Rainer Dietz

The EuroHeart Failure survey programme-- a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis.

BACKGROUND The European Society of Cardiology (ESC) has published guidelines for the investigation of patients with suspected heart failure and, if the diagnosis is proven, their subsequent management. Hospitalisation provides a key point of care at which time diagnosis and treatment may be refined to improve outcome for a group of patients with a high morbidity and mortality. However, little international data exists to describe the features and management of such patients. Accordingly, the EuroHeart Failure survey was conducted to ascertain if appropriate tests were being performed with which to confirm or refute a diagnosis of heart failure and how this influenced subsequent management. METHODS The survey screened consecutive deaths and discharges during 2000-2001 predominantly from medical wards over a 6-week period in 115 hospitals from 24 countries belonging to the ESC, to identify patients with known or suspected heart failure. RESULTS A total of 46788 deaths and discharges were screened from which 11327 (24%) patients were enrolled with suspected or confirmed heart failure. Forty-seven percent of those enrolled were women. Fifty-one percent of women and 30% of men were aged >75 years. Eighty-three percent of patients had a diagnosis of heart failure made on or prior to the index admission. Heart failure was the principal reason for admission in 40%. The great majority of patients (>90%) had had an ECG, chest X-ray, haemoglobin and electrolytes measured as recommended in ESC guidelines, but only 66% had ever had an echocardiogram. Left ventricular ejection fraction had been measured in 57% of men and 41% of women, usually by echocardiography (84%) and was <40% in 51% of men but only in 28% of women. Forty-five percent of women and 22% of men were reported to have normal left ventricular systolic function by qualitative echocardiographic assessment. A substantial proportion of patients had alternative explanations for heart failure other than left ventricular systolic or diastolic dysfunction, including valve disease. Within 12 weeks of discharge, 24% of patients had been readmitted. A total of 1408 of 10434 (13.5%) patients died between admission and 12 weeks follow-up. CONCLUSIONS Known or suspected heart failure comprises a large proportion of admissions to medical wards and such patients are at high risk of early readmission and death. Many of the basic investigations recommended by the ESC were usually carried out, although it is not clear whether this was by design or part of a general routine for all patients being admitted regardless of diagnosis. The investigation most specific for patients with suspected heart failure (echocardiography) was performed less frequently, suggesting that the diagnosis of heart failure is still relatively neglected. Most men but a minority of women who underwent investigation of cardiac function had evidence of moderate or severe left ventricular dysfunction, the main target of current advances in the treatment of heart failure. Considerable diagnostic uncertainty remains for many patients with suspected heart failure, even after echocardiography, which must be resolved in order to target existing and new therapies and services effectively.

Guidelines on the management of stable angina pectoris: executive summary

We thank the authors for raising the interesting discussion regarding the treatment of hypertension in patients with concomitant coronary disease. The J-shaped association between on-treatment blood pressure and risk has been described in longitudinal cohorts of patients with treated hypertension as well as in clinical trial populations, both in on-treatment and control arms. However, it is not absolutely clear that the association is treatmentrelated; in fact, one meta-analysis of seven randomized controlled trials including data on more than 40 000 patients has shown that the J-shaped relationship between blood pressure and mortality was not related to antihypertensive treatment. In this meta-analysis, noncardiovascular death was inversely related to blood pressure (both systolic and diastolic) in contrast to the J-shaped relationships for cardiovascular and total mortality, leading the authors to hypothesize that poor health conditions leading to low blood pressure and an increased risk of death might in part explain the J-shaped curve. Secondly, as discussed in the full-text version of the guidelines, there is accumulating evidence that blood pressure lowering in the ‘normal’ range is associated with improved cardiovascular outcomes in the population with known coronary disease. In the CAMELOT study, patients with coronary disease and mean blood pressure of 129/78 were randomized to enalapril, amlodipine, or placebo. Blood pressure reductions were similar (5/2 mm) in both treatment groups and associated with similar relative reductions in the composite endpoint of cardiovascular death, MI, and stroke, although not statistically significant in either group because of the small sample size. An intravascular ultrasound substudy demonstrated a significant inverse correlation between progression of atherosclerosis and blood pressure reduction even in this normal blood pressure range, with the greatest benefit observed in patients whose blood pressure fell below 120/80. Thus, the task force has felt it important, in the absence of unequivocal evidence to the contrary, to preserve consistency between guidelines on prevention and angina with regard to targets for institution of therapy for hypertension in the presence of coronary disease. No lower limit has yet been identified as a definite cutoff beyond which blood pressure should not be lowered further, although, clearly, symptomatic hypotension or postural hypotension will limit aggressive blood pressure lowering in the lower range.

Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.

Signaling Pathways in Reactive Oxygen Species–Induced Cardiomyocyte Apoptosis

BACKGROUND The importance of free radical homeostasis and apoptosis in normal and diseased hearts and their interrelationships are poorly defined. We tested whether reactive oxygen species can trigger apoptosis in cardiomyocytes, and we explored the underlying pathways. METHODS AND RESULTS A cell culture model of isolated cardiac cells and different reactive oxygen species (ROS)-generating systems were used. Apoptosis became evident when cardiomyocytes were exposed to either H2O2 or superoxide anion (O2-). Both H2O2- and O2--induced apoptosis of cardiomyocytes were associated with an increase in p53 protein content, whereas protein levels of Bax and Bcl-2 were unaltered. H2O2, but not O2-, induced an increase in the protein content of Bad. Furthermore, H2O2 elicited translocation of Bax and Bad from cytosol to mitochondria, where these factors formed heterodimers with Bcl-2, which was followed by the release of cytochrome c, activation of CPP32, and cleavage of poly(ADP-ribose) polymerase. Interestingly, this pathway was not activated by O2-. Instead, O2- used Mch2alpha to promote the apoptotic pathway, as revealed by the activation of Mch2alpha and the cleavage of its substrate, lamin A. CONCLUSIONS Taken together, these results indicate that ROS may play an important pathophysiological role in cardiac diseases characterized by apoptotic cell death and suggest that different ROS-induced activations of the apoptotic cell death program in cardiomyocytes involve distinct signaling pathways.

Contrast Media–Enhanced Magnetic Resonance Imaging Visualizes Myocardial Changes in the Course of Viral Myocarditis

BACKGROUND The course of tissue changes in acute myocarditis in humans is not well understood. Diagnostic tools currently available are unsatisfactory. We tested the hypothesis that inflammation is reflected by signal changes in contrast-enhanced magnetic resonance imaging (MRI). METHODS AND RESULTS We assessed 44 consecutive patients with symptoms of acute myocarditis. Nineteen patients met the inclusion criteria revealing ECG changes, reduced myocardial function, elevated creatine kinase, positive troponin T, serological evidence for acute viral infection, exclusion of coronary heart disease, and positive antimyosin scintigraphy. We studied these patients on days 2, 7, 14, 28, and 84 after the onset of symptoms. We obtained ECG-triggered, T1-weighted images before and after application of 0.1 mmol/kg gadolinium. We measured the global relative signal enhancement of the left ventricular myocardium related to skeletal muscle and compared it with measurements in 18 volunteers. The global relative enhancement was higher in patients on days 2 (4.8+/-0.3 [mean+/-SE] versus 2.5+/-0.2; P<.0001); 7 (4.7+/-0.5, P<.0001); 14 (4.6+/-0.5, P<.0002); and 28 (3.9+/-0.4, P=.009) but not on day 84 (3.1+/-0.3; P=NS). On day 2, the enhancement was focal, whereas at later time points, the enhancement was diffuse. In patients with evidence of ongoing disease, the values remained elevated. CONCLUSIONS Acute myocarditis evolves from a focal to a disseminated process during the first 2 weeks after onset of symptoms. Contrast media-enhanced MRI visualizes the localization, activity, and extent of inflammation and may serve as a powerful noninvasive diagnostic tool in acute myocarditis.

Delayed Enhancement and T2-Weighted Cardiovascular Magnetic Resonance Imaging Differentiate Acute From Chronic Myocardial Infarction

Background—Delayed enhancement (DE) cardiovascular magnetic resonance (CMR) detects acute and chronic myocardial infarction (MI) by visualizing contrast media accumulation in infarcted segments. T2-weighted CMR depicts infarct-related myocardial edema as a marker of acute but not chronic myocardial injury. We investigated the clinical utility of an approach combining both techniques to differentiate acute from chronic MI. Methods and Results—Seventy-three MI patients were studied in 2 groups. Group A consisted of 15 acute MI patients who were studied twice, on day 1 and 3 months after MI. In group B, 58 patients with acute or chronic MI underwent 1 CMR scan. T2-weighted and DE images of matched slices were acquired on a 1.5-T system. In group A, quantitative segmental and region of interest–based analyses were performed to observe signal changes between the acute and chronic phases. In group B, T2-weighted and DE images were examined visually by 2 blinded observers for the presence or absence of hyperintense areas in corresponding segments. For infarct localization, coronary angiography and/or ECG changes served as the reference standard. In group A, the contrast-to-noise ratio on T2-weighted images dropped in the infarcted segments from 2.7±1.1 on day 1 to 0.1±1.2 after 3 months (P <0.0001). There was no significant change in contrast-to-noise ratio in DE images (1.9±1.5 versus 1.3±1.0; P =NS). The qualitative assessment of T2-weighted and DE images in group B yielded a specificity of 96% to differentiate acute from chronic lesions. Conclusions—An imaging approach combining DE and T2-weighted CMR accurately differentiates acute from chronic MI.

