Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Heart rate increase and inappropriate sinus tachycardia after cryoballoon pulmonary vein isolation for atrial fibrillation.

BACKGROUND: Cryoballoon pulmonary vein isolation (PVI) is a common therapy for atrial fibrillation (AF). While moderately increased sinus rhythm heart rate (HR) after PVI has been observed, inappropriate sinus tachycardia (IST) is a rare phenomenon. We aimed to investigate the prevalence and natural history of an abnormal sinus HR response after cryoballoon PVI. METHODS: We included 169/646 (26.2%) patients with AF undergoing PVI with available Holter recordings before and 3, 6 and 12 months after the procedure. Patients with AF on Holter monitoring were excluded. Mean HR increase ≥ 20 bpm or an IST-like pattern (mean HR > 90 bpm or > 80 bpm when beta-blocking agents were used) following PVI was categorised as abnormal sinus HR response. RESULTS: Following PVI, mean HR ± standard deviation increased in the entire group from 63.5 ± 8.4 to 69.1 ± 9.9 bpm at 3 months (p < 0.001), and to 71.9 ± 9.4 bpm at 6 months (p < 0.001). At 12 months, mean HR was 71.2 ± 10.1 bpm (p < 0.001). Only 7/169 patients (4.1%) met criteria for abnormal sinus HR response: mean HR was 61.9 ± 10.6 bpm (pre-ablation), 84.6 ± 9.8 bpm (3 months), 80.1 ± 6.5 bpm (6 months) and 76.3 ± 10.1 bpm (12 months). Even at 12 months, mean HR was significantly different from that pre-ablation in this group (p = 0.033). However, in patients meeting IST-like pattern criteria, mean HR at 12 months was no longer significantly different from that pre-ablation. CONCLUSION: Few patients had an abnormal sinus HR response after PVI. Peak HR was observed 3 months after PVI, but HR was still significantly increased 12 months post-ablation compared with pre-ablation. An IST-like pattern was rarely observed. In these patients, HR decreased to pre-ablation values within a year.

Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin-2 (PKP2) identified with microarray analysis and/or multiplex ligation-dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.

Recurrent and founder mutations in the Netherlands : Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p.Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 in the Dutch population. METHODS: Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p.Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p.Arg79X mutation was a recurrent or a founder mutation. RESULTS: The p.Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first- or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women. CONCLUSION: We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010;18:583-91.).

Pulmonary vein isolation of symptomatic refractory paroxysmal and persistent atrial fibrillation: A single centre and single operator experience in the Netherlands.

Aim. To investigate long-term outcome and to determine predictors of successful pulmonary vein isolation (PVI) in patients with symptomatic paroxysmal or persistent atrial fibrillation (AF) who are refractory or intolerant to antiarrhythmic drugs.Background. The treatment of AF has traditionally been pharmacological aimed at rate or rhythm control. However, rhythm control remains difficult to establish. PVI is reported to be effective in selected patient groups.Methods. Ninety-nine consecutive patients with a mean age of 54+/-10 years who had paroxysmal or persistent AF were treated in the University Medical Center Groningen. All patients underwent PVI by the same electrophysiologist. Successful PVI was defined as absence of AF on Holter or electrocardiogram (ECG), and no symptoms of AF.Results. After six months of follow-up, 60 (61%) patients were free of AF episodes, both on 96-hour Holter monitoring and on ECGs, and had no symptoms related to AF. Thirty-nine of these 60 patients (65%) were no longer treated with any class I or III antiarrhythmic drugs. Independent determinants of successful PVI were paroxysmal AF (OR 18 [3.5-93], p=0.001), and left pulmonary vein ablation time >55 minutes (OR 15 [2.7-81], p=0.002). Left atrial (parasternal view 42+/-6 vs. 40+/-5 mm, p<0.05 and apical view 61+/-9 vs. 58+/-8 mm, p<0.05) and right atrial (59+/-7 vs. 56+/-5 mm, p<0.05) sizes decreased significantly in the successfully treated patients after six months of follow-up.Conclusion. Independent determinants of a successful outcome after PVI are paroxysmal AF and a longer left atrial ablation time. (Neth Heart J 2009;17:366-72.).

Phlebotomies as a treatment of serious heart failure due to haemochromatosis: a case report.

