Early detection of obstructive coronary artery disease in the asymptomatic high-risk population:objectives and study design of the EARLY-SYNERGY trial

Background: Coronary artery disease (CAD) burden for society is expected to steeply increase over the next decade. Improved feasibility and efficiency of preventive strategies is necessary to flatten the curve. Acute myocardial infarction (AMI) is the main determinant of CAD-related mortality and morbidity, and predominantly occurs in individuals with more advanced stages of CAD causing subclinical myocardial ischemia (obstructive CAD; OCAD). Unfortunately, OCAD can remain subclinical until its destructive presentation with AMI or sudden death. Current primary preventive strategies are not designed to differentiate between non-OCAD and OCAD and the opportunity is missed to treat individuals with OCAD more aggressively. Methods: EARLY-SYNERGY is a multicenter, randomized-controlled clinical trial in individuals with coronary artery calcium (CAC) presence to study (1.) the yield of cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) for early OCAD diagnosis and (2) whether early OCAD diagnosis improves outcomes. Individuals with CAC score ≥300 objectified in 2 population-based trials (ROBINSCA; ImaLife) are recruited for study participation. Eligible candidates are randomized 1:1 to cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) or no additional functional imaging. In the CMR-MPI arm, feedback on imaging results is provided to primary care provider and participant in case of guideline-based actionable findings. Participants are followed-up for clinical events, healthcare utilization and quality of life. Conclusions: EARLY-SYNERGY is the first randomized-controlled clinical trial designed to test the hypothesis that subclinical OCAD is widely present in the general at-risk population and that early differentiation of OCAD from non-OCAD followed by guideline-recommended treatment improves outcomes

Accurate electrocardiographic assessment of the QT interval: teach the tangent

BACKGROUND: Long QT-Syndrome (LQTS) is a prevalent and possibly lethal disease. Unfortunately, it has recently been shown that the majority of physicians, including many cardiologists, do not recognize a long QT interval when they see one. Conversely, almost 40% of patients referred to specialized centers with a presumed diagnosis of LQTS have a normal QT. OBJECTIVE: The purpose of this study was to investigate whether we are able to teach inexperienced electrocardiogram (ECG) readers a method that will result in a higher accuracy of QT measurements. METHODS: Four previously published ECGs (two LQTS, two normal) were assessed by 151 medical students using the following QT measurement method: (1) the end of the T wave is the intersection of a tangent to the steepest slope of the last limb of the T wave and the baseline, in lead II or V5; (2) QTc = QT/ radicalRR; (3) QTc>450 ms is prolonged. Four months later, 71 students measured the ECGs again. Student results were compared with previously published results on the same ECGs of 25 LQTS experts, 106 arrhythmia experts, and 771 cardiologists and noncardiologists. RESULTS: Correct QT interval interpretations were achieved by 71% and 77% of students during the first and second test, respectively, as compared with 62% by the arrhythmia experts and <25% by the cardiologists and noncardiologists. CONCLUSIONS: In this proof-of-principle study, inexperienced ECG readers were able to rather accurately and reproducibly diagnose prolonged and normal QT intervals on four ECGs, as opposed to 877 cardiologists and noncardiologists. If the presented method is used by physicians, a better stratification of their patients' risk for sudden death due to LQTS (drug induced or congenital) should be possibl

Relationship Between Cardiac Dysfunction and Cerebral Perfusion in Patients with Aneurysmal Subarachnoid Hemorrhage

Cardiac dysfunction may occur after aneurysmal subarachnoid hemorrhage (aSAH). Although it is associated with poor outcome, the pathophysiological mechanism of this association remains unclear. We investigated the relationship between cardiac function and cerebral perfusion in patients with aSAH. We studied 72 aSAH patients admitted within 72 h after ictus with echocardiography and cerebral CT perfusion within 24 h after admission. Cardiac dysfunction was defined as myocardial wall motion abnormalities or positive troponin. In patients with and without cardiac dysfunction, we calculated the mean perfusion [cerebral blood flow (CBF) and time-to-peak (TTP)] in standard regions of interest and calculated differences with 95% confidence intervals (95% CI). In 35 patients with cardiac dysfunction minimal CBF was 15.83 mL/100 g/min compared to 18.59 in 37 without (difference of means -2.76; 95% CI -5.43 to -0.09). Maximal TTP was 26.94 s for patients with and 23.10 s for patients without cardiac dysfunction (difference of means 3.84; 95% CI 1.63-6.05). Mean global CBF was 21.71 mL/100 g/min for patients with cardiac dysfunction and 24.67 mL/100 g/min for patients without cardiac dysfunction (-2.96; 95% CI -6.19 to 0.27). Mean global TTP was 25.27 s for patients with cardiac dysfunction and 21.26 for patients without cardiac dysfunction (4.01; 95% CI 1.95-6.07). aSAH patients with cardiac dysfunction have decreased focal and global cerebral perfusion. Further studies should evaluate whether this relation is explained by a direct effect of cardiac dysfunction on cerebral circulation or by an external determinant, such as a hypercatecholaminergic or hypometabolic state, influencing both cardiac function and cerebral perfusio

