Established interventions for mitral valve regurgitation. Current evidence.

Severe mitral regurgitation (MR) is a growing medical challenge in today's aging population, leading to increased health expenditure due to the resultant morbidity and mortality. Surgery, either replacement or repair, has been the mainstay of therapy for primary MR. In high-risk or inoperable patients, treatment was limited to medical therapy until 2008. Since then, alternative percutaneous therapies have been introduced and have proven to be safe and effective in patients with secondary MR. Edge-to-edge repair with the MitraClip system is applied worldwide for primary and secondary MR. Randomized data do not support its application in low-risk patients with primary MR. Results from ongoing and future randomized trials will clarify its impact on important clinical endpoints in high-risk and inoperable patients. The Carillon device is a percutaneous indirect annuloplasty technique introduced in 2009 for secondary MR. Clinical data for the novel Cardioband system, using a different intra-atrial annuloplasty technique, have been gathered from more than 40 patients and the system recently received CE mark approval. Other percutaneous repair devices and implantable valves are under development and may be introduced into clinical practice soon. The percutaneous interventional therapy of MR is a highly dynamic field of cardiovascular medicine and has the potential to improve quality of life as well as morbidity and mortality in selected patients.

[Echocardiography as primary diagnostic tool for valvular heart diseases]. / Echokardiographie als Primärdiagnostik für Erkrankungen der Herzklappen.

Echocardiography is the method of choice for diagnostics and decision making in valvular heart diseases. It is a universally available diagnostic tool not limited by radiation exposure or toxicity of contrast agents. It is capable of displaying cardiac anatomy, function and blood flow allowing an integrative approach to diagnosing valvular heart diseases. Quantification of stenotic valve lesions by calculating the valve opening area is well established. On the other hand, quantification of valve regurgitation is more difficult as it relies on simplifications and assumptions on geometry of the regurgitation orifice and its boundaries. Three dimensional assessments of the regurgitation orifice and flow may improve the accuracy of grading of cardiac valve regurgitation.

[Interventional Mitral valve repair with the MitraClip® procedure. Patient selection criteria]. / Interventionelle Mitralklappenrekonstruktion mit dem MitraClip®-Verfahren. Patientenauswahlkriterien.

In current practice the MitraClip® procedure is increasingly being used for patients unsuitable or at high risk for cardiac surgery. This article initially describes the patient groups that are suitable for percutaneous edge-to-edge repair. For this purpose the echocardiographic criteria for severe mitral regurgitation are first characterized and treatment algorithms for patients with primary as well as secondary mitral regurgitation according to current guidelines are illustrated. Basic anatomical requirements for the successful implantation of a MitraClip® are described and a distinction is made between various valve morphologies ranging from optimal to unsuitable anatomical conditions. Finally, three patient groups eligible for percutaneous edge-to-edge repair considering clinical and anatomical criteria are defined: (1) optimal for MitraClip®, (2) MitraClip® could be considered and (3) MitraClip® only in exceptional cases.

Impact of the type of centre on management of AF patients: surprising evidence for differences in antithrombotic therapy decisions.

Atrial fibrillation (AF) patients may receive treatment from specialists or from general medicine physicians representing different levels of care within a structured health care system. This "choice" is influenced by patient flow within a health care system, patient preference, and individual access to health care resources. We analysed how the postgraduate training and work environment of treating physicians affects management decisions in AF patients. Patient characteristics and treatment decisions were analysed at the time of enrolment into the registry of the German Atrial Fibrillation NETwork (AFNET). A total of 9,577 patients were enrolled from 2004 to 2006 in 191 German centres that belonged to the following four levels of care: 13 tertiary care centres (TCC) enrolled 3,795 patients (39.6%), 58 district hospitals (DH) enrolled 2,339 patients (24.4%), 62 office-based cardiologists (OC) enrolled 2,640 patients (27.6%), and 58 general practitioners or internists (GP) enrolled 803 patients (8.4%). Patients with new-onset AF were often treated in DH. TCC treated younger patients who more often presented with paroxysmal AF. Older patients and patients in permanent AF more often received outpatient care. Consistent with recommendations, younger patients and patients with non-permanent AF received rhythm control therapy more often. In addition, the type of centre affected the decision for rhythm control. Stroke risk was similar between centre types (mean CHADS2 scores 1.6 -1.9). TCC (68.8%) and OC (73.6%) administered adequate antithrombotic therapy more often than DH (55.1%) or GP (52.0%, p<0.001 between groups). Upon multivariate analysis, enrolment by TCC or OC was associated with a 1.60 (1.20-2.12, p=0.001) fold chance for adequate antithrombotic treatment. This difference between centre types was consistent irrespective of the type of stroke risk estimation (ESC 2001 guidelines, CHADS2 score), and also consistent when the recently suggested CHA2DS2-VASc score was used to estimate stroke risk. In conclusion, management decisions in AF are influenced by the education and clinical background of treating physicians in Germany. Inpatients receive more rhythm control therapy. Adequate antithrombotic therapy is more often administered in specialist (cardiologist) centres.

[Registry and studies of the German Competence Network on Atrial Fibrillation (AFNET)]. / Register und Studien des Deutschen Kompetenznetzes Vorhofflimmern (AFNET).

The German Competence Network on Atrial Fibrillation (AFNET) is a national interdisciplinary research network funded by the Federal Ministry of Education and Research (BMBF). AFNET was initiated in 2003 and aims at improving treatment of atrial fibrillation (AF), the most frequent sustained cardiac arrhythmia. AFNET has established a nationwide patient registry on diagnostics, therapy, course and complications of AF in Germany. The data analyzed to date demonstrate that patients with AF are likely to have multiple co-morbidities, such as hypertension, valvular heart disease, coronary artery disease, diabetes mellitus and advanced age. Oral anticoagulation is provided to the majority of patients in accordance with the recommendations given by guidelines. Further areas of research deal with the optimal duration of antiarrhythmic therapy following electrical cardioversion of atrial fibrillation and the value of strategies to prevent arrhythmogenic changes, such as fibrosis in the atria, for prevention of further episodes of atrial fibrillation. Additional registry projects were established for patients with catheter-based interventional therapy of atrial fibrillation and surgical ablation to define success, complications and long term results of these recently developed procedures more clearly. Data and insights gathered from these projects were used to further develop standards of care in two international conferences.

The delay of contrast arrival in magnetic resonance first-pass perfusion imaging: a novel non-invasive parameter detecting collateral-dependent myocardium.

AIM: To establish the regional delay of contrast arrival in magnetic resonance perfusion imaging (MRPI) for the detection of collateral-dependent myocardium in patients with coronary artery disease. DESIGN AND SETTING: Observational study, case series; single centre, university hospital. PATIENTS: 30 patients with coronary artery disease and collateral-dependent myocardium and 17 healthy volunteers. METHODS: Resting and hyperaemic (adenosine) MRPI was used to determine the delay time (Deltat(d)) of contrast arrival between the left ventricle and collateral-dependent or antegradely perfused myocardium, and myocardial perfusion (MP, ml/min/g). RESULTS: In healthy volunteers, mean (SD) Deltat(d) at rest and during hyperaemia were 0.8 (0.4) and 0.3 (0.3) s, and MP was 1.14 (0.21) and 4.23 (1.12) ml/min/g. In patients Deltat(d) in antegradely perfused vs collateral-dependent myocardium was 0.9 (0.7) vs 1.7 (1.0) s at rest (p<0.001), and 0.4 (0.3) vs 1.1 (0.6) s (p<0.001) during hyperaemia. MP was 1.12 (0.11) and 0.98 (0.28) ml/min/g (p = NS) at rest and 2.46 (0.85) vs 1.86 (0.91) ml/min/g (p<0.01) during hyperaemia. Receiver operating characteristics analysis showed the best sensitivity and specificity of 90% and 83% for hyperaemic Deltat(d) of >0.6 s (area under the curve (AUC) = 0.89) to detect collateral-dependent myocardium, while resting Deltat(d) (AUC = 0.77) and perfusion (AUC = 0.69 at rest or 0.70 during hyperaemia) were less accurate. CONCLUSIONS: MRPI-derived hyperaemic delay of contrast arrival detects collateral-dependent myocardium with high sensitivity and specificity. Perfusion was less sensitive, emphasising the clinical role of Deltat(d) in non-invasive detection of collateral-dependent myocardium.

[Magnetic resonance imaging for the assessment of myocardial perfusion: value of various semiquantitative perfusion parameters]. / MRT zur Beurteilung der Myokardperfusion: Aussagekraft verschiedener semiquantitativer Perfusionsparameter.

PURPOSE: The aim of this study was to determine the diagnostic accuracy of various semiquantitative perfusion parameters of the magnetic resonance perfusion examination of the myocardium compared to conventional coronary angiography. PATIENTS, MATERIAL AND METHODS: Twenty patients with suspicion of coronary artery disease who underwent coronary angiography were examined by MR imaging within 14 days before or after coronary angiography. A perfusion examination during adenosine application (140 microg/kg/min) and at rest was performed using a saturation recovery turboFLASH sequence. The semi-quantitative parameters maximum signal intensity (SIM), time-to-peak (TTP), area under the curve (AUC) and upslope (US) were determined using dedicated software (Dynamic Signal Analysis, ARGUS, Siemens Medical Solutions) for the evaluation of the signal-intensity-time curves. In addition, the ratio of these parameters (MPRI: myocardial perfusion reserve index) were determined by dividing the values of the stress examination by the values of the rest examination. RESULTS: Accuracy was 78.4% (SIM), 64.9% (TTP), 64.2% (AUC) and 70.4% (US) for the evaluation of the stress examination. Accuracy for the MPRI of the semi-quantitative parameters was 72.2% (SIM), 50.9% (TTP), 72.2% (AUC) und 89.1% (US). CONCLUSION: A combined semi-quantitative evaluation of the MPRI values using the ratio of the upslope values of the stress and rest examination was shown to be the most accurate method. MPRI (US(Stress)/US(Rest)) is superior to an evaluation of the stress examination alone.

Long QT syndrome. Why does sex matter?

There is increased awareness of the extent to which cardiac function is influenced by gender. One of the most dramatic and potentially lethal differences is that seen in cardiac repolarization reflected in the QT interval of the surface ECG. Gender differences in QT and QTc intervals have been observed to change during the lifetime in the general population. These differences can be explained to a large extent by sex hormone driven differences in gene expression of myocardial ion channels. Numerous studies have shown that women's risk to suffer arrhythmias in the context of QT prolonging drugs is doubled compared to men. For familial long QT syndrome there is no conclusive evidence for gender effects with respect to disease onset or mortality. Only subgroup analysis by genotype demonstrated a higher risk in female patients carrying mutations in the LQT2 locus. Special attention should be given to drug-induced QT prolongation in women.

Shu 508 A (Levovist)-enhanced Doppler echocardiography improves the assessment of valvular heart disease.

OBJECTIVE: To investigate whether intravenous injection of SHU 508 A improves the diagnostic accuracy of Doppler echocardiography in the assessment of valvular pathologies. METHODS AND RESULTS: One hundred and twenty-five consecutive patients with valvular pathology (aortic stenosis, n = 48; aortic regurgitation, n = 20; mitral stenosis, n = 21; and mitral regurgitation, n = 36) and diagnostically insufficient Doppler signal were enrolled in this multicenter study. The severity of valvular pathology was graded on a four-point scale using unenhanced and contrast-enhanced Doppler echocardiography as well as cardiac catheterization. Agreement with cardiac catheterization findings increased from 63% using the unenhanced examination to 73% using the contrast-enhanced Doppler examination. Grading was possible in all patients using SHU 508 A, whereas the unenhanced Doppler examination remained inconclusive in six patients. The weighted kappa coefficient between contrast-enhanced Doppler and cardiac catheterization for all diagnoses was 0.76 as compared to 0.68 between unenhanced Doppler and cardiac catheterization. Agreement was especially improved in aortic stenosis (kappa 0.69 unenhanced vs 0.81 contrast-enhanced) and in aortic regurgitation (kappa 0.45 unenhanced vs 0.75 contrast-enhanced). Patients with mitral stenosis and mitral regurgitation experienced less improvement. CONCLUSIONS: In case of an inconclusive unenhanced Doppler echo study, the administration of a left heart contrast agent should be considered. SHU 508 A is especially useful in improving the severity grading of aortic stenosis and aortic regurgitation, while grading of mitral stenosis and mitral regurgitation is less improved.

Na+-channel modulating effect of the inotropic compound S(-)BDF 9196 in human myocardium.

S(-)BDF 9196, the active enantiomer of racemic (+/-)BDF 9148, has been shown to increase force of contraction in myocardium from different species including humans. The present study aimed to investigate the mechanism of the positive inotropic action of the active enantiomer S(-)BDF 9196 in human myocardium. In electrically driven human left ventricular papillary muscle strips (dilated cardiomyopathy, NYHA IV, cardiac transplantation, n=9), S(-)BDF 9196 increased force of contraction concentration-dependently. The maximal positive inotropic effect remained unchanged after the addition of carbachol (1 mmol/l, indicating a cAMP-independent mode of action of S(-)BDF 9196. While [3H]ouabain binding in human myocardial membranes was not influenced by S(-)BDF 9196 up to 10 micromol/l, the inward Na(+)-current in isolated human left ventricular myocytes was increased significantly by S(-)BDF 9196 (1 micromol/l, n=5). These results provide evidence that S(-)BDF 9196 increases force of contraction in human myocardium primarily by enhancing Na(+)-influx, while cAMP-dependent or Na(+),K(+)-ATPase blocking effects do not seem to play a role.

Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density.

BACKGROUND: Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K+ currents-prominently, the Ca2+-independent transient outward current (Ito). The mechanism for the reduction of Ito in heart failure is unknown. The K+ channel alpha-subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac Ito in humans. METHODS AND RESULTS: We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and Ito in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak Ito density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (HERG, Kv1.4, Kir2.1, Kvss1.3, and the alpha1C subunit of the Ca2+ channel). mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle. CONCLUSIONS: These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac Ito in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.

Potassium channel down-regulation in heart failure.

Prolongation of action potential duration is the most consistent electrophysiological abnormality in myocardium and myocytes from hypertrophied and failing hearts. Measurements of currents in myocytes from hypertrophied and failing hearts indicate that, in most cases, this is due to a decrease in outward potassium currents. If present, a calcium-independent transient outward current is usually substantially reduced, but delayed rectifier and inward rectifier currents have also been found to be diminished. There is increasing evidence that potassium current down-regulation contributes significantly to the enhanced lability of the repolarization process in heart failure, predisposing to early after-depolarizations, dispersion of repolarization and ventricular arrhythmias. The reduction of outward potassium currents may also be involved in the enhanced sensitivity of failing myocardium to triggering factors like hypokalemia, ischemia, and antiarrhythmic agents with Class III effects. A thorough understanding of the mechanisms of cardiac excitability and arrhythmogenesis at the cellular and molecular level under normal and pathological conditions will be essential for the development of new pharmacological strategies to prevent sudden cardiac death in heart failure.

Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle.

BACKGROUND: Recordings of outward currents in human ventricular myocytes revealed the presence of a large calcium-insensitive transient outward current. This current has been suggested to contribute significantly to regional electrophysiological heterogeneity in myocardial cells and tissue of several animal species and to cause electrical gradients across the ventricular wall. METHODS AND RESULTS: The patch-clamp technique was used to record action potentials and outward currents in myocytes enzymatically isolated from thin subepicardial and subendocardial layers of human nonfailing and failing left ventricle. In all subepicardial cells studied, a calcium-insensitive transient outward current (Ito1) could be recorded with large density (10.6 +/- 1.08 pA/pF at 40 mV), whereas current density of Ito1 in subendocardial cells was fourfold smaller (2.63 +/- 0.31 pA/pF, P<.0001, nonfailing myocardium). In failing hearts, the density of Ito1 was significantly smaller in subepicardial cells (7.81 +/- 0.53 pA/pF, P=.012) but not different in subendocardial myocytes (2.01 +/- 0.23 pA/pF, P=.25). Rate-dependent reduction of peak Ito1 at a 2-Hz depolarization rate was minimal in subepicardial cells (to 92.3 +/- 1.9%), whereas peak Ito1 in subendothelial myocytes was almost suppressed at 2 Hz (reduction to 13.2 +/- 2.1%, P<.0001). The different rate-dependent reduction of the transient outward current was due to a much slower time course of recovery from inactivation in subendocardial cells. Kinetic data, including action potentials recorded at 35 degree C, allow assessment of the role of the transient outward current for electrical activity and transmural voltage gradients in human left ventricle. CONCLUSIONS: Marked regional differences in density and rate-dependent properties of the transient outward current exist in subendocardial and subepicardial layers in human left ventricular myocardium, causing transmural electrical gradients that are important for normal and pathological electrical behavior of the human heart. The difference in recovery rates of the transient outward current is a distinguishing feature between subepicardial and subendocardial myocytes.

Altered diastolic [Ca2+]i handling in human ventricular myocytes from patients with terminal heart failure.

To investigate whether the slow diastolic decay of [Ca2+]i in myocardium of patients with heart failure is a result of alterations of the Ca2+ adenosine triphosphatase of the sarcoplasmic reticulum of the sarcolemma, [Ca2+]i transients were recorded in voltage-clamped ventricular cells isolated from hearts of patients with terminal heart failure or from undiseased donor hearts. To isolate the [Ca2+]i-reuptake function of the sarcoplasmic reticulum, myocytes were dialyzed via the patch pipette with Na(+)-free solution and incubated in Ca(2+)-free and Na(+)-free solution to inhibit Na+/Ca2+ exchange. After superfusion with Ca(2+)-containing, Na(+)-free medium, the sarcoplasmic reticulum was loaded with Ca2+ through repetitive voltage-clamp pulses to +10 mV. Under these conditions, [Ca2+]i decay was significantly slower in myocytes from patients with heart failure (538 +/- 66 msec) than in controls (305 +/- 16 msec; p < 0.05). After the addition of 10 mmol/L of caffeine, [Ca2+]i levels did not show appreciable decay between two voltage-clamp pulses in diseased and undiseased myocytes. We conclude that diastolic decay of [Ca2+]i in ventricular myocytes from patients with terminal heart failure is partially the result of a decreased rate of Ca2+ reuptake by the sarcoplasmic reticulum. Sarcolemmal Ca2+ adenosine triphosphatase does not contribute significantly to cytoplasmic [Ca2+]i removal during an individual heartbeat.

[Spontaneous hemothorax in dermatomyositis and long-term glucocorticoid treatment]. / Spontaner Hämatothorax bei Dermatomyositis und langjähriger Glucocorticoidtherapie.

A 65-year-old woman with dermatomyositis for which she had been treated for ten years with prednisone (latterly 15 mg daily) suddenly experienced severe pain in the left thoracolumbar region. Cardiovascular, pulmonary and vertebral causes of the pain were excluded. But serological tests indicated inflammatory disease and the haemoglobin concentration was low (10.4 g/dl). Left pleural effusions were repeatedly aspirated and some haemorrhagic fluid obtained (haematocrit 0.31 in blood, 0.28 in the pleural effusion). Five days after admission her cardiovascular status became unstable and she developed respiratory failure (haemoglobin 7.6 g/dl). Chest radiograph showed increased pleural effusion. Subsequent thoracotomy revealed a left coagulothorax which was removed and flushed. During this procedure severe bleeding occurred from a covered perforation of the descending aorta, 1.5 x 1.5 cm in size. Although the aortic wall was thin, there was no aneurysm but arteriosclerotic changes and an external erosion near an abscessing mediastinitis, originating from a chronic purulent pleuritis and bronchopneumonia. The severe blood loss caused circulatory failure from which the patient could not be resuscitated.

Intracellular calcium handling in isolated ventricular myocytes from cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure.

Intracellular [Ca2+]i handling has been shown to be altered in isolated ventricular myocytes from patients with terminal heart failure. The aim of this study was to evaluate if alterations of intracellular [Ca2+]i handling and triggering Ca2+ currents in cardiomyopathic hamsters (strain BIO 14.6) with congestive heart failure might be similar to changes found in myocytes of patients with terminal heart failure and, therefore if the hamster might serve as a model for heart failure in man. Cells were isolated from hearts of hamsters developing hereditary cardiomyopathy (CMP) (strain BIO 14.6) at 12-14 months of age with overt signs of congestive heart failure. Results were compared with age-matched, undiseased control animals (CTRL). [Ca2+]i transients and Ca2+ currents were recorded simultaneously from isolated cells under voltage clamp perfused internally with the Ca2+ indicator, Fura-2. Ca2+ current densities in myocytes from CMP hamsters were -6.6 +/- 0.6 versus -8.3 +/- 0.5 microA/cm2 (P < 0.05) in CTRL. Resting [Ca2+]i levels were not significantly different. Peak [Ca2+]i transients were significantly decreased in CMP cells (450 +/- 52 nM versus 1031 +/- 98 nM in CTRL, P < 0.05). The rate of diastolic [Ca2+]i decay was slower in cells from CMP animals (t1/2: 167 +/- 19 versus 109 +/- 16 ms; P < 0.05). A moderate negative correlation was found between cell surface area and [Ca2+]i transients (r = 0.42; P < 0.05). It is concluded that changes of intracellular [Ca2+]i handling may play an important role in altered contractility of the myocardium of hamsters with hereditary cardiomyopathy in the late stage of congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure.

Prolongation of the action potential has been postulated to be a major reason for the altered diastolic relaxation of the heart in patients with severe heart failure. To investigate the electrophysiological basis for this action potential prolongation in terminal heart failure, K+ currents were recorded in single ventricular myocytes isolated from 16 explanted hearts of patients undergoing transplantation. Results from diseased hearts were compared with ventricular cells isolated from six undiseased donor hearts. Action potential duration was significantly prolonged in cells from patients with heart failure. A delayed rectifier K+ current was hardly detectable in most cells, and if it could be recorded, it was very small in both diseased and undiseased cells. When currents were normalized for cell surface area, the average current density of the inward rectifier K+ current was significantly reduced in diseased cells when compared with normal control cells (hyperpolarization at -100 mV, -15.9 +/- 2.2 vs -9.0 +/- 1.2 microA/cm2; P < .01). In addition, a large transient outward K+ current could be recorded in human myocytes. The average current density of the time-dependent component of this transient outward K+ current was significantly reduced in heart failure (depolarization at +40 mV, 9.1 +/- 1.0 vs 5.8 +/- 0.64 microA/cm2; P < .01). Action potential prolongation in severe heart failure may partially be explained by a reduction in current densities of the inward rectifier K+ current and of the transient outward K+ current. These alterations may thereby have a significant effect on cardiac relaxation.