Search

Purpose: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. Methods: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40–50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. Results: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8–31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. Conclusions: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Objective: To determine the potential impact of on-site CT-derived fractional flow reserve (CT-FFR) on the diagnostic efficiency and effectiveness of coronary CT angiography (CCTA) in patients with obstructive coronary artery disease (CAD) on CCTA. Methods: This observational cohort study included patients with suspected CAD who had been randomized to cardiac CT in the CRESCENT I and II trials. On-site CT-FFR was blindly performed in all patients with at least one ≥ 50% stenosis on CCTA and no exclusion criteria for CT-FFR. We retrospectively assessed the effect of adding CT-FFR to the CT protocol in patients with a stenosis ≥ 50% on CCTA in terms of diagnostic effectiveness, i.e., the number of additional tests required to determine the final diagnosis, reclassification of the initial management strategy, and invasive coronary angiography (ICA) efficiency, i.e., ICA rate without ≥ 50% CAD. Results: Fifty-three patients out of the 372 patients (14%) had at least one ≥ 50% stenosis on CCTA of whom 42/53 patients (79%) had no exclusion criteria for CT-FFR. CT-FFR showed a hemodynamically significant stenosis (≤ 0.80) in 27/53 patients (51%). The availability of CT-FFR would have reduced the number of patients requiring additional testing by 57%-points compared with CCTA alone (37/53 vs. 7/53, p < 0.001). The initial management strategy would have changed for 30 patients (57%, p < 0.001). Reserving ICA for patients with a CT-FFR ≤ 0.80 would have reduced the number of ICA following CCTA by 13%-points (p = 0.016). Conclusion: Implementation of on-site CT-FFR may change management and improve diagnostic efficiency and effectiveness in patients with obstructive CAD on CCTA. Key Points: • The availability of on-site CT-FFR in the diagnostic evaluation of patients with obstructive CAD on CCTA would have significantly reduced the number of patients requiring additional testing compared with CCTA alone. • The implementation of on-site CT-FFR would have changed the initial man

Trastuzumab prolongs progression-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, trastuzumab treatment is hampered by cardiotoxicity, defined as a left ventricular ejection fraction (LVEF) decline with a reported incidence ranging from 3 to 27% depending on variable factors. Early identification of patients at increased risk of trastuzumab-induced myocardial damage is of great importance to prevent deterioration to irreversible cardiotoxicity. Although current cardiac monitoring with multi gated acquisition (MUGA) scanning and/or conventional 2D-echocardiography (2DE) have a high availability, their reproducibility are modest, and more sensitive and reliable techniques are needed such as 3D-echocardiography (3DE) and speckle tracking echocardiography (STE). But which other diagnostic imaging modalities are available for patients before and during trastuzumab treatment? In addition, what is the optimal frequency and duration of cardiac monitoring? At last, which biomarker monitoring strategies are currently available for the identification of cardiotoxicity in patients treated with trastuzumab?

Objective: Troponin and high signal intensity on T2-weighted (HighT2) cardiovascular magnetic resonance imaging (CMRi) are both markers of myocardial injury in hypertrophic cardiomyopathy (HCM). The interplay between exercise and disease development remains uncertain in HCM. We sought to assess the occurrence of postexercise troponin rises and its determinants. Methods: Multicentre project on patients with HCM and mutation carriers without hypertrophy (controls). Participants performed a symptom limited bicycle test with hs-cTnT assessment pre-exercise and 6 hours postexercise. Pre-exercise CMRi was performed in patients with HCM to assess measures of hypertrophy and myocardial injury. Depending on baseline troponin (< or >13 ng/L), a rise was defined as a >50% or >20% increase, respectively. Results: Troponin rises occurred in 18% (23/127) of patients with HCM and 4% (2/53) in mutation carriers (p=0.01). Comparing patients with HCM with and without a postexercise troponin rise, maximum heart rates (157±19 vs 143±23, p=0.004) and maximal wall thickness (20 mm vs 17 mm, p=0.023) were higher in the former, as was the presence of late gadolinium enhancement (85% vs 57%, p=0.02). HighT2 was seen in 65% (13/20) and 19% (15/79), respectively (p<0.001). HighT2 was the only independent predictor of troponin rise (adjusted odds ratio 7.9; 95% CI 2.7 to 23.3; p<0.001). Conclusions: Postexercise troponin rises were seen in about 20% of patients with HCM, almost five times more frequent than in mutation carriers. HighT2 on CMRi may identify a group of particularly vulnerable patients, supporting the concept that HighT2 reflects an active disease state, prone to additional injury after a short episode of high oxygen demand.

Radboud University, 17 januari 2019, Promotores : Boer, M.J. de, Verheugt, F.W.A. Co-promotores : Brouwer, M.A., Kofflard, M.J.M., Contains fulltext : 199076.pdf (publisher's version ) (Open Access)

Contains fulltext : 196083.pdf (publisher's version ) (Open Access), INTRODUCTION: Optical coherence tomography (OCT) enables detailed imaging of the coronary wall, lumen and intracoronary implanted devices. Responding to the lack of specific appropriate use criteria (AUC) for this technique, we conducted a literature review and a procedure for appropriate use criteria. METHODS: Twenty-one of all 184 members of the Dutch Working Group on Interventional Cardiology agreed to evaluate 49 pre-specified cases. During a meeting, factual indications were established whereupon members individually rated indications on a 9-point scale, with the opportunity to substantiate their scoring. RESULTS: Twenty-six indications were rated 'Appropriate', eighteen indications 'May be appropriate', and five 'Rarely appropriate'. Use of OCT was unanimously considered 'Appropriate' in stent thrombosis, and 'Appropriate' for guidance in PCI, especially in distal left main coronary artery and proximal left anterior descending coronary artery, unexplained angiographic abnormalities, and use of bioresorbable vascular scaffold (BVS). OCT was considered 'Rarely Appropriate' on top of fractional flow reserve (FFR) for treatment indication, assessment of strut coverage, bypass anastomoses or assessment of proximal left main coronary artery. CONCLUSIONS: The use of OCT in stent thrombosis is unanimously considered 'Appropriate' by these experts. Varying degrees of consensus exists on the appropriate use of OCT in other settings.

Contains fulltext : 196255.pdf (publisher's version ) (Open Access), In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE >/=15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p=0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L-sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGEext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables.

Introduction: Optical coherence tomography (OCT) enables detailed imaging of the coronary wall, lumen and intracoronary implanted devices. Responding to the lack of specific appropriate use criteria (AUC) for this technique, we conducted a literature review and a procedure for appropriate use criteria. Methods: Twenty-one of all 184 members of the Dutch Working Group on Interventional Cardiology agreed to evaluate 49 pre-specified cases. During a meeting, factual indications were established whereupon members individually rated indications on a 9-point scale, with the opportunity to substantiate their scoring. Results: Twenty-six indications were rated ‘Appropriate’, eighteen indications ‘May be appropriate’, and five ‘Rarely appropriate’. Use of OCT was unanimously considered ‘Appropriate’ in stent thrombosis, and ‘Appropriate’ for guidance in PCI, especially in distal left main coronary artery and proximal left anterior descending coronary artery, unexplained angiographic abnormalities, and use of bioresorbable vascular scaffold (BVS). OCT was considered ‘Rarely Appropriate’ on top of fractional flow reserve (FFR) for treatment indication, assessment of strut coverage, bypass anastomoses or assessment of proximal left main coronary artery. Conclusions: The use of OCT in stent thrombosis is unanimously considered ‘Appropriate’ by these experts. Varying degrees of consensus exists on the appropriate use of OCT in other settings.

In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE ≥15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p = 0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff

Contains fulltext : 169685.pdf (publisher's version ) (Closed access), OBJECTIVE: Areas of high signal intensity (HighT2) on T2-weighted cardiovascular magnetic resonance (CMR) imaging have been demonstrated in hypertrophic cardiomyopathy (HCM). It has been hypothesised that HighT2 may indicate active tissue injury in HCM. In this context, we studied HighT2 in relation to cardiac troponin. METHODS: Outpatient HCM patients without a history of coronary artery disease underwent CMR imaging at 1.5 T using T2-weighted, cine and late gadolinium enhancement (LGE) imaging to assess HighT2, left ventricular (LV) function, LV mass and the presence and extent of LGE. Highly sensitive cardiac troponin T (hs-cTnT) was assessed as a marker of injury, with hs-cTnT >/=14 and >3 ng/L defined as an elevated and detectable troponin. RESULTS: HighT2 was present in 28% of patients (28/101). An elevated hs-cTnT was present in 54% of patients with HighT2 (15/28) compared with 14% of patients without HighT2 (10/73) (p<0.001). Hs-cTnT was detectable in 96% of patients with HighT2 (27/28) compared with 66% of patients without HighT2 (48/73) (p=0.002). In case of an undetectable hs-cTnT, HighT2 was only seen in 4% (1/26). In addition, the extent of HighT2 was related with increasing hs-cTnT concentrations (Spearman's rho: 0.42, p<0.001). CONCLUSIONS: In this CMR study of patients with HCM, we observed HighT2 in a quarter of patients, and demonstrated that HighT2 was associated with an elevated hs-cTnT. This observation, combined with the very high negative predictive value of an undetectable hs-cTnT for HighT2, provides supportive evidence for the hypothesis that HighT2 is indicative of recently sustained myocyte injury.

Aims In patients with atrial fibrillation, minor troponin I elevation is regularly detected; however, the prognostic significance of this finding is unknown. We therefore sought to examine the prognostic value of elevated troponin I in patients with atrial fibrillation. Methods and results A prospective study was conducted analysing all consecutive patients admitted with atrial fibrillation in a 2-year period. Patients with an ST-elevation myocardial infarction (MI) were excluded. Minor troponin elevation was defined as a troponin I level between 0.15 and 0.65 ng/mL, which is still below the 99th percentile of the upper reference limit. A positive troponin I was defined as >0.65 ng/mL. Study outcomes were all-cause mortality (death), death and myocardial infarction (death/MI), or all major adverse cardiac events (MACE: death, MI, or revascularization). A total of 407 patients were eligible for inclusion. The median duration of follow-up was 688 days. A minor elevation occurred in 81 (20) patients and 77 (19) had a positive troponin I. In a multivariate model, minor troponin I elevation and a positive troponin I were independently associated with death [hazard ratio (HR): 2.36, 95 confidence interval (CI): 1.174.73 for minor elevation and HR: 3.77, 95 CI: 1.4210.02 for positive troponin I]. Also, there was an independent correlation between the combined endpoints of death/MI and MACE and both a minor elevation and a positive troponin I. Conclusion Minor elevations in troponin I on hospital admission are associated with mortality and cardiac events in patients with atrial fibrillation and might be useful for risk stratification.

The development of left ventricular hypertrophy in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a rol

BACKGROUND: Ischemia occurs frequently in hypertrophic cardiomyopathy (HCM) without evidence of epicardial stenosis. This study evaluates the hypothesis that the occurrence of ischemia in HCM is related to remodeling of the coronary microcirculation. METHODS AND RESULTS: End-diastolic septal wall thickness was significantly increased in patients with HCM (25.8+/-2.9 mm) in comparison with cardiac transplant recipients (control subjects: 11.4+/-3.0 mm; P<0.05). Although the diameter of the left anterior descending coronary artery was similar in both groups (3.0+/-0.8 versus 3.0+/-0.5 mm, P=NS), the coronary resistance reserve (CRR=CRRbasal/CRRhyperemic), corrected for extravascular compression (end-diastolic left ventricular pressure), was reduced to 1.5+/-0.6 in HCM (P<.05; control, 2.6+/-0.8). Arteriolar lumen (AL) divided by wall area was lower in HCM (21+/-5% versus 30+/-4%; P<.05), and capillary density tended to decrease (from 1824+/-424 to 1445+/-513 per mm2, P=.11) in HCM. CRR was linearly related to normalized AL according to the formula CRR=O.1 AL-0.45 (r=.57; P<.05). Further analysis revealed that CRR, AL, and capillary density were all linearly related to the degree of hypertrophy. CONCLUSIONS: Decrements in CRR were related to changes of the coronary microcirculation. Both the decrease in CRR and these changes in the coronary microcirculation were related to the degree of hypertrophy. All these factors might contribute to the well-known occurrence of ischemia in this patient group.

The development of left ventricular hypertrophy (LVH) in subjects with hypertrophic cardiomyopathy (HCM) is variable, suggesting a role for modifying factors such as angiotensin II. We investigated whether the angiotensin II type 1 receptor (AT1-R) A/C1166 polymorphism, the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and/or plasma renin influence LVH in HCM. Left ventricular mass index (LVMI) and interventricular septal thickness were determined by 2-dimensional echocardiography in 104 genetically independent subjects with HCM. Extent of hypertrophy was quantified by a point score (Wigle score). Plasma prorenin, renin, and ACE were measured by immunoradiometric or fluorometric assays, and ACE and AT1-R genotyping were performed by polymerase chain reactions. The ACE D allele did not affect any of the measured parameters except plasma ACE (P<0.04). LVMI was higher (P<0.05) in patients carrying the AT1-R C allele (190+/-8.3 g/m2) than in AA homozygotes (168+/-7.2 g/m2), and similar patterns were observed for interventricular septal thickness (23.0+/-0.7 versus 21. 6+/-0.7 mm) and Wigle score (7.0+/-0.3 versus 6.3+/-0.3). Plasma renin was higher (P=0.05) in carriers of the C allele than in AA homozygotes. Multivariate regression analysis, however, revealed no independent role for renin in the prediction of LVMI. Plasma prorenin and ACE were not affected by the AT1-R A/C1166 polymorphism, nor did the ACE and AT1-R polymorphisms interact with regard to any of the measured parameters. We conclude that the AT1-R C1166 allele modulates the phenotypic expression of hypertrophy in HCM, independently of plasma renin and the ACE I/D polymorphism.

Hypertrophic cardiomyopathy is a primary cardiac disorder with a heterogeneous expression. Although relatively uncommon, the disease has been studied extensively as appears from the numerous studies that have explored specific facets of hypertrophic cardiomyopathy. This review will focus on the anatomic abnormalities, the prevalence, symptoms and clinical outcome, therapeutic interventions and genetic mutations responsible for the disease.

This study analyzes the alterations in size and geometry of the left ventricular (LV) outflow tract that occur in hypertrophic cardiomyopathy (HC) using transthoracic 3-dimensional echocardiography. Transthoracic 3- dimensional echocardiography was performed in 17 patients with HC (4 after myectomy) and in 10 normal subjects. Images were acquired with the rotational approach, with electrocardiographic and respiratory gating. From the 3- dimensional datasets, short-axis parallel slicing of the LV outflow tract at a 1 mm distance was performed at the onset of systole. For each slice, cross- sectional area and maximal and minimal diameter were calculated. Reconstruction of the LV outflow tract could be displayed in 3 dimensions in all patients, allowing orientation and clear definition of the irregular geometry. In patients with HC, the minimal LV outflow tract cross-sectional area was smaller than in normal subjects (2.3 ± 1.0 vs 5.0 ± 0.9cm2, p <0.0001).The ratio between maximal and minimal cross-sectional areas was higher in patients with HC than in normal subjects (2.6 ± 0.9 vs 1.4 ± 0.2, p <0.0001). The ratio between maximal and minimal diameter of the smallest cross section of the LV outflow tract was also significantly higher in patients with HC than in normal subjects (1.6 ± 0.3 vs 1.2 ± 0.1, p <0.001); a value of 1.36 separated normal subjects from HC patients without previous myectomy. In conclusion, precordial 3-dimensional echocardiography allows detailed qualitative and quantitative information on the LV outflow tract. Patients with HC are characterized by a highly eccentric and asymmetric shape of the LV outflow tract, and by a smaller minimal cross- sectional area than that seen in normal subjects.

Background The purpose of this pilot study was to identify biological risk factors for restenosis after percutaneous transluminal coronary angioplasty (PTCA) to predict the long-term outcome of PTCA before treatment. Methods and Results To investigate whether blood granulocytes and monocytes could determine luminal renarrowing after PTCA, several characteristics of these phagocytes were assessed before angioplasty in 32 patients who underwent PTCA of one coronary artery and who had repeat angiograms at 6-month follow-up. The plasma levels of interleukin (IL)-1ß, tumor necrosis factor-, IL-6, fibrinogen, C-reactive protein, and lipoprotein(a) before angioplasty were assessed as well. We found that the expression of the membrane antigens CD64, CD66, and CD67 by granulocytes was inversely associated with the luminal renarrowing normalized for vessel size (relative loss) at 6 months after PTCA, while the production of IL-1ß by stimulated monocytes was positively associated with the relative loss. Next, these univariate predictors were corrected for the established clinical risk factors of dilation of the left anterior descending coronary artery and current smoking, which were statistically significant classic predictors in our patient group. Only the expression of CD67 did not predict late lumen loss independent of these established clinical risk factors. Multiple linear regression analysis showed that luminal renarrowing could be predicted reliably (R2=.65; P<.0001) in this patient group on the basis of the vessel dilated and only two biological risk factors that reflect the activation status of blood phagocytes, ie, the expression of CD66 by granulocytes and the production of IL-1ß by stimulated monocytes. Conclusions The results of the present study indicate that activated blood granulocytes prevent luminal renarrowing after PTCA, while activated blood monocytes promote late lumen loss. To validate this new finding, further study in an independent patient group is re

Overall annual cardiac mortality in hypertrophic cardiomyopathy (HC) has been reported to be between 2 and 4%, although these numbers are primarily from retrospective studies of patients referred to large research institutions. A clinic population of 113 patients with HC was prospectively studied to assess cardiac mortality in the overall group and in selected subgroups commonly thought to be at high risk for sudden death. The mean age at diagnosis was 37 ± 16 years. During follow-up, there were 11 cardiac and 2 noncardiac deaths. The annual cardiac mortality was 1% (95% confidence interval 0.2–1.8%). Because of the small number of deaths, relative risk for cardiac death was not significantly different in the presence of young age (≤30 years), family history of HC and sudden death, history of syncope or previous cardiac arrest, or both, ventricular tachycardia on 24-hour Holter monitoring, or septal myotomy/myectomy for refractory symptoms and outflow tract obstruction. It is concluded that HC has a relatively benign prognosis (1% annual cardiac mortality) that is 2 to 4 times less than that previously reported.