Haemochromatosis is a disturbance in the iron metabolism leading to excessive accumulation of iron in various organs such as the liver, pancreas, joints, skin, pituitary, testes and heart, with the last mentioned leading to heart failure. In this report we describe a patient with serious heart failure, attributed to homozygosity for C282Y in the haemochromatosis (HFE) gene, in whom repetitive phlebotomies led to normalisation of left ventricular function. (Neth Heart J 2009;17:438-41.).

[Cardiogenetics: the importance of identifying patients with hereditary heart disease]. / Cardiogenetica: het belang van identificatie van patiënten met een genetische hartaandoening.

During the past decade, developments in the field of DNA diagnostics have resulted in the confirmation of the genetic nature of several cardiac diseases. In a cardiogenetics outpatient clinic, a cardiologist and a clinical geneticist together evaluate persons with a (possible) hereditary cardiac disease. It is of utmost importance that patients with hereditary cardiac diseases be recognised and subsequently referred for genetic counselling as several preventive and therapeutic options are available.

[Life-threatening ventricular tachycardia during flecainide treatment for symptomatic atrial fibrillation in a patient with a structural cardiac disorder]. / Levensbedreigende ventrikeltachycardie bij flecainidebehandeling voor symptomatisch boezemfibrilleren bij structureel cardiaal lijden.

A 37-year-old man with symptomatic acute atrial fibrillation and a low-voltage electrocardiogram was treated with flecainide intravenously. Instead of conversion to sinus rhythm, he developed a wide-complex tachycardia suggestive of ventricular tachycardia. The patient recovered following electric cardioversion. First-choice therapy for symptomatic atrial fibrillation of recent onset (duration < 48 hours) is chemical conversion with a class IC antiarrhythmic drug (e.g. flecainide, propafenone). However, in patients with structural heart disorders, these drugs may induce ventricular tachycardia. A low-voltage electrocardiogram is suggestive of left ventricular damage. For these patients, electric cardioversion is a better alternative.

[Arrhythmogenic right-ventricular cardiomyopathy: different manifestations as precursors of sudden death which might be prevented]. / Aritmogene rechterventrikelcardiomyopathie: verschillende uitingen als voorbode van mogelijk te voorkomen plotse hartdood.

Two men aged 47 and 56 and one woman aged 21 presented at our cardiology department with presyncope, heart failure and exercise induced palpitations, respectively. Using the criteria of McKenna et al., a diagnosis of arrhythmogenic right-ventricular cardiomyopathy (ARVC) was made. Following implantation of a defibrillator, one of the men experienced seven appropriate interventions within six months and also developed psychological problems. The other man was problem-free and the woman recovered reasonably well, having only one appropriate intervention from the defibrillator one year after implantation. Indications of ARVC were also found in her mother but not in any other family members. Because ARVC manifests itself in various different ways it is difficult to diagnose. It is important to consider ARVC in patients with exercise-induced palpitations, presyncope, and unexplained cardiomyopathies or arrhythmias, especially if there is a family history of unexpected deaths. ARVC is a potentially life-threatening disease, that may require implantation of a cardioverter defibrillator. Furthermore, since genetics play an important role and ARVC can be asymptomatic, evaluation of close relatives for preclinical symptoms is important.

Radiofrequency ablation of atrial fibrillation.

UNLABELLED: Twenty-five patients (16 males, mean age 46 years) underwent radiofrequency ablation because of either paroxysmal (13 patients) or persistent atrial fibrillation (12 patients). Ablation aimed at earliest activation of spontaneous and catheter-induced repetitive ectopy in left and right atria and appendages, and pulmonary veins. Catheter-induced repetitive ectopy was defined as acute onset of a burst of rapid atrial premature beats on touching the wall, sustained irritability while at the spot and acute termination of rapid activity upon release of the catheter. Post-ablation patients received antiarrhythmic drugs to prevent tachycardias, thereby allowing reversal of atrial remodeling. RESULTS: Lone atrial fibrillation was present in 19 patients, 4 patients had hypertension and 2 patients coronary artery disease with preserved left ventricular function. The median duration of the history of atrial fibrillation was 4 years (range 1-14 years) and the median number of antiarrhythmic drug failures 5 (range 1-6). Ablation was successful, i.e. no recurrences of atrial fibrillation with or without antiarrhythmic drugs in eight patients (32%) during a median follow-up of 28 months (range 18-52). The median number of foci was 3 (range 2-6) and 2 (range 1-7) in the successfully and unsuccessfully treated patients, respectively. Minor complications occurred in three patients. CONCLUSIONS: Radiofrequency ablation of atrial fibrillation aiming at spontaneous and catheter-induced repetitive ectopy is a safe procedure. However, it is only successful in one third of the patients. Further investigations are warranted to identify the ideal patient, as well as to develop better ablation strategies.

Electrophysiological changes of angiotensin-converting enzyme inhibition after myocardial infarction.

To investigate whether prevention of remodeling would translate into a more stable electrophysiological profile, the investigators randomized 56 patients to treatment with angiotensin-converting enzyme (ACE) inhibition or placebo for 3 months after myocardial infarction. Programmed electrical stimulation revealed no significant differences in inducibility of monomorphic sustained ventricular tachycardia (VT), whereas ventricular fibrillation (VF) tended to be lower in the ACE-inhibitor group. Effective refractory periods were consistently longer, and dispersion of refractoriness was significantly shorter in the ACE-inhibitor group. The investigators conclude that in this small patient group ACE inhibition may mildly add to a more stable electrophysiological profile.

Beta adrenergic blockade in the treatment of sustained ventricular tachycardia or ventricular fibrillation.

The value of beta-blockers as antiarrhythmic drugs in patients with sustained VT or VF has received only little attention. This article summarizes the current state of knowledge regarding the identification of patients with sustained VT or VF with the highest benefit of beta-blockade. The antiarrhythmic mechanisms of beta-blockade and its efficacy as single or adjuvant therapy in patients with sustained VT or VF are reviewed. Current insights into the effects of beta-blockade in patients suffering from VT, in particular in the setting of heart failure, are discussed and future directions are considered.

Electrophysiological, rate dependent, and autonomic effects of the class III antiarrhythmic almokalant after myocardial infarction in the pig.

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 mumol.kg-1.min-1, continuous infusion: 0.0025 mumol.kg-1.min-1) from 292 +/- 25 to 308 +/- 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 +/- 19 to 261 +/- 16 ms (PCL 400 ms +1ES), and from 209 +/- 18 to 219 +/- 18 ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 +/- 27 to 186 +/- 29 ms (P < 0.05) and at PCL 300 ms: from 150 +/- 29 to 174 +/- 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 +/- 2.5 ms to 5.4 +/- 4.2 ms (P = NS). After programmed stimulation, it further decreased to 2.8 +/- 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 +/- 2.2 ms before stimulation and 3.3 +/- 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.

Rate-dependent effects of the class III antiarrhythmic drug almokalant on refractoriness in the pig.

The electrophysiologic effects of intravenously administered almokalant, a new class III antiarrhythmic drug, in 7 isoflurane-anesthetized pigs after low and high dose were investigated. Low-dose almokalant included bolus infusion of 0.05 mumol/kg/min for 5 min followed by a continuous infusion of 0.0025 mumol/kg/min for 40 min. Thereafter, a high dose of 0.2 mumol/kg/min for 5 min and 0.01 mumol/kg/min for 40 min was given. PR, QRS, AH, and HV intervals did not change during almokalant administration. The QT interval increased dose dependently from 337 +/- 17 to 442 +/- 20 ms at high dose (p < 0.05). Atrial refractory periods (AERP) were prolonged dose dependently at a 500-ms pacing cycle length from 178 +/- 15 at baseline to 227 +/- 27 and 253 +/- 23 ms during low- and high-dose almokalant infusion, respectively. For pacing cycle lengths of 400 and 300 ms, these values were 180 +/- 11, 207 +/- 25, and 259 +/- 34 and 157 +/- 12, 193 +/- 21, and 234 +/- 28 ms, respectively. At a pacing cycle length of 500 ms, mean ventricular effective refractory period (VERP) was 270 +/- 25 ms as compared with 306 +/- 24 and 337 +/- 17 during low and high dose, respectively. A similar pattern of VERP changes during both low- and high-dose infusion was noted at the shorter pacing cycle lengths, with an increase from 240 +/- 23 to 274 +/- 22 and 279 +/- 24 ms during a 400-ms cycle length and from 210 +/- 17 to 235 +/- 19 and 234 +/- 21 ms during a 300-ms cycle length. The ratio of the VERP and ventricular monophasic action potential duration (VAPD) did not change significantly. The Wenckebach cycle length increased by 36 +/- 36 and 83 +/- 37 ms with low- and high-dose almokalant infusion, respectively. The percent increase of AERP at pacing cycle lengths of 500, 400, and 300 ms during high-dose almokalant was 42, 44, and 49%, respectively; these increases for VERP were 25, 16, and 11%, respectively. In conclusion, prolongation of refractoriness by almokalant was more pronounced at the atrial than the ventricular level. Prolongation of refractoriness was maintained at short pacing cycle lengths especially in the atrium, indicating absence of reverse-use dependence of almokalant in the porcine heart. The marked atrial effects, paralleled by atrioventricular conduction slowing, and the absence of reverse use-dependence all contribute to the feasibility of use of almokalant, in particular in the treatment of supraventricular tachyarrhythmias.

Angiographic left ventricular wall motion score to predict arrhythmia recurrence in patients with sustained ventricular tachycardia or fibrillation.

METHODS: Sixty-nine patients with sustained ventricular tachyarrhythmias were followed up to evaluate the predictive value of functional capacity (i.e., New York Heart Association class and peak oxygen consumption) and resting left ventricular function (i.e. radionuclide left ventricular ejection fraction, angiographic left ventricular wall motion score and echocardiographic dimensions) with respect to arrhythmia recurrence. RESULTS: During a mean follow-up of 19 months 18 patients (26%) had an arrhythmia recurrence. Parameters of functional capacity and echocardiographic dimensions were not related to arrhythmia recurrence. Left ventricular ejection fraction and wall motion score were worse in patients with a recurrence compared with the arrhythmia-free patients: 30 +/- 16% versus 40 +/- 19% (mean +/- SD, P = 0.035) and 25 +/- 7 versus 20 +/- 7 (P = 0.01), respectively. Multivariately the most powerful parameter was left ventricular wall motion score (odds ratio 1.12, 95% Cl 1.02-1.23). CONCLUSIONS: Arrhythmia recurrence in ventricular tachyarrhythmia patients relates to resting left ventricular function and not to functional capacity. Since angiographic left ventricular wall motion score is prognostically more important than ejection fraction this parameter should be considered for risk stratification in these patients.

Favourable outcome in idiopathic ventricular fibrillation with treatment aimed at prevention of high sympathetic tone and suppression of inducible arrhythmias.

OBJECTIVE: In the absence of an obvious cause for cardiac arrest, patients with idiopathic ventricular fibrillation are difficult to manage. A subset of patients has inducible arrhythmias. In others sympathetic excitation plays a role in the onset of the cardiac arrest. This study evaluates a prospective stepped care approach in the management of idiopathic ventricular fibrillation, with therapy first directed at induced arrhythmias and secondly at adrenergic trigger events. SETTING: University Hospital. PATIENTS: 10 consecutive patients successfully resuscitated from idiopathic ventricular fibrillation. INTERVENTIONS: Programmed electrical stimulation to determine inducibility, followed by serial drug treatment. Assessment of pre-arrest physical activity and mental stress status by interview, followed by beta blockade. Cardioverter-defibrillator implantation in non-inducible patients not showing significant arrest related sympathetic excitation. MAIN OUTCOME MEASURE: Recurrent cardiac arrest or ventricular tachycardia. RESULTS: Five patients were managed with serial drug treatment and four with beta blockade. In one patient a defibrillator was implanted. During a median follow up of 2.8 years (range 6 to 112 months) no patient died or experienced defibrillator shocks. One patient had a recurrence of a well tolerated ventricular tachycardia on disopyramide. CONCLUSIONS: Idiopathic ventricular fibrillation may be related to enhanced sympathetic activation. Prognosis may be favourable irrespective of the method of treatment. Whether the present approach enhances prognosis of idiopathic ventricular fibrillation remains to be determined. However, it may help to avoid potentially hazardous antiarrhythmic drugs or obviate the need for implantation of cardioverter-defibrillators.