TrimetaziDine as a Performance-enhancING drug in heart failure with preserved ejection fraction (DoPING-HFpEF): rationale and design of a placebo-controlled cross-over intervention study.

BACKGROUND: Currently, no specific treatment exists for heart failure with preserved ejection fraction (HFpEF). Left ventricular (LV) relaxation during diastole is a highly energy-demanding process, while energy homeostasis is known to be compromised in HFpEF. We hypothesise that trimetazidine - a fatty acid ß­oxidation inhibitor - improves LV diastolic function in HFpEF, by altering myocardial substrate use and improving the myocardial energy status. OBJECTIVES: To assess whether trimetazidine improves LV diastolic function by improving myocardial energy metabolism in HFpEF. METHODS: The DoPING-HFpEF trial is a randomised, double-blind, placebo-controlled cross-over intervention trial comparing the efficacy of trimetazidine and placebo in 25 patients with stable HFpEF. The main inclusion criteria are: New York Heart Association functional class II to IV, LV ejection fraction ≥50%, and evidence of LV diastolic dysfunction. Patients are treated with one 20-mg trimetazidine tablet or placebo thrice daily (twice daily in the case of moderate renal dysfunction) for two periods of 3 months separated by a 2-week washout period. The primary endpoint is the change in pulmonary capillary wedge pressure during different intensities of exercise measured by right heart catheterisation. Our key secondary endpoint is the myocardial phosphocreatine (PCr)/ATP ratio measured by phosphorus-31 magnetic resonance spectroscopy and its relation to the primary endpoint. Exploratory endpoints are 6­min walk distance, N-terminal pro-brain natriuretic peptide levels, and quality of life. CONCLUSION: The DoPING-HFpEF is a phase-II trial that evaluates the effect of trimetazidine, a metabolic modulator, on diastolic function and myocardial energy status in HFpEF. [EU Clinical Trial Register: 2018-002170-52; NTR registration: NL7830].

Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance.

Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory.

The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors.

BACKGROUND: The Late Effects of Childhood Cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) developed a guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors (CCS). In this paper, we present the methods, available evidence and final recommendations of our guideline. MATERIALS AND METHODS: A multidisciplinary working group specified clinical questions that should be answered to get to recommendations for the guideline. We carried out short or extensive evidence summaries and determined methodological quality of studies and levels of evidence in order to answer all clinical questions. When evidence was lacking for CCS, we carefully extrapolated evidence from other populations. Final recommendations were based on evidence and consensus. RESULTS: There was high-level evidence for the increased risk of cardiac dysfunction in CCS and its main risk factors. Evidence was lacking regarding the prognosis, diagnosis and treatment of cardiac dysfunction in CCS. We recommended echocardiographic screening for asymptomatic cardiac dysfunction in CCS treated with cardiotoxic treatments and counseling about potential advantages and disadvantages of our screening recommendations. CONCLUSION: The DCOG LATER guideline recommends risk-based screening for asymptomatic cardiac dysfunction in CCS, but it should be noted that recommendations are not completely supported by evidence in CCS.

[Second-degree atrioventricular block caused by Lyme disease]. / Tweedegraads atrioventriculair blok door lymeziekte.

BACKGROUND: Tick-borne diseases, including Lyme disease, are becoming increasingly common in Europe. Lyme disease has a wide variety of clinical manifestations, as a result of which physicians of diverse disciplines are coming into contact with such patients. CASE DESCRIPTION: A 58-year-old man was seen at the emergency room with a symptomatic Wenckebach-type second-degree atrioventricular (AV) block and periods of 2:1 AV block. Four weeks previously the patient had noticed a red skin lesion on his left lower leg. Under the working diagnosis of early disseminated Lyme disease with cardiac involvement, treatment with ceftriaxone was started. This diagnosis was supported by a positive Borrelia PCR and culture of a skin biopsy and positive Borreliaserology. The AV conduction disorders resolved completely after 2 weeks of treatment with antibiotics and it was not necessary to implant a pacemaker. CONCLUSION: A Borrelia infection is a reversible but rare cause of AV conduction disorders. In the event of sudden onset of symptoms or a severe or progressive AV conduction disorder, Lyme carditis should be considered, especially if the medical history or physical examination provides clues for Lyme disease.

Pregnancy and the risk of torsades de pointes in congenital long-QT syndrome.

Patients with congenital long-QT syndrome (LQTS) are at increased risk of ventricular arrhythmias during stressful situations. Large-scale studies have pointed out that affected individuals are particularly at risk in the period following pregnancy (post-partum). This is recognised especially for women with an LQTS type 2. Here, we describe two cases of young women with LQTS type 2, both admitted to our institution with symptomatic torsades de pointes a few weeks after delivery. Both patients carried a mutation in the KCNH2 gene. One patient was nullipara, while the other had had an uneventful previous pregnancy. In both cases treatment with a beta-blocker did not prevent life-threatening cardiac arrhythmias. The risk of arrhythmias is thought to gradually decrease to pre-pregnancy values in the nine months after delivery. Considering the difficulties related to continuous monitoring of a patient for such a long period and the desire of these patients to have more children in the foreseeable future, ICD implantation was performed. (Neth Heart J 2008;16:422-5.).

Recurrent acute pulmonary oedema after aortic and mitral valve surgery due to trachea malacia and obstructive sleep apnoea syndrome.

In this report we describe a patient with recurrent episodes of acute pulmonary oedema after aortic and mitral valve surgery. The first episode of pulmonary oedema was caused by mitral valve dysfunction. The second episode of pulmonary oedema was not clearly associated with a mitral valve problem, but reoperation was performed in the absence of another explanation. After the third episode of acute pulmonary oedema occurred, the diagnosis of obstructive sleep apnoea syndrome (OSAS) was considered and confirmed. After starting treatment with continuous positive airway pressure (CPAP) during his sleep the patient had no further episodes of acute respiratory failure. Our case demonstrates that acute pulmonary oedema after cardiothoracic surgery can be caused or at least be precipitated by OSAS and should be suspected in patients with unexplained episodes of (recurrent) pulmonary oedema. (Neth Heart J 2008;16:310-2.).

Combination and triple therapy in patients with stable angina pectoris not adequately controlled by optimal ß-blocker therapy.

In 60 to 80% of patients with stable angina pectoris at low risk for future coronary events, monotherapy with a ß-blocker is an effective treatment. When patients with stable angina pectoris and low risk for events do not respond adequately to optimal ß-blocker monotherapy, combination therapy or even triple therapy is may be recommended, but little is known of the actual benefit of such a strategy. We reviewed the evidence from the literature on the effectiveness of combination and triple therapy. Combination therapy with a calcium antagonist or nitrate was found to be more effective than ß-blocker monotherapy in the majority of studies, but only an estimated 30% of patients objectively benefit from these combination therapies. Direct comparison shows that combination therapy of a ß-blocker with a calcium antagonist is more effective than the combination of a ß-blocker with a nitrate. An inadequate response to ß-blocker monotherapy is more effectively improved by addition of a calcium antagonist than by alternative use of a calcium antagonist. The use of triple therapy is controversial and not recommended in patients with mild angina pectoris, while for patients with severe angina pectoris not responding to combination therapy of a ß-blocker with a nitrate, triple therapy may be of advantage, although the number of patients studied has been small.