The value of a new cardiac magnetic resonance imaging protocol in Myocardial Infarction with Non-obstructive Coronary Arteries (MINOCA) - a case-control study using historical controls from a previous study with similar inclusion criteria.

BACKGROUND: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is common with a prevalence of 6% of all patients fulfilling the diagnosis of myocardial infarction. MINOCA should be considered a working diagnosis. Cardiac Magnetic Resonance (CMR) imaging has recently been suggested to be of great value to determine the cause behind MINOCA. The objectives of this paper are to describe the rationale behind the second Stockholm Myocardial Infarction with Normal Coronaries (SMINC-2) study and to discuss the protocol for investigation of MINOCA patients in the light of the recently published position paper from the European Society of Cardiology. METHODS: The SMINC-2 study is an open non-randomised study using historical controls for comparison. The primary aim is to prove that MINOCA patients investigated with the latest CMR imaging technique can achieve a diagnosis in 70% of all cases entirely by imaging. By including 150 patients we will have >80% chance to prove that the diagnostic accuracy can be improved by 20 absolute % with a p-value of less than 0.05 when compared with CMR imaging in the SMINC-1 study. Furthermore, in addition to invasive coronary angiography, coronary arteries are evaluated by computed tomography angiography to investigate coronary causes and questionnaires are used to describe Quality-of-Life (QoL). By January 1st 2017, 75 patients have been included. DISCUSSION: Whether CMR imaging can provide a diagnosis to an adequate proportion of MINOCA patients is unknown. Well-defined inclusion and exclusion criteria will be used to compare a MINOCA cohort from the population with an appropriate control group. Positive results are likely to influence future guidelines of the management of MINOCA. Furthermore, the study will give mechanistic insights into MINOCA in particular in patients with "true" myocardial infarction and describe QoL in this vulnerable group of patients. TRIAL REGISTRATION: Clinical Trials NCT02318498 .

Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil.

Block of the hERG potassium channel and prolongation of the QT interval are predictors of drug-induced torsade de pointes. However, drugs that block the hERG potassium channel may also block other channels that mitigate torsade risk. We hypothesized that the electrocardiogram can differentiate the effects of multichannel drug block by separate analysis of early repolarization (global J-Tpeak) and late repolarization (global Tpeak-Tend). In this prospective randomized controlled clinical trial, 22 subjects received a pure hERG potassium channel blocker (dofetilide) and three drugs that block hERG and either calcium or late sodium currents (quinidine, ranolazine, and verapamil). The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

Improving the assessment of heart toxicity for all new drugs through translational regulatory science.

Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

Enlarged right-sided dimensions and fibrosis of the right ventricular insertion point on cardiovascular magnetic resonance imaging is seen early in patients with pulmonary arterial hypertension associated with connective tissue disease.

OBJECTIVES: To describe the findings of cardiovascular magnetic resonance (CMR) imaging in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) and in consecutive patients with systemic sclerosis (SSc) without PAH. METHODS: The study comprised nine consecutive patients who were admitted for right heart catheterization (RHC) under a suspicion of CTD-PAH and 25 consecutive patients who were admitted for evaluation because of a clinical suspicion of SSc. In addition to the regular assessment, they also underwent examination by CMR. RESULTS: CMR measurements of right ventricular (RV) volumes and function showed severe pathology in patients with CTD-PAH. Patients with SSc without PAH had similar but much less severe findings. Right ventricular end-diastolic volume (RVEDV) and right ventricular ejection fraction (RVEF) were abnormal in all patients with CTD-PAH. In eight out of nine patients with CTD-PAH, fibrosis was seen in the RV insertion point, probably caused by increased tension, but only in one of the consecutive SSc patients. This patient was diagnosed with CTD-PAH 20 months later. CONCLUSIONS: In CTD-PAH, CMR shows severe changes in RV volumes and function, but also fibrosis in the RV insertion point. Similar abnormalities, although much less severe, may be seen at diagnosis of SSc. Further evaluation is warranted to determine whether these findings are of value in screening for early signs of PAH in SSc.

A method for assembling a collaborative research team from multiple disciplines and academic centers to study the relationships between ECG estimation and MRI measurement of myocardial infarct size.

A method has been developed for establishing a "University Without Walls" for the purpose of studying the relationship between electrocardiographic estimation and magnetic resonance imaging measurements of myocardial infarct size. The research team includes faculty and students from 4 medical centers, with expertise extending from clinical to technical. Weekly interactive videoconferences provide the key research communication method. Study patients are recruited from 2 of the sites, and the correlations between their electrocardiographic and magnetic resonance imaging data are considered by the research team in conference. Outcomes of this program are both scientific publications in international peer-review journals and formal postdoctoral degree attainment by the research trainees.