Publications by authors named "Mischa T Rijnierse"

18 Publications

  • Page 1 of 1

Sex-specific differences in outcome and risk stratification of ventricular arrhythmias in implantable cardioverter defibrillator patients.

ESC Heart Fail 2021 10 29;8(5):3726-3736. Epub 2021 Jun 29.

Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands.

Aims: Risk stratification models of sudden cardiac death (SCD) are based on the assumption that risk factors of SCD affect risk to a similar extent in both sexes. The aim of the study is to evaluate differences in clinical outcomes between sexes and evaluate whether risk factors associated with appropriate device therapy (ADT) differ between men and women.

Methods And Results: We performed a cohort study of implantable cardioverter defibrillator (ICD) patients referred for primary or secondary prevention of SCD between 2009 and 2018. Multivariable Cox regression models for prediction of ADT were constructed for men and women separately. Of 2300 included patients, 571 (25%) were women. Median follow-up was 4.6 (inter-quartile range: 4.4-4.9) years. Time to ADT was shorter for men compared with women [hazard ratio (HR) 1.71, P < 0.001], as was time to mortality (HR 1.37, P = 0.003). In women, only secondary prevention ICD therapy (HR 1.82, P < 0.01) was associated with ADT, whereas higher age (HR 1.20, P < 0.001), absence of left bundle branch block (HR 0.72, P = 0.01), and secondary prevention therapy (HR 1.80, P < 0.001) were independently associated with ADT in men. None of the observed parameters showed a distinctive sex-specific pattern in ADT.

Conclusions: Male ICD patients were at higher risk of ADT and death compared with female ICD patients, irrespective of an ischaemic or non-ischaemic underlying cardiomyopathy. Our study highlights the importance to stratify outcomes of ICD trials by sex, as study results differ between men and women. However, none of the available clinical parameters showed a clear sex-specific relation to ventricular arrhythmias. As a consequence, sex-specific risk stratification models of SCD using commonly available clinical parameters could not be derived.
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http://dx.doi.org/10.1002/ehf2.13444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497372PMC
October 2021

Reversible Cause of Cardiac Arrest and Secondary Prevention Implantable Cardioverter Defibrillators in Patients With Coronary Artery Disease: Value of Complete Revascularization and LGE-CMR.

J Am Heart Assoc 2021 04 6;10(8):e019101. Epub 2021 Apr 6.

Department of Cardiology Amsterdam UMC, Vrije Universiteit AmsterdamAmsterdam Cardiovascular Sciences Amsterdam Netherlands.

Background In survivors of sudden cardiac arrest with obstructive coronary artery disease, it remains challenging to distinguish ischemia as a reversible cause from irreversible scar-related ventricular arrhythmias. We aimed to evaluate the value of implantable cardioverter-defibrillator (ICD) implantation in sudden cardiac arrest survivors with presumably reversible ischemia and complete revascularization. Methods and Results This multicenter retrospective cohort study included 276 patients (80% men, age 67±10 years) receiving ICD implantation for secondary prevention. Angiography was performed before ICD implantation. A subgroup of 166 (60%) patients underwent cardiac magnetic resonance imaging with late gadolinium enhancement before implantation. Patients were divided in 2 groups, (1) ICD-per-guideline, including 228 patients with incomplete revascularization or left ventricular ejection fraction ≤35%, and (2) ICD-off-label, including 48 patients with complete revascularization and left ventricular ejection fraction >35%. The primary outcome was time to appropriate device therapy (ADT). During 4.0 years (interquartile range, 3.5-4.6) of follow-up, ADT developed in 15% of the ICD-off-label group versus 43% of the ICD-per-guideline group. Time to ADT was comparable in the ICD-off-label and ICD-per-guideline groups (hazard ratio (HR), 0.46; =0.08). No difference in mortality was observed (HR, 0.95; =0.93). Independent predictors of ADT included age (HR, 1.03; =0.01), left ventricular end-diastolic volume HR, (1.05 per 10 mL increase; <0.01) and extent of transmural late gadolinium enhancement (HR, 1.12; =0.04). Conclusions This study demonstrates that sudden cardiac arrest survivors with coronary artery disease remain at high risk of recurrent ventricular arrhythmia, even after complete revascularization and with preserved left ventricular function. Late gadolinium enhancement-cardiac magnetic resonance imaging derived left ventricular volumes and extent of myocardial scar were independently associated with.
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http://dx.doi.org/10.1161/JAHA.120.019101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174172PMC
April 2021

Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients.

Pulm Circ 2020 Apr-Jun;10(2):2045894019873548. Epub 2020 Apr 20.

Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [C]-hydroxyephedrine positron emission tomography ([C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [C]HED retention index was lower compared to LV tracer uptake (p<0.01) and was related to systolic wall tension (R = 0.4731, p<0.01) and RV function (R = 0.44, p = 0.01). In RV failure, the tolerated dosage of bisoprolol did not result in an improvement of RV function nor in a reduction in RV sympathetic activity.
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http://dx.doi.org/10.1177/2045894019873548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187746PMC
April 2020

Value of CMR and PET in Predicting Ventricular Arrhythmias in Ischemic Cardiomyopathy Patients Eligible for ICD.

JACC Cardiovasc Imaging 2020 08 15;13(8):1755-1766. Epub 2020 Apr 15.

Department of Cardiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands. Electronic address:

Objectives: This study presents a head-to-head comparison of the value of cardiac magnetic resonance (CMR)-derived left-ventricular (LV) function and scar burden and positron emission tomography (PET)-derived perfusion and innervation in predicting ventricular arrhythmias (VAs).

Background: Improved risk stratification of VA is important to identify patients who should benefit of prophylactic implantable cardioverter-defibrillator (ICD) implantation. Perfusion abnormalities, sympathetic denervation, and scar burden have all been linked to VA, although comparative studies are lacking.

Methods: Seventy-four patients with ischemic cardiomyopathy and left-ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention ICD placement were enrolled prospectively. Late gadolinium-enhanced (LGE) CMR was performed to assess LV function and scar characteristics. [O]HO and [C]hydroxyephedrine positron emission tomography (PET) were performed to quantify resting and hyperemic myocardial blood flow (MBF), coronary flow reserve (CFR), and sympathetic innervation. During follow-up of 5.4 ± 1.9 years, the occurrence of sustained VA, appropriate ICD therapy, and mortality were evaluated.

Results: In total, 20 (26%) patients experienced VA. CMR and PET parameters showed considerable overlap between patients with VA and patients without VA, caused by substantial heterogeneity within groups. Univariable analyses showed that lower LVEF (hazard ratio [HR]: 0.92; p = 0.03), higher left-ventricular end-diastolic volume index (LVEDVi) (HR 1.02; p < 0.01), and larger scar border zone (HR 1.11; p = 0.03) were related to VA. Scar core size, resting MBF, hyperemic MBF, perfusion defect size, innervation defect size, and the innervation-perfusion mismatch were not found to be associated with VA.

Conclusions: In patients with ischemic cardiomyopathy, lower LVEF, higher LVEDVi, and larger scar border zone were related to VA. PET-derived perfusion and sympathetic innervation, as well as CMR-derived scar core size were not associated with VA. These results suggest that improved prediction of VA by advanced imaging remains challenging for the individual patient.
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http://dx.doi.org/10.1016/j.jcmg.2020.01.026DOI Listing
August 2020

The Benefit of Prophylactic Implantable Cardioverter Defibrillator Implantation in Asymptomatic Heart Failure Patients With a Reduced Ejection Fraction.