Prevalence and Characterization of ECG Abnormalities After Intracerebral Hemorrhage

Background Although electrocardiographic (ECG) abnormalities are well known in ischemic stroke and subarachnoid hemorrhage, these changes have only rarely been investigated systematically in patients with intracerebral hemorrhage (ICH). The purpose of this study is to investigate the prevalence and type of ECG abnormalities in a consecutive series of ICH patients, and their possible association with pre-defined neurological and radiological parameters. Methods The study population consisted of all consecutive patients with non-traumatic, intraparenchymal ICH admitted to the Academic Medical Center (AMC) between January 1, 2007 and October 1, 2007. Baseline information was prospectively registered in the AMC Stroke Register. ECGs obtained within 2 days after the initial hemorrhage were analyzed by one blinded observer. Admission cranial CT scans were re-analyzed by two blinded observers. Results Thirty-one patients were included. Twenty-five patients (81%) had one or more ECG abnormalities. The most frequently observed ECG abnormality was QTc prolongation (36%), followed by ST-T morphologic changes (23%), sinus bradycardia (16%), and inverted T wave (16%). No patient was initially misdiagnosed for having myocardial ischemia. QTc prolongation was associated with ICH involvement of the insular cortex [OR 10.9 (95% CI 1.0-114.6)] and presence of intraventricular blood and hydrocephalus on admission CT scan [OR 10.8 (95% CI 1.6-70.9)]. Conclusions In ICH patients ECG abnormalities are common. QTc prolongation seems associated with insular cortex involvement, with the presence of intraventricular blood, and with hydrocephalus. A larger cohort of continuously monitored ICH patients is necessary to investigate whether these ECG abnormalities are associated with poor outcome or deat

Myocarditis in patients with subarachnoid hemorrhage: A histopathologic study

Cardiac abnormalities after subarachnoid hemorrhage (SAH) such as electrocardiographic changes, echocardiographic wall motion abnormalities, and elevated troponin levels are independently associated with a poor prognosis. They are caused by catecholaminergic stress coinciding with influx of inflammatory cells into the heart. These abnormalities could be a sign of a myocarditis, potentially giving insight in pathophysiology and treatment options. These inflammatory cells are insufficiently characterized, and it is unknown whether myocarditis is associated with SAH. Myocardium of 25 patients who died of SAH and 18 controls was stained with antibodies identifying macrophages (CD68), lymphocytes (CD45), and neutrophil granulocytes (myeloperoxidase). Myocytolysis was visualized using complement staining (C3d). CD31 was used to identify putative thrombi. We used Mann-Whitney U testing for analysis. In the myocardium of SAH patients, the amount of myeloperoxidase-positive (P < .005), CD45-positive (P < .0005), and CD68-positive (P < .0005) cells was significantly higher compared to controls. Thrombi in intramyocardial arteries were found in 22 SAH patients and 1 control. Myocytolysis was found in 6 SAH patients but not in controls. Myocarditis, consisting of an influx of neutrophil granulocytes, lymphocytes, and macrophages, coinciding with myocytolysis and thrombi in intramyocardial arteries, occurs in patients with SAH but not in controls. These findings might explain the cardiac abnormalities after SAH and may have implications for treatmen

Early detection of obstructive coronary artery disease in the asymptomatic high-risk population: objectives and study design of the EARLY-SYNERGY trial

BACKGROUND: Coronary artery disease (CAD) burden for society is expected to steeply increase over the next decade. Improved feasibility and efficiency of preventive strategies is necessary to flatten the curve. Acute myocardial infarction (AMI) is the main determinant of CAD-related mortality and morbidity, and predominantly occurs in individuals with more advanced stages of CAD causing subclinical myocardial ischemia (obstructive CAD; OCAD). Unfortunately, OCAD can remain subclinical until its destructive presentation with AMI or sudden death. Current primary preventive strategies are not designed to differentiate between non-OCAD and OCAD and the opportunity is missed to treat individuals with OCAD more aggressively. METHODS: EARLY-SYNERGY is a multicenter, randomized-controlled clinical trial in individuals with coronary artery calcium (CAC) presence to study (1.) the yield of cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) for early OCAD diagnosis and (2) whether early OCAD diagnosis improves outcomes. Individuals with CAC score ≥300 objectified in 2 population-based trials (ROBINSCA; ImaLife) are recruited for study participation. Eligible candidates are randomized 1:1 to cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) or no additional functional imaging. In the CMR-MPI arm, feedback on imaging results is provided to primary care provider and participant in case of guideline-based actionable findings. Participants are followed-up for clinical events, healthcare utilization and quality of life. CONCLUSIONS: EARLY-SYNERGY is the first randomized-controlled clinical trial designed to test the hypothesis that subclinical OCAD is widely present in the general at-risk population and that early differentiation of OCAD from non-OCAD followed by guideline-recommended treatment improves outcomes

HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy

Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause. This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause. Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis. The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia. Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardiu