Syncope and Total Atrioventricular Block Associated With Alcohol Consumption in a Healthy Young Man.

Association between alcohol intake and atrioventricular block is rare. This case describes a previously healthy 27-year-old man experiencing syncopes preceded by moderate alcohol intake. An implantable loop recorder demonstrated episodes of total atrioventricular block coinciding with an additional syncope after alcohol intake, resulting in pacemaker implantation. (Level of Difficulty: Intermediate.).

Automated detection of focal seizures using subcutaneously implanted electrocardiographic device: A proof-of-concept study.

Phase 2 studies showed that focal seizures could be detected by algorithms using heart rate variability (HRV) in patients with marked autonomic ictal changes. However, wearable surface electrocardiographic (ECG) devices use electrode patches that need to be changed often and may cause skin irritation. We report the first study of automated seizure detection using a subcutaneously implantable cardiac monitor (ICM; Confirm Rx, Abbott). For this proof-of-concept (phase 1) study, we recruited six patients admitted to long-term video-electroencephalographic monitoring. Fifteen-minute epochs of ECG signals were saved for each seizure and for control (nonseizure) epochs in the epilepsy monitoring unit (EMU) and in the patients' home environment (1-8 months). We analyzed the ICM signals offline, using a previously developed HRV algorithm. Thirteen seizures were recorded in the EMU, and 41 seizures were recorded in the home-monitoring period. The algorithm accurately identified 50 of 54 focal seizures (sensitivity = 92.6%, 95% confidence interval [CI] = 85.6%-99.6%). Twelve of the 13 seizures in the EMU were detected (sensitivity = 92.3%, 95% CI = 77.2%-100%), and 38 of the 41 seizures in the out-of-hospital setting were detected (sensitivity = 92.7%, 95% CI = 84.7%-100%). Four false detections were found in the 141 control (nonseizure) epochs (false alarm rate = 2.7/24 h). Our results suggest that automated seizure detection using a long-term, subcutaneous ICM device is feasible and accurate in patients with focal seizures and autonomic ictal changes.

Growth-restricted human fetuses have preserved respiratory sinus arrhythmia but reduced heart rate variability estimates of vagal activity during quiescence.

The aim was to assess the association between fetal growth restriction (FGR) and fetal heart rate variability (FHRV) in relation to fetal movements. A prospective observational cohort study was performed. Non-invasive fetal electrocardiography (NI-FECG) allowed beat-to-beat assessments with <5% corrections of RR intervals. FHRV analyses included: Root mean square of successive RR interval differences (RMSSD), high frequency power (HF power), and low frequency power (LF power). Fetal movements were categorized by continuous ultrasound scanning. We enrolled 36 singleton pregnant women expecting a small fetus (< the 2.3 percentile of mean weight for gestational age) diagnosed by ultrasound, of whom 25 presented with a birthweight < the 2.3 percentile. Among these, 11 were excluded due to low quality NI-FECG recordings, leaving 14 women with 28 recordings eligible for inclusion in the analyses. The control group consisted of 22 healthy fetuses with birthweights between the 10th and the 90th percentile (average for gestational age [AGA]). In FGR fetuses the HRV response to respiratory activity was comparable to that of AGA fetuses. RMSSD (Ratio 1.54 [95% CI: 1.33; 1.79]) and HF power (Ratio 2.88 [95% CI: 2.12; 3.91]) increased, whereas LF/HF power (Ratio: 0.44 [95% CI: 0.31;0.63]) decreased. However, during fetal quiescence, FGR fetuses differed significantly from AGA fetuses. Compared to AGA fetuses, FGR fetuses displayed lower RMSSD (Ratio 0.77 (95% CI: 0.58; 1.02)) and HF power (Ratio 0.56 (95% CI:0.32; 0.98)). This reduction was associated with the severity of the FGR. In conclusion, FGR fetuses displayed a respiratory sinus arrhythmia (RSA) comparable to AGA fetuses; however, more important, parameters representing cardiac vagal activity were impaired in FGR fetuses during quiescence. RSA may constitute an intrinsic function of the cardiovascular system, which is unaffected by fetal compromise. However, the basic cardiac outflow assessed during fetal quiescence indicates a suppressed cardiac vagal activity in the FGR fetuses.

Pacemaker Implantation in Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)-A Long-Term Follow-Up Study.

It is well documented that deteriorating heart function due to deposition of ceroid lipopigment is a significant co-morbidity in Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease) although the exact disease mechanisms remain unknown in any NCL form. An increasing frequency of cardiac conduction disorders including severe bradycardia and sinus arrest is seen in the late teens, as is a left ventricular hypertrophy in the early 20s. Only a few case reports of pacemaker implantation have been published, and so far, no long-term follow-up study exists. As new treatment options emerge, more patients will live longer and the need for pacemaker will likely increase, why knowledge of long-term outcome is needed. In the present study, we present the course of six patients from the original Danish CLN3-heart population study (n = 29) published in 2011 in whom pacemaker implantation was indicated from a cardiac point of view. In two cases, the families deselected pacemaker implantation. In four males, aged 19-29 years, all having a good general condition, a dual-chamber pacemaker (St. Jude Medical™ Accent/Assurity MRI™) was implanted in general anesthesia without any complications. At follow-up 9 years later, three were still alive. According to the parents' opinion they still have a good quality of life, now 26, 30, and 36 years old. Pacemaker treatment is safe and may have great impact on quality of life. However, the medical indication for pacemaker treatment is relative and it is important that various aspects, including the patient's general condition and family preferences, are thoroughly discussed before making the final decision.

Towards better reliability in fetal heart rate variability using time domain and spectral domain analyses. A new method for assessing fetal neurological state?

OBJECTIVES: Fetal heart rate variability (FHRV) has shown potential in fetal surveillance. Therefore, we aimed to evaluate the reliability of time domain and spectral domain parameters based on non-invasive fetal electrocardiography (NI-FECG). METHOD: NI-FECG, with a sampling frequency of 1 kHz, was obtained in 75 healthy, singleton pregnant women between gestational age (GA) 20+0 to 41+0. The recording was divided into a) heart rate pattern (HRP) and b) periods fulfilling certain criteria of stationarity of RR-intervals, termed stationary heart rate pattern (SHRP). Within each recording, the first and the last time series from each HRP with less than 5% artifact correction were analyzed and compared. Standard deviation of normal-to-normal RR-intervals (SDNN), root mean square of successive differences (RMSSD), high frequency power (HF-power), low frequency power (LF-power), and LF-power/HF-power were performed. A multivariate mixed model was used and acceptable reliability was defined as intraclass correlation coefficient (ICC) ≥ 0.80 and a coefficient of variation (CV) ≤ 15%. Based on these results, the CV and ICC were computed if the average of two to six time series was used. RESULTS: For GA 28+0 to 34+6, SDNN and RMSSD exhibited acceptable reliability (CV < 15%; ICC > 90%), whereas GA 35+0 to 41+0and 20+0 to 27+6 showed higher CVs. Spectral domain parameters also showed high CVs However, by using the mean value of two to six time series, acceptable reliability in SDNN, RMSSD and HF-power from GA 28+0 was achieved. Stationarity of RR-intervals showed high influence on reliability and SHRP was superior to HRP, whereas the length of the time series showed minor influence. CONCLUSION: Acceptable reliability seems achievable in SDNN, RMSSD and HF-power from gestational week 28. However, stationarity of RR-intervals should be considered when selecting time series for analyses.

Fetal respiratory movements improve reliability of heart rate variability and suggest a coupling between fetal respiratory arrhythmia and vagal activity.

Fetal heart rate variability (FHRV) reflects autonomic cardiac regulation. The autonomic nervous system constantly adjusts the heart rate to maintain homeostasis. By providing insight into the fetal autonomic state, FHRV has the potential to become an investigational and clinical instrument. However, the method needs standardization and the influence of fetal movements, including fetal respiratory movements, is not well explored. Therefore, in a highly standardized setting, the aim was to evaluate the association between fetal movements and fetal heart rate variability (FHRV) including their impact on reliability. Fetal heart rate was obtained by noninvasive fetal electrocardiography (NI-FECG) and fetal movements by simultaneous ultrasound scanning in 30 healthy singleton pregnant women on two occasions with a maximum interval of 7 days. The standard deviation of normal-to-normal RR-intervals (SDNN), root mean square of successive RR-interval differences (RMDDS), high-frequency power (HF-power), low-frequency power (LF-power), and LF/HF were measured. A multivariate mixed model was used and reliability was defined as acceptable by a coefficient of variance (CV) ≤15% and an intraclass correlation coefficient (ICC) ≥0.80. During time periods with fetal respiratory movements, the highest reliability was achieved. Intra- and inter-observer reliability measurements were very high (CV: 0-9%; ICC â‰§ 0.86). Within the same recording, SDNN and RMSSD achieved acceptable reliability (CV: 14-15%; ICC â‰§ 0.80). However, day-to-day reliability displayed high CV's. In time periods with fetal respiratory movements, as compared to periods with quiescence RMSSD and HF-power were higher (Ratio: 1.33-2.03) and LF/HF power lower (Ratio: 0.54). In periods with fetal body movements SDNN, RMSSD and HF-power were higher (Ratio: 1.27-1.65). In conclusion, time periods with fetal respiratory movements were associated with high reliability of FHRV analyses and the highest values of parameters supposed to represent vagal activity.

Burden of arrhythmia and silent ischemia in heart transplant patients with cardiac allograft vasculopathy.

BACKGROUND: The incidence of sudden cardiac death (SCD) following heart transplantation (HTx) accounts for approximately 10% of post-HTx deaths. Ischemia, brady- and tachy-arrhythmias caused by rejection and cardiac allograft vasculopathy (CAV) seem related to SCD. Hence, we aimed to investigate the relation between CAV, arrhythmias and silent ischemia in long-term HTx patients. Methods. 49 HTx patients were included. Patients were CAV classified in accordance with guidelines from the International Society of Heart and Lung Transplantation. Patients were divided into predefined CAV groups (CAV 0, CAV 1, CAV 2 + 3). Incidences of arrhythmia and silent ischemia were detected by 48-h electrocardiogram monitoring and analyzed blinded to CAV-status. Results. Median time since transplantation was 9 years [IQR 4-14]. We observed a higher incidence of non-sustained ventricular tachycardia (NSVT) in CAV 2 + 3 patients than CAV 0 and 1 patients (p = .01). Likewise, isolated premature ventricular complexes (PVC) (p = .01) and PQ-interval prolongation (p = .01) were more frequent in CAV 2 + 3 patients than CAV 0 and 1 patients. Silent ischemia was only observed among CAV 3 patients (p = .04). We saw no significant difference in the incidence of supraventricular tachycardia among CAV groups (p = .21). Likewise, no difference in the right bundle branch block was observed (p = .68). Conclusion. NSVT was associated with CAV status in long-term HTx patients. Patients with moderate to severe CAV showed higher incidences of PVCs and PQ-interval prolongation than patients with mild or no CAV. Silent ischemia was only seen in patients with severe CAV.

A systematic approach to weaning from extracorporeal membrane oxygenation in patients with refractory cardiac failure.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is commonly used to provide haemodynamic support for patients with severe cardiac failure. However, timing ECMO weaning remains challenging. We aimed to examine if an integrative weaning approach based on predefined haemodynamic, respiratory and echocardiographic criteria is associated with successful weaning. METHODS: All patients weaned from ECMO between April 2017 and April 2019 at Aarhus University Hospital, Denmark, were consecutively enrolled. Predefined haemodynamic, respiratory and echocardiographic criteria were assessed before and during ECMO flow reduction. A weaning attempt was commenced in haemodynamic stable patients and patients remaining stable at minimal flow were weaned from ECMO. Comparisons were made between patients who met the criteria for weaning at first attempt and patients who did not meet these criteria. Patients completing a full weaning attempt with no further need for mechanical support within 24 h were defined as successfully weaned. RESULTS: A total of 38 patients were included in the study, of whom 26 (68%) patients met the criteria for weaning. Among these patients, 25 (96%) could be successfully weaned. Successfully weaned patients were younger and had less need for inotropic support and ECMO duration was shorter. Fulfilling the weaning criteria was associated with successful weaning and both favourable 30-d survival and survival to discharge. CONCLUSION: An integrative weaning approach based on haemodynamic, respiratory and echocardiographic criteria may strengthen the clinical decision process in predicting successful weaning in patients receiving ECMO for refractory cardiac failure.

Fetal Heart Rate Variability Is Affected by Fetal Movements: A Systematic Review.

Introduction: Fetal heart rate variability (FHRV) evaluates the fetal neurological state, which is poorly assessed by conventional prenatal surveillance including cardiotocography (CTG). Accurate FHRV on a beat-to-beat basis, assessed by time domain and spectral domain analyses, has shown promising results in the scope of fetal surveillance. However, accepted standards for these techniques are lacking, and the influence of fetal breathing movements and gross movements may be especially challenging. Thus, current standards for equivalent assessments in adults prescribe rest and controlled respiration. The aim of this review is to clarify the importance of fetal movements on FHRV. Methods: A systematic review in accordance with the PRISMA guidelines based on publications in the EMBASE, the MEDLINE, and the Cochrane Library databases was performed. Studies describing the impact of fetal movements on time domain, spectral domain and entropy analyses in healthy human fetuses were reviewed. Only studies based on fetal electrocardiography or fetal magnetocardiography were included. PROSPERO registration number: CRD42018068806. Results: In total, 14 observational studies were included. Fetal movement detection, signal processing, length, and selection of appropriate time series varied across studies. Despite these divergences, all studies showed an increase in overall FHRV in the moving fetus compared to the resting fetus. Especially short-term, vagal mediated indexes showed an increase during fetal breathing movements including an increase in Root Mean Square of the Successive Differences (RMSSD) and High Frequency power (HF) and a decrease in Low Frequency power/High Frequency power (LF/HF). These findings were present even in analyses restricted to one specific fetal behavioral state defined by Nijhuis. On the other hand, fetal body movements seemed to increase parameters supposed to represent the sympathetic response [LF and Standard Deviation of RR-intervals from normal sinus beats (SDNN)] proportionally more than parameters representing the parasympathetic response (RMSSD, HF). Results regarding entropy analyses were inconclusive. Conclusion: Time domain analyses as well as spectral domain analyses are affected by fetal movements. Fetal movements and especially breathing movements should be considered in these analyses of FHRV.

Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives.

BACKGROUND: It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center. METHODS: Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives (P<0.001). RESULTS: Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing. CONCLUSIONS: A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.

Heart rate increases in liraglutide treated chronic heart failure patients: association with clinical parameters and adverse events.

Background. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. Methods. This was a sub-study of the LIVE study. CHF patients (N = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms (N = 117) and readouts from cardiac implanted electronic devices (N = 20) were analysed for HR and arrhythmias. Results. In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all p<.005). Increases in HR correlated with liraglutide dose (p=.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes. Conclusions. During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure-Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

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.

Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy.

Background As pathogenic variants in the gene for RBM20 appear with a frequency of 6% among Danish patients with dilated cardiomyopathy (DCM), it was the aim to investigate the associated disease expression in affected families. Methods and Results Clinical investigations were routinely performed in DCM index-patients and their relatives. In addition, ≥76 recognized and likely DCM-genes were investigated. DNA-sequence-variants within RBM20 were considered suitable for genetic testing when they fulfilled the criteria of (1) being pathogenic according to the American College of Medical Genetics and Genomics-classification, (2) appeared with an allele frequency of <1:10.000, and (3) segregated with DCM in ≥7 affected individuals. A total of 80 individuals from 15 families carried 5 different pathogenic RBM20-variants considered suitable for genetic testing. The penetrance was 66% (53/80) and age-dependent. Males were both significantly younger and had lower ejection fraction at diagnosis than females (age, 29±11 versus 48±12 years; P<0.01; ejection fraction, 29±13% versus 38±9%; P<0.01). Furthermore, 11 of 31 affected males needed a cardiac transplant while none of 22 affected females required this treatment ( P<0.001). Thirty percent of RBM20-carriers with DCM died suddenly or experienced severe ventricular arrhythmias although no adverse events were identified among healthy RBM20-carriers with a normal cardiac investigation. The event-free survival of male RBM20-carriers was significantly shorter compared with female carriers ( P<0.001). Conclusions The disease expression associated with pathogenic RBM20-variants was severe especially in males. The findings of the current study suggested that close clinical follow-up of RBM20-carriers is important which may ensure early detection of disease development and thereby improve management.

Heart rate variability is impaired in adults after closure of ventricular septal defect in childhood: A novel finding associated with right bundle branch block.

BACKGROUND: Ventricular septal defects (VSDs) generally have benign long-term prognoses, but recent studies have indicated increased pulmonary vascular resistance. A potential tool for monitoring pulmonary artery pressure is heart rate variability, and therefore, the aim of this study was to assess heart rate variability in adults with a surgically repaired or unrepaired VSD. METHODS: In a long-term, follow-up study, three groups were included; VSD-patients operated in early childhood, patients with an open VSD, and controls. For each patient, 24-hour Holter monitoring was performed and heart rate variability was assessed. RESULTS: In total, 30 participants with a surgically closed VSD, 30 participants with an unrepaired VSD, and 36 controls were included. In the closed VSD group, there was a higher proportion of participants, who had low sNN50 (p = 0.005) and low sNN6% (p = 0.017) than in the other two groups. Similar differences were found when sNN50 was divided into increases and decreases (p = 0.007 and p = 0.005, respectively) as well as sNN6% (p = 0.014 and p = 0.014, respectively). Lastly, there was a higher proportion of patients in the closed VSD group with low rMSSD than in the other two groups (p = 0.005). For the closed VSD group, the proportion of participants with low total sNN50 (p = 0.046) and low total sNN6% (p = 0.046) were higher among participants with a complete right bundle branch block (RBBB) than among participants with no or an incomplete RBBB. CONCLUSIONS: Adults who had surgical VSD closure in early childhood had impaired heart rate variability and, particularly, participants with complete RBBB had lower heart rate variability.

The clinical outcome of LMNA missense mutations can be associated with the amount of mutated protein in the nuclear envelope.

AIMS: Lamin A/C mutations are generally believed to be associated with a severe prognosis. The aim of this study was to investigate disease expression in three affected families carrying different LMNA missense mutations. Furthermore, the potential molecular disease mechanisms of the mutations were investigated in fibroblasts obtained from mutation carriers. METHODS AND RESULTS: A LMNA-p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. Disease expression was unusual with a late onset and a favourable prognosis. Two smaller families with severe disease expression were shown to carry a LMNA-p.Arg471Cys and LMNA-p.Arg471His mutation, respectively. LMNA gene and protein expression was investigated in eight different mutation carriers by quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry, and protein mass spectrometry. The results showed that all mutation carriers incorporated mutated lamin protein into the nuclear envelope. Interestingly, the ratio of mutated to wild-type protein was only 30:70 in LMNA-p.Arg216Cys carriers with a favourable prognosis while LMNA-p.Arg471Cys and LMNA-p.Arg471His carriers with a more severe outcome expressed significantly more of the mutated protein by a ratio of 50:50. CONCLUSION: The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.

[Neurogenic autonomic dysfunction in adults].

Neurogenic autonomic dysfunction (NAD) is underdiagnosed, and it is likely in patients, who have orthostatic hypotension and symptoms from multiple organ systems as well as abnormal results from a neurological examination. A clinical and neurophysiological examination of the autonomic nervous system combined with a standardised paraclinical evaluation should be performed. NAD may be present in neurodegenerative disorders, vitamin deficiency, toxicity, infection, and in paraneoplastic, metabolic, hereditary and immune-mediated conditions.

[Neurogenic autonomic dysfunction in primary amyliodosis].

Neurogenic autonomic dysfunction (NAD) and polyneuropathy occur in common conditions like diabetes and alcoholism. However, it can also be seen in rare diseases like in this case report of amyloid light-chain amyloidosis: primary amyloidosis. A 56-year-old man presented with polyneuropathy, a sympathetic dysfunction causing orthostatic intolerance, syncope, parasympathetic dysfunction and involvement of the enteric nervous system. The report illustrates, that routine screening can be insufficient in diagnosing amyloidosis. NAD and polyneuropathy without clear aetiology may require a multidisciplinary elucidation of more rare diseases.

Abnormal Coronary Flow Velocity Reserve and Decreased Myocardial Contractile Reserve Are Main Factors in Relation to Physical Exercise Capacity in Cardiac Amyloidosis.

BACKGROUND: The aim of the present study was to evaluate the clinical importance of echocardiographic coronary flow velocity reserve (CFVR), resting and exercise left ventricular global longitudinal strain (LVGLS), and myocardial work efficiency (MWE) in patients with cardiac amyloidosis (CA). METHODS: The study population comprised 69 subjects: group A, 27 patients with CA confirmed by endomyocardial biopsy (CA positive); group B, 42 healthy control subjects. The amyloid phenotype in group A was as follows: patients with wild-type transthyretin-related amyloidosis (n = 10), carriers of the Danish familial transthyretin amyloidosis mutation with cardiac involvement (n = 5), and patients with amyloid light chain amyloidosis with cardiac involvement (n = 12). All subjects underwent comprehensive echocardiographic evaluation during rest and during symptom-limited, semisupine exercise testing. Furthermore, CFVR was assessed using Doppler echocardiography. RESULTS: Patients with CA had significantly lower CFVR (1.7 ± 0.6 vs 3.9 ± 0.8, P < .0001), MWE (1.9 ± 1.0 vs 3.0 ± 0.7, P < .0001), and LVGLS magnitude (11% [10%-14%] vs 20% [18%-21%], P < .0001) than control subjects. Patients with CA showed severely reduced deformation and efficiency reserve compared with control subjects (ΔLVGLS 0.9 ± 2.8% vs 5.6 ± 2.3%, P < .0001; ΔMWE 2.5 ± 2.8 vs 8.8 ± 2.6, P < .0001). In patients with CA, a strong relation was seen between physical capacity by the metabolic equivalent of tasks test and CFVR (r = 0.55, P < .01), peak exercise LVGLS (r = 0.64, P < .0001), and peak exercise MWE (r = 0.60, P < .01). CONCLUSIONS: Patients with CA had a profound lack of CFVR and longitudinal myocardial deformation reserve compared with healthy control subjects. Both parameters were significantly associated with exercise capacity and may prove useful for evaluating cardiac performance in patients with CA.

Inotropic myocardial reserve deficiency is the predominant feature of exercise haemodynamics in cardiac amyloidosis.

AIMS: This study aimed to characterize invasive haemodynamics during exercise in subjects with cardiac amyloidosis (CA). METHODS AND RESULTS: The study population numbered 44 subjects. Group A (CA-positive, n = 24) comprised wild-type transthyretin patients (n = 10), familial transthyretin amyloidosis mutation carriers (ATTRm) with cardiac involvement (n = 5), and light-chain amyloidosis patients with cardiac involvement (n = 9). Group B (CA-negative, n = 20) comprised four healthy ATTRm subjects without cardiac involvement documented by 11 C-PIB positron emission tomography and 16 healthy controls. All subjects underwent a symptom-limited, semi-supine exercise test with expired gas analysis and simultaneous right heart catheterization. CA patients had lower peak oxygen consumption [15 ± 6 mL/min/kg bodyweight (bwt) vs. 33 ± 7 mL/min/kg bwt; P < 0.0001] than controls. Myocardial reserve during exercise was significantly reduced in CA patients as reflected in a small increase in stroke volume index (SVI) and cardiac index (CI) compared with controls [ΔSVI: 4 mL/m2 (range: -1 to 8) vs. 14 mL/m2 (range: 5-25); P < 0.0001; ΔCI: 2 ± 2 L/min vs. 7 ± 2 L/min; P < 0.0001]. During exercise, CA patients had significantly higher left and right ventricular filling pressures than controls. Furthermore, CA patients had severely impaired pulmonary arterial compliance (PAC) compared with controls [2.9 mL/mmHg (range: 2.1-4.5) vs. 7.5 mL/mmHg (range: 5.7-10.4); P < 0.0001]. CONCLUSIONS: Cardiac amyloid deposits are associated with severely reduced inotropic myocardial reserve and increased left and right ventricular filling pressures during exercise. Furthermore, CA subjects have severely reduced PAC, which may contribute to right heart failure and reduced exercise capacity.

Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy.

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.