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: Putting guidelines into practice

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well‐being and prolong life. This may be due to unfamiliarity with the evidence‐base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta‐blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non‐specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.

p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2

Downstream mediators of p53 in apoptosis induction remain to be elucidated. We report that p53‐induced apoptosis occurred in the absence of cytochrome c release into the cytosol. Although Bax was upregulated, it remained largely in the cytosol and there was no detectable translocation to the mitochondria. Bid was not activated as no cleavage could be detected. Thus, the absence of cytochrome c release may be due to the lack of Bax translocation to mitochondria and/or Bid inactivation. Nevertheless, p53‐induced apoptosis is still caspase dependent because it could be abolished by z‐VAD‐fmk. To search for alternative downstream targets of p53, we detected production of reactive oxygen species (ROS) as well as mitochondrial membrane potential (Δψ). p53 induced ROS generation, which then caused a transient increase of Δψ followed by a decrease. Antioxidants could inhibit the alterations of Δψ, thereby preventing apoptosis. z‐VAD‐fmk was unable to abrogate Δψ elevation but inhibited Δψ decrease, indicating that Δψ elevation and its decrease are two independent events. Bcl‐2 may abolish elevation as well as decrease of Δψ without interfering with ROS levels. Thus, the ROS‐mediated disruption of Δψ constitutes a pivotal step in the apoptotic pathway of p53, and this pathway does not involve cytochrome c release.

Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients with Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)

Åke Hjalmarson, MD, PhD Sidney Goldstein, MD Björn Fagerberg, MD, PhD Hans Wedel, PhD Finn Waagstein, MD, PhD John Kjekshus, MD, PhD John Wikstrand, MD, PhD Dia El Allaf, MD Jirı́ Vı́tovec, MD, PhD Jan Aldershvile, MD, PhD Matti Halinen, MD, PhD Rainer Dietz, MD Karl-Ludwig Neuhaus, MD András Jánosi, MD, DSc Gudmundur Thorgeirsson, MD, PhD Peter H. J. M. Dunselman, MD, PhD Lars Gullestad, MD Jerzy Kuch, MD Johan Herlitz, MD, PhD Peter Rickenbacher, MD Stephen Ball, MD, PhD Stephen Gottlieb, MD Prakash Deedwania, MD for the MERIT-HF Study Group

The application of methods of non-linear dynamics for the improved and predictive recognition of patients threatened by sudden cardiac death

OBJECTIVES This study introduces new methods of non-linear dynamics (NLD) and compares these with traditional methods of heart rate variability (HRV) and high resolution ECG (HRECG) analysis in order to improve the reliability of high risk stratification. METHODS Simultaneous 30 min high resolution ECGs and long-term ECGs were recorded from 26 cardiac patients after myocardial infarction (MI). They were divided into two groups depending upon the electrical risk, a low risk group (group 2, n = 10) and a high risk group (group 3, n = 16). The control group consisted of 35 healthy persons (group 1). From these electrocardiograms we extracted standard measures in time and frequency domain as well as measures from the new non-linear methods of symbolic dynamics and renormalized entropy. RESULTS Applying discriminant function techniques on HRV analysis the parameters of non-linear dynamics led to an acceptable differentiation between healthy persons and high risk patients of 96%. The time domain and frequency domain parameters were successful in less than 90%. The combination of parameters from all domains and a stepwise discriminant function separated these groups completely (100%). Use of this discriminant function classified three patients with apparently low (no) risk into the same cluster as high risk patients. The combination of the HRECG and HRV analysis showed the same individual clustering but increased the positive value of separation. CONCLUSIONS The methods of NLD describe complex rhythm fluctuations and separate structures of non-linear behavior in the heart rate time series more successfully than classical methods of time and frequency domains. This leads to an improved discrimination between a normal (healthy persons) and an abnormal (high risk patients) type of heart beat generation. Some patients with an unknown risk exhibit similar patterns to high risk patients and this suggests a hidden high risk. The methods of symbolic dynamics and renormalized entropy were particularly useful measures for classifying the dynamics of HRV.