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Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but—per definition—causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio-and vasoactive drugs used in the hospitalization phase to stabilize the patient’s hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g. catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans.

Late potentials are detected at various noise levels in clinical studies. The aim of this study was to assess the effect of residual noise level on the reproducibility of the signal-averaged electrocardiogram (ECG). Two consecutive raw 15-minute ECG from each of 188 patients with coronary artery disease were digitized and stored on optical discs. Each raw ECG was analyzed by two signal-averaging procedures to noise level 0.2 microV or 0.4 microV. Standard time-domain parameters were measured: QRS duration (SA-QRS), late potential (LP) duration, and root-mean-square voltage of the terminal 40 ms of the filtered QRS (RMS40). The SA-QRS was prolonged by 12 +/- 14 ms by the reduction in noise level from 0.4 microV to 0.2 microV, LP duration was prolonged by 10 +/- 10 ms, and RMS40 was reduced by 19 +/- 22 microV. The temporal variation of the measured SA-QRS from ECG1 to ECG2 was significantly lower at noise level 0.2 microV (9 +/- 13 ms) than at noise level 0.4 microV (13 +/- 14 ms) (P < .001). The LP duration was also more stable at noise level 0.2 microV than at noise level 0.4 microV (0.5 +/- 11 ms vs 2 +/- 13 ms, P < .05). The presence of any two of three abnormal parameters (SA-QRS > 120 ms, RMS40 < 25 microV, LP duration > 40 ms) was used as the criterion for the presence of LPs. At noise level 0.4 microV, the proportion of patients with diagnosed LPs in ECG1 was 25% and at noise level 0.2 microV it was 62%. At noise level 0.4 microV, 20% were reclassified from LP-negative in ECG1 to LP-positive in ECG2, and 7% were reclassified from LP-positive in ECG1 to LP-negative in ECG2. At noise level 0.2 microV, 20% were reclassified from LP-negative in ECG1 to LP-positive in ECG2, and 9% were reclassified from LP-positive in ECG1 to LP-negative in ECG2. It was concluded that (1) the diagnosis of LPs is significantly dependent on the extent of noise reduction by signal averaging: and (2) the numerical reproducibility of signal-averaged QRS duration and LP duration is lower at noise level 0.4 microV then at noise level 0.2 microV; and the diagnostic reproducibility of LPs is similar at both noise levels.

To investigate the impact of pre-operative autonomic balance and atrial ectopic activity on the risk of atrial fibrillation or flutter after aorto-coronary artery bypass surgery 24-hour Holter monitoring was analyzed in 102 patients before coronary artery bypass grafting. Index for vagal tone was calculated as % successive RR-interval differences > 6%. Twenty-nine (28%) of the 102 patients developed atrial fibrillation or flutter. Independent predictors (90% confidence interval) of postoperative atrial fibrillation or flutter were identified by logistic regression analysis: the independent predictors were older age, relative risk 1.07/year (1.02-1.12), vagal index < 10%, relative risk 4.50 (1.40-14.5), > or= 10 ectopic supraventricular beats/24 hour, relative risk 3.03 (1.05-8.72), and one or more event of non-sustained supraventricular tachycardia, relative risk 3.02 (1.11-8.22). Thus, age of the patient, attenuated preoperative cardiac vagal modulation, ectopic supraventricular beats, and paroxysmal non-sustained supraventricular tachycardia are independent risk factors for the development of atrial fibrillation or flutter after coronary artery bypass surgery.

Of patients undergoing coronary artery bypass grafting 30% develop atrial fibrillation (AF) or flutter. To determine if AF is initiated from the right or left atrium, atrial electrograms were continuously recorded in patients undergoing this procedure. In addition, to study whether the prematurity index of premature atrial contractions (PACs) eliciting AF differs from PACs not provoking AF, the distribution of prematurity indices was evaluated from R-R interval analysis. The right and left atrial recording electrodes were first activated by the ectopic beat provoking AF in six and eight patients, respectively. The prematurity index of the PAC eliciting AF was located in the middle (in half of the patients) or to the left of the median distribution of prematurity indices. The variability in activation of the atrial electrodes suggests that the PAC provoking AF can have its origin in the right, the septal, or the left region of the atrium. The initiation of AF depends on the prematurity index of the PAC.

To evaluate the impact of ectopic atrial activity and cardiac autonomic function for development of atrial fibrillation or flutter we studied 128 consecutive patients undergoing elective coronary artery bypass grafting. The patients were Holter monitored during a 96-h postoperative period. Autonomic balance was estimated by heart rate variability measurement. Thirty-eight (30%) patients developed sustained atrial fibrillation or flutter. Holter recordings were analyzed in a case-base design matching for age, beta-blocker treatment, and time elapsed after the operation. The number of supraventricular ectopic beats/h was increased (P < 0.01) in the case group during each of the last 7 h before onset of atrial fibrillation or flutter. Episodes of supraventricular tachycardia 62% vs. 26%; cases vs. controls (P = 0.007), episodes of non-sustained atrial fibrillation 29% vs. 0% (P = 0.0009), and episodes of non-sustained atrial flutter 15% vs. 0% (P = 0.05) were significant predictors of atrial fibrillation or flutter. Mean heart rate/h was increased in each of the 24 h preceding the arrhythmia. However, indexes of autonomic heart function did not differ significantly between groups. Patients developing atrial fibrillation or flutter after coronary artery bypass surgery present 'warning' atrial arrhythmias: numerous supraventricular ectopic beats, paroxysmal supraventricular tachycardia, and episodes of nonsustained atrial fibrillation and flutter.

Late potentials in the QRS complex can be detected with signal-averaged electrocardiography and are associated with delayed and disorganized ventricular activation. This article reviews the technique, describes the pathophysiological basis of late potentials, and assesses the prognostic value of late potentials for subsequent development of ventricular tachyarrhythmias and sudden cardiac death in postmyocardial infarction patients.

The appearance of microalbuminuria in diabetic patients predicts development of macroalbuminuria and coronary heart disease. Autonomic dysfunction in ischaemic heart disease is related to an increased incidence of arrhythmic deaths. To assess sympathovagal balance in relation to microalbuminuria we performed 24-h spectral analysis of RR interval oscillations in 37 insulin-dependent diabetic patients. Patients were divided according to urinary albumin excretion as normo-(< 20 micrograms/min) (n = 12), micro-(> 20 and < 200 micrograms/min) (n = 14) and macro-albuminuria (> 200 micrograms/min) (n = 11). None had symptoms or signs of ischaemic heart disease at clinical examination or during stress testing. Fourteen matched healthy subjects served as controls. Overall RR interval variability was calculated as the 24-h standard deviation. The square root of power of the low-frequency (0.04-0.15 Hz) and high-frequency (0.15-0.40 Hz) component were considered indices of the sympathovagal interaction and vagal function, respectively. Patients with micro and macroalbuminuria had, compared to control subjects, significantly reduced 24-h standard deviation, a much smaller day/night difference in mean RR level and a significantly reduced amplitude of the low frequency and high frequency oscillations, which were even more reduced in macroalbuminuria. The differences in vagal function were also present after correction for mean RR level, and differences in physical training level and smoking. Insulin-dependent diabetic patients who develop microalbuminuria have significantly impaired vagal function and abnormal sympathovagal interaction, which is further deranged in macroalbuminuria. This early autonomic dysfunction may later contribute to a increased risk for sudden cardiac death.

The activity of the cardiac autonomic nervous system can be estimated by measurement of beat to beat variations in heart rate-heart rate variability (HRV). In survivors after myocardial infarction, reduced 24-hour HRV, is an independent predictor of mortality/sudden cardiac death. The attenuated HRV is presumed to indicate reduced vagal function and concomitant high sympathetic activity. In experimental studies, this combination reduces the threshold for inducing malignant tachyarrhythmias, and is very probably a clinically important factor for the evolution of ventricular arrhythmias. Measurement of HRV in ordinary 24-hour ECG recordings can, together with other non-invasive measurements, stratify arrhythmic risk in survivors of myocardial infarction.

Atrial fibrillation and atrial flutter are common arrhythmias after coronary artery bypass grafting. Although the consequences of the arrhythmia are generally not life-threatening, it constitutes a major clinical problem often requiring conversion to sinus rhythm. Atrial fibrillation or flutter can result in hypotension, heart failure, pneumonia, and stroke. This article reviews the literature on epidemiology, electrophysiology, risk factors, and preventive trials. The major conclusions are: (1) In patients undergoing coronary artery bypass surgery, the incidence of postoperative atrial fibrillation or flutter is 20-30%, the peak incidence being on the second or third postoperative day. (2) The strongest independent preoperative predictor for atrial fibrillation or flutter is the patients' age. (3) Intra-atrial conduction delay recorded pre and peroperatively may predict development of atrial fibrillation. (4) Peroperative inducibility of atrial fibrillation by pacing the right atrium may identify patients at risk for postoperative atrial fibrillation. (5) Development of postoperative atrial fibrillation or flutter has not been associated with peroperative or postoperative events. (6) The specificity and sensitivity of age and other possible relevant factors for prediction of atrial fibrillation or flutter after coronary artery bypass grafting is low. (7) No effective prophylactic regimen has yet been established.