Am J Cardiol 2019 08 29;124(4):560-566. Epub 2019 May 29.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Cardiology, Amsterdam, the Netherlands. Electronic address:

Recommendations for prophylactic implantable cardioverter defibrillator (ICD) implantation in asymptomatic heart failure patients with a reduced left ventricular ejection fraction (LVEF) differ between guidelines. Evidence on the risk of appropriate device therapy (ADT) and death in New York Heart Association (NYHA) class I patients is scarce. Aim of this study is to evaluate ADT and mortality in NYHA-I primary prevention ICD patients with a LVEF ≤35%. A retrospective cohort was studied, including 572 patients with LVEF ≤35% who received a prophylactic ICD with or without resynchronization therapy (CRT-D). To evaluate the incidence of ADT and mortality, NYHA-I was compared with NYHA-II-III using Cox regression analysis. During a follow-up of 4.1 ± 2.4 years, 33% of the NYHA-I patients received ADT compared with 20% of the NYHA-II-III patients (hazard ratio 1.5, 95% confidence interval 1.04 to 2.31, p = 0.03). No differences in mortality were observed (hazard ratio 0.70, 95% confidence interval 0.49 to 1.07, p = 0.10). Additional analyses showed no difference in time to ADT excluding CRT patients (ICD-NYHA-I patients vs ICD-NYHA-II-III patients, p = 0.17) and comparing ischemic and nonischemic cardiomyopathy NYHA-I patients (p = 0.13). Multivariable Cox regression analyses showed that NYHA class was the strongest independent predictor of ADT. In conclusion, primary prevention NYHA-I ICD patients showed a higher incidence of ADT compared with NYHA-II-III ICD patients. These results strongly suggest that primary prevention NYHA-I patients with a LVEF ≤35% are likely to benefit from ICD therapy and should not be excluded from a potentially life-saving therapy.
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http://dx.doi.org/10.1016/j.amjcard.2019.05.026DOI Listing
August 2019

Myocardial Blood Flow and Coronary Flow Reserve During 3 Years Following Bioresorbable Vascular Scaffold Versus Metallic Drug-Eluting Stent Implantation: The VANISH Trial.

JACC Cardiovasc Interv 2019 05 24;12(10):967-979. Epub 2019 Apr 24.

Department of Cardiology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, the Netherlands. Electronic address:

Objectives: The randomized clinical VANISH (Impact of Vascular Reparative Therapy on Vasomotor Function and Myocardial Perfusion: A Randomized [O]HO PET/CT Study) trial was conducted to assess quantitative myocardial blood flow (MBF) during resting, hyperemia, and cold pressor testing (CPT) with positron emission tomographic perfusion imaging after the implantation of a bioresorbable everolimus-eluting scaffold compared with a drug-eluting stent.

Background: Long-term resorption of the bioresorbable everolimus-eluting scaffold reinstates normal vessel geometry, allowing natural regeneration of the newly formed endothelium with revival of vasomotor function.

Methods: Sixty patients (18 to 65 years of age) with single-vessel disease and type A or B1 lesions were randomized in a 1-to-1 fashion. Approximately 1 month, 1 year, and 3 years after device implantation, patients underwent [O]HO cardiac positron emission tomography. The primary endpoint was the interaction of device type and evolution over time of hyperemic MBF, coronary flow reserve, or CPT reserve. At 3-year follow-up, control invasive coronary angiography with optical coherence tomography was performed.

Results: Fifty-nine (98%), 56 (93%), and 51 (85%) patients successfully completed 1-month, 1-year, and 3-year follow-up positron emission tomography, respectively, and no culprit vessel events were registered during follow-up time. The primary study endpoint (i.e., interaction between device type and time) was nonsignificant for hyperemic MBF, CPT reserve, and coronary flow reserve (p > 0.05 for all). In all patients, hyperemic MBF decreased from 1 to 3 years (p = 0.02), while coronary flow reserve was lower at 3-year follow-up compared with 1-month and 1-year follow-up (p = 0.03 for both). After 3 years, percentage area stenosis measured with optical coherence tomography was higher within the bioresorbable everolimus-eluting scaffold compared with the drug-eluting stent (p = 0.03).

Conclusions: The hypothesized beneficial effects of scaffold resorption did not translate to improved MBF during maximal hyperemia or endothelium-dependent vasodilation by CPT.
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http://dx.doi.org/10.1016/j.jcin.2019.03.004DOI Listing
May 2019

Usefulness of Left Atrial Emptying Fraction to Predict Ventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillators.

Am J Cardiol 2017 Jul 27;120(2):243-250. Epub 2017 Apr 27.

Department of Cardiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. Electronic address:

Impaired left atrial emptying fraction (LAEF) is an important predictor of mortality in patients with heart failure. As it may reflect increased LV wall stress, it might predict ventricular arrhythmia (VA) specifically. This study evaluated the predictive value of LAEF assessed with cardiovascular magnetic resonance (CMR) imaging with respect to appropriate device therapy (ADT) for VA and compared its role with CMR assessed scar size and other risk factors. In total, 229 patients (68% male, 63 ± 10 years, 61% ischemic cardiomyopathy) with LV ejection fraction ≤35% who underwent CMR and implantable cardioverter defibrillator (ICD) implantation for primary prevention in 2005 to 2012 were included. CMR was used to quantify LV volumes and function. LV scar size was quantified when late gadolinium enhancement was available (n = 166). Maximum and minimum left atrial volumes and LAEF were calculated using the biplane area-length method. The occurrence of ADT and mortality was assessed during a median follow-up of 3.9 years. Sixty-two patients (27%) received ADT. Univariable Cox analysis showed that male gender, creatinine level, minimum left atrial volume, LAEF, and total scar size were significant predictors of ADT. In multivariable Cox analysis, LAEF (hazard ratio 0.75 per 10%, p <0.01), and scar size (hazard ratio 1.03 per g, p = 0.03) remained the only independent predictors of ADT. Patients with both LAEF > median and scar size < median were at low risk (13% ADT at 5 years), whereas those with LAEF < median and scar size > median experienced 40% ADT at 5 years (log-rank p = 0.01). In conclusion, LAEF independently predicts ADT in patients with primary prevention ICDs. Combined assessment of LAEF and scar size identifies a group with low risk of ADT. Therefore, LAEF assessment could assist in risk stratification for VA to select patients with the highest benefit from ICD implantation.
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http://dx.doi.org/10.1016/j.amjcard.2017.04.015DOI Listing
July 2017

Prevalence of ischaemia in patients with a chronic total occlusion and preserved left ventricular ejection fraction.

Eur Heart J Cardiovasc Imaging 2017 Sep;18(9):1025-1033

Department of Cardiology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Aims: Previous studies on invasive assessment of collateral function in patients with a chronic total occlusion (CTO) have displayed only a limited increase in collateral flow and high occurrence of coronary steal during pharmacological stress. This could question the necessity for ischaemia testing prior to revascularization of CTOs in the presence of myocardial viability. The purpose of the present study was to determine the prevalence of perfusion impairments in patients with a CTO as assessed by [15O]H2O positron emission tomography (PET).

Methods And Results: Seventy-six consecutive patients (60 men, 62 ± 10 years) with a documented CTO and preserved left ventricular ejection fraction (LVEF) were included. All patients underwent PET to assess (hyperaemic) myocardial blood flow (MBF) and coronary flow reserve (CFR). Collateral connection score was 0 in 7 (9%), 1 in 13 (17%), and 2 in 56 (74%) of the cases, with predominantly a high Rentrop grade (96% ≥2). MBF of the target area during hyperaemia was significantly lower when compared with the remote area (1.37 ± 0.37 vs. 2.63 ± 0.71 mL min-1 g-1, P < 0.001). Target to remote ratio during hyperaemia was on average 0.54 ± 0.13, and 73 (96%) patients demonstrated a significantly impaired target to remote ratio (≤0.75). Only 7 (9%) patients displayed a preserved CFR of ≥2.50, whereas coronary steal (CFR <1.0) was observed in 10 (13%) patients.

Conclusions: Even in the presence of angiographically well-developed collateral arteries, the vast majority of CTO patients with a preserved LVEF showed significantly impaired perfusion. These results suggest that collateral function during increased blood flow demand in viable myocardium is predominantly insufficient.
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http://dx.doi.org/10.1093/ehjci/jew188DOI Listing
September 2017

Noninvasive Quantification of Myocardial 11C-Meta-Hydroxyephedrine Kinetics.

J Nucl Med 2016 Sep 26;57(9):1376-81. Epub 2016 May 26.

Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.

Unlabelled: (11)C-meta-hydroxyephedrine ((11)C-HED) kinetics in the myocardium can be quantified using a single-tissue-compartment model together with a metabolite-corrected arterial blood sampler input function (BSIF). The need for arterial blood sampling, however, limits clinical applicability. The purpose of this study was to investigate the feasibility of replacing arterial sampling with imaging-derived input function (IDIF) and venous blood samples.

Methods: Twenty patients underwent 60-min dynamic (11)C-HED PET/CT scans with online arterial blood sampling. Thirteen of these patients also underwent venous blood sampling. Data were reconstructed using both 3-dimensional row-action maximum-likelihood algorithm (3DR) and a time-of-flight (TF) list-mode reconstruction algorithm. For each reconstruction, IDIF results were compared with BSIF results. In addition, IDIF results obtained with venous blood samples and with a transformed venous-to-arterial metabolite correction were compared with results obtained with arterial metabolite corrections.

Results: Correlations between IDIF- and BSIF-derived K1 and VT were high (r(2) > =0.89 for 3DR and TF). Slopes of the linear fits were significantly different from 1 for K1, for both 3DR (slope = 0.94) and TF (slope = 1.06). For VT, the slope of the linear fit was different from 1 for TF (slope = 0.93) but not for 3DR (slope = 0.98). Use of venous blood data introduced a large bias in VT (r(2) = 0.96, slope = 0.84) and a small bias in K1 (r(2) = 0.99, slope = 0.98). Use of a second-order polynomial venous-to-arterial transformation was robust and greatly reduced bias in VT (r(2) = 0.97, slope = 0.99) with no effect on K1 CONCLUSION: IDIF yielded precise results for both 3DR and TF. Venous blood samples can be used for absolute quantification of (11)C-HED studies, provided a venous-to-arterial transformation is applied. A venous-to-arterial transformation enables noninvasive, absolute quantification of (11)C-HED studies.
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http://dx.doi.org/10.2967/jnumed.115.167437DOI Listing
September 2016

Non-invasive imaging to identify susceptibility for ventricular arrhythmias in ischaemic left ventricular dysfunction.

Heart 2016 06 3;102(11):832-40. Epub 2016 Feb 3.

Department of Cardiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, the Netherlands.

Objective: Non-invasive imaging of myocardial perfusion, sympathetic denervation and scar size contribute to enhanced risk prediction of ventricular arrhythmias (VA). Some of these imaging parameters, however, may be intertwined as they are based on similar pathophysiology. The aim of this study was to assess the predictive role of myocardial perfusion, sympathetic denervation and scar size on the inducibility of VA in patients with ischaemic cardiomyopathy in a head-to-head fashion.

Methods: 52 patients with ischaemic heart disease and left ventricular ejection fraction (LVEF) ≤35%, referred for primary prevention implantable cardioverter-defibrillator (ICD) implantation, were included. Late gadolinium-enhanced cardiovascular MRI was performed to assess LV volumes, function and scar size. Using [(15)O]H2O and [(11)C]hydroxyephedrine positron emission tomography, both resting and hyperaemic myocardial blood flow (MBF), and sympathetic innervation were assessed. After ICD implantation, an electrophysiological study (EPS) was performed and was considered positive in case of sustained VA.

Results: Patients with a positive EPS (n=25) showed more severely impaired global hyperaemic MBF (p=0.003), larger sympathetic denervation size (p=0.048) and tended to have larger scar size (p=0.07) and perfusion defect size (p=0.06) compared with EPS-negative patients (n=27). No differences were observed in LV volumes, LVEF and innervation-perfusion mismatch size. Multivariable analysis revealed that impaired hyperaemic MBF was the single best independent predictor for VA inducibility (OR 0.78, 95% CI 0.65 to 0.94, p=0.007). A combination of risk markers did not yield incremental predictive value over hyperaemic MBF alone.

Conclusions: Of all previously validated approaches to evaluate the arrhythmic substrate, global impaired hyperaemic MBF was the only independent predictor of VA inducibility. Moreover, a combined approach of different imaging variables did not have incremental value.
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http://dx.doi.org/10.1136/heartjnl-2015-308467DOI Listing
June 2016

Principles and techniques of imaging in identifying the substrate of ventricular arrhythmia.

J Nucl Cardiol 2016 Apr 14;23(2):218-34. Epub 2015 Dec 14.

Department of Cardiology and Institute for Cardiovascular Research (IcaR-VU), VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Life-threatening ventricular arrhythmias (VA) are a major cause of death in patients with cardiomyopathy. To date, impaired left ventricular ejection fraction remains the primary criterion for implantable cardioverter-defibrillator therapy to prevent sudden cardiac death. In recent years, however, advanced imaging techniques such as nuclear imaging, cardiac magnetic resonance imaging, and computed tomography have allowed for a more detailed evaluation of the underlying substrate of VA. These imaging modalities have emerged as a promising approach to assess the risk of sudden cardiac death. In addition, non-invasive identification of the critical sites of arrhythmias may guide ablation therapy. Typical anatomical substrates that can be evaluated by multiple advanced imaging techniques include perfusion abnormalities, scar and its border zone, and sympathetic denervation. Understanding the principles and techniques of different imaging modalities is essential to gain more insight in their role in identifying the arrhythmic substrate. The current review describes the principles of currently available imaging techniques to identify the substrate of VA.
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http://dx.doi.org/10.1007/s12350-015-0344-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785206PMC
April 2016

Myocardial denervation coincides with scar heterogeneity in ischemic cardiomyopathy: A PET and CMR study.

J Nucl Cardiol 2016 12 9;23(6):1480-1488. Epub 2015 Nov 9.

Department of Cardiology and Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands.

Background: Mismatch between myocardial innervation and perfusion assessed with positron emission tomography (PET) is a potential risk marker for ventricular arrhythmias in patients with ischemic cardiomyopathy. This mismatch zone originates from residual viable myocardium that has sustained ischemic nerve injury. Heterogenic scar size assessed with late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR) is also a risk marker of ventricular arrhythmias. These two imaging parameters may represent identical morphological tissue features. The current study explored the relation between innervation-perfusion mismatch and heterogenic scar size.

Methods: Twenty-eight patients (26 males, age 67 ± 8 years) with ischemic cardiomyopathy and a left ventricular ejection fraction below 35%, eligible for ICD implantation were included. All patients underwent both [C]-hydroxyephedrine and [O]-water PET studies to assess myocardial sympathetic innervation and perfusion. LGE CMR was conducted to assess total myocardial scar size, scar core size, and heterogenic scar size.

Results: Perfusion defect size was 16.6 ± 9.9% and innervation defect size was 33.7 ± 10.8%, which resulted in an innervation-perfusion mismatch of 17.6 ± 8.9%. Total scar size, scar core size, and heterogenic scar size were 21.2 ± 8.6%, 14.7 ± 6.6%, and 6.5 ± 2.9%, respectively. No relation between scar core size and perfusion deficit size was observed (r = 0.18, P = .36). Total scar size was correlated with the innervation defect size (r = 0.52, P = .004) and the heterogenic scar zone displayed a significant correlation with the innervation-perfusion mismatch area (r = 0.67, P < .001).

Conclusions: Denerved residual viable myocardium in ischemic cardiomyopathy as observed with innervation-perfusion PET is related to the heterogenic scar zone as assessed with LGE CMR.
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http://dx.doi.org/10.1007/s12350-015-0316-zDOI Listing
December 2016

Quantification of [(11)C]-meta-hydroxyephedrine uptake in human myocardium.

EJNMMI Res 2014 Dec 26;4(1):52. Epub 2014 Sep 26.

Department of Radiology and Nuclear Medicine, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, the Netherlands,

Background: The aims of this study were to determine the optimal tracer kinetic model for [(11)C]-meta-hydroxyephedrine ([(11)C]HED) and to evaluate the performance of several simplified methods.

Methods: Thirty patients underwent dynamic 60-min [(11)C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (V T) data.

Results: The reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, V T derived using the single-tissue model correlated highly with that of the two-tissue model (r (2) = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in V T. RI and SUV can provide misleading results because of non-linear relationships with V T.

Conclusions: Although the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with V T, and therefore, care has to be taken when using RI as a quantitative measure.
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http://dx.doi.org/10.1186/s13550-014-0052-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452641PMC
December 2014

Clinical Impact of Cardiac Magnetic Resonance Imaging Versus Echocardiography-Guided Patient Selection for Primary Prevention Implantable Cardioverter Defibrillator Therapy.

Am J Cardiol 2015 Aug 8;116(3):406-12. Epub 2015 May 8.

Department of Cardiology and Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands. Electronic address:

The main eligibility criterion for primary prevention implantable cardioverter defibrillator (ICD) therapy, that is, left ventricular ejection fraction (LVEF), is based on large clinical trials using primarily 2-dimensional echocardiography (2DE). Presently, cardiac magnetic resonance imaging (MRI) is considered the gold standard for LVEF assessment. It has been demonstrated that cardiac MRI assessment results in lower LVEFs compared with 2DE. Consequently, cardiac MRI-LVEF assessment may lead to more patients eligible for ICD implantation with potential clinical consequences. The aim of this study was to evaluate the clinical impact of cardiac MRI-LVEF versus 2DE-LVEF assessment for ICD eligibility. A total of 149 patients with cardiac MRI-LVEF ≤35% referred for primary prevention ICD implantation who underwent both 2DE and cardiac MRI-LVEF assessment were retrospectively included. 2DE-LVEF was computed by Simpson's biplane method. Cardiac MRI-LVEF was computed after outlining the endocardial contours in short-axis cine images. Appropriate device therapy (ADT) and all-cause mortality were evaluated during 2.9 ± 1.7 years of follow-up. The present study found that cardiac MRI-LVEF was significantly lower compared with 2DE-LVEF (23 ± 8% vs 30 ± 8%, respectively, p <0.001), resulting in 29 (19%) more patients eligible for ICD implantation according to the current guidelines (LVEF ≤35%). Patients with 2DE-LVEF >35% but cardiac MRI-LVEF ≤35% experienced a lower ADT rate compared with patients having 2DE-LVEF ≤35% (2.1% vs 10.4% per year, respectively, p = 0.02). Application of cardiac MRI-LVEF cutoff of 30% resulted in 119 eligible patients experiencing 9.9% per year ADT, comparable with 2DE-LVEF cut-off value of 35%. In conclusion, cardiac MRI-LVEF assessment resulted in more patients eligible for ICD implantation compared with 2DE who showed a relatively low event rate during follow-up. The event rate in patients with cardiac MRI-LVEF ≤30% was comparable with patients having a 2DE-LVEF ≤35%. This study suggests the need for re-evaluation of cardiac MRI-based LVEF cut-off values for ICD eligibility.
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http://dx.doi.org/10.1016/j.amjcard.2015.04.059DOI Listing
August 2015

Sympathetic denervation is associated with microvascular dysfunction in non-infarcted myocardium in patients with cardiomyopathy.

Eur Heart J Cardiovasc Imaging 2015 Jul 21;16(7):788-98. Epub 2015 Feb 21.

Department of Cardiology, VU University Medical Center, De Boelelaan 1117, PO Box 7057, Amsterdam, HV 1081, The Netherlands Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands

Aims: Sympathetic denervation typically occurs in the infarcted myocardium and is associated with sudden cardiac death. Impaired innervation was also demonstrated in non-infarcted myocardium in ischaemic and dilated cardiomyopathy (ICMP and DCMP). Factors affecting sympathetic nerve integrity in remote myocardium are unknown. Perfusion abnormalities, even in the absence of epicardial coronary artery disease, may relate to sympathetic dysfunction. This study was aimed to assess the interrelations of myocardial blood flow (MBF), contractile function, and sympathetic innervation in non-infarcted remote myocardium.

Methods And Results: Seventy patients with ICMP or DCMP and LVEF ≤35% were included. [(15)O]H2O- and [(11)C]hydroxyephedrine (HED) PET was performed to quantify resting MBF, hyperaemic MBF, and sympathetic innervation. Cardiovascular magnetic resonance (CMR) imaging was performed to assess left ventricular function, mass, wall thickening, and scar size. Wall thickening, [(11)C]HED retention index (RI), and MBF were assessed in remote segments without scar, selected on CMR. [(11)C]HED RI was correlated with resting MBF (r = 0.41, P < 0.001) and hyperaemic MBF (r = 0.55, P < 0.001) in remote myocardium in both ICMP and DCMP. In addition, LV volumes (r = -0.40, P = 0.001), LV mass (r = -0.31, P = 0.008), and wall thickening (r = 0.45, P < 0.001) correlated with remote [(11)C]HED RI. Multivariable analysis revealed that hyperaemic MBF (B = 0.79, P < 0.001), wall thickening (B = 0.01, P = 0.03), and LVEDV (B = -0.03, P = 0.02) were independent predictors for remote [(11)C]HED RI.

Conclusion: Hyperaemic MBF is independently associated with sympathetic innervation in non-infarcted remote myocardium in patients with ICMP and DCMP. This suggests that microvascular dysfunction might be an important factor related to sympathetic nerve integrity. Whether impaired hyperaemic MBF is the primary cause of this relation remains unclear.
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http://dx.doi.org/10.1093/ehjci/jev013DOI Listing
July 2015

Relative flow reserve derived from quantitative perfusion imaging may not outperform stress myocardial blood flow for identification of hemodynamically significant coronary artery disease.

Circ Cardiovasc Imaging 2015 Jan;8(1)

From the Departments of Cardiology (W.J.S., I.D., M.T.R., K.M.M., N.v.R., P.K.), Radiology and Nuclear Medicine (P.G.R., A.A.L, H.J.H., M.C.H.), Department of Epidemiology and Biostatistics (M.W.H.), VU University Medical Center, Amsterdam, The Netherlands; Turku PET Centre, Turku University Hospital and University of Turku, Turku, Finland (V.U., A.S., S.A.K, M.P., J.K.); and Department of Nuclear Medicine and PET, Institution of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden (T.K., J.S.).

Background: Quantitative myocardial perfusion imaging is increasingly used for the diagnosis of coronary artery disease. Quantitative perfusion imaging allows to noninvasively calculate fractional flow reserve (FFR). This so-called relative flow reserve (RFR) is defined as the ratio of hyperemic myocardial blood flow (MBF) in a stenotic area