severe systolic dysfunction the addition of low dose aldosterone antagonists to an ACE inhibitor and betablocker reduced mortality and hospitalizations already in functional class NYHA II. A resting heart rate above 70 bpm is an independent risk factor in systolic heart failure. If this high heart rate persists despite the maximal tolerated betablocker dose, isolated heart rate reduction by ivabradine may lower the rate of hospital admissions due to worsening heart failure. Iron deficiency should be substituted independently of the presence of anemia to improve symptoms and exercise capacity. In patients with severe systolic dysfunction (ejection fraction < 30 %) and a wide QRS complex ≥ 150 ms cardiac resynchronization therapy (CRT) may be considered even when only mild symptoms are present to reduce hospitalizations.

[Detection of atrial fibrillation after stroke]. / Detektion von Vorhofflimmern beim Schlaganfall.

Approximately every fourth stroke results from cardiac embolism. Atrial fibrillation has been recognized as a common cause for thromboembolic stroke. Detection of unknown atrial fibrillation is an important clinical challenge, as anticoagulation may effectively reduce the risk of recurrent ischemic stroke. In all patients with a cryptogenic stroke 24-h Holter monitoring should be performed in addition to a standard ECG to detect paroxysmal atrial fibrillation. In addition, it is useful to pay attention to atrial fibrillation during continuous bedside ECG monitoring on the stroke unit and in pacemaker interrogation. The indication for longer ECG monitoring by implantable loop recorders may be considered individually based on the expected probability of atrial fibrillation. The potential benefit of these devices is currently being evaluated in clinical trials.

[Renal sympathetic denervation. A novel interventional treatment option for therapy-resistant arterial hypertension]. / Renale Sympathikusdenervation. Ein neues interventionelles Verfahren bei therapierefraktärer arterieller Hypertonie.

As much as one third of patients with arterial hypertension are treatment refractory as they do not reach sufficient blood pressure control despite antihypertensive combination therapy of significant duration. In patients with therapy-resistant hypertension, the kidneys play a central role as activator of the sympathetic nervous system. Sympathetic nervous activation via efferent nerve fibers lying in the adventitia of the renal arteries leads to increased Na(+) reabsorption, increased renin secretion and reduction of renal plasma flow. Via afferent sympathetic fibers in the dorsal root of the spinal chord, the kidneys induce a further augmentation of central sympathetic nervous activity. With the method of renal sympathetic denervation (RSD) an interventional minimally invasive procedure has become available to precisely ablate afferent and efferent sympathetic nervous fibers surrounding the renal artery. Via an ablation catheter with an electrode tip and a radiofrequency generator a series of 4-6 ablation sites are administered in both renal arteries leading to denervation of the sympathetic nerve fibers while keeping the renal artery intact. Recent studies showed a significant and continuous reduction of blood pressure of 25-30 mmHg systolic and 10-15 mmHg diastolic for at least 2 years. Concerning the role of elevated sympathetic nervous system activity in forms of hypertension associated with other disorders, further applications of the procedure appear possible, although these are of a rather speculative nature at this time. The current mainstay of therapy-refractive hypertension is RSD, which is well supported by recent clinical data.

[Heart failure update 2010 and current ESC guidelines]. / Herzinsuffizienz Update 2010 und aktuelle ESC-Leitlinien.

Chronic heart failure may be caused by systolic pump failure and/or impairment of diastolic filling of the ventricles. Standard pharmacotherapy of systolic heart failure includes an ACE inhibitor, betablocker, diuretics and in patients with severe symptoms a low-dose aldosterone antagonist. An AT(1) receptor blocker is indicated in those not tolerating ACE inhibitors. If patients remain in functional class NYHA III-IV despite optimal medication and have cardiac dyssynchrony, biventricular pacing may improve symptoms and prognosis. While evidence-based treatment significantly reduces morbidity and mortality in systolic heart failure, hardly any results of clinical trials are available for diastolic heart failure. Therefore, therapy in patients with diastolic heart failure remains symptomatic in most cases.

[Ranolazine--an additional anti-anginal drug]. / Ranolazin - ein ergänzendes Antianginosum.

Ranolazine is a new drug for use in patients with stable angina pectoris. Unlike other antianginal drugs ranolazine does not alter heart rate or systemic blood pressure. Inhibition of the persistent or late sodium current (I(Na,late)) by ranolazine reduces [Na(+) ](i)-dependent Ca(2+) overload and the effects of ischaemia. Moreover, ranolazine holds potential promise to be effective in treatment of atrial fibrillation and diastolic heart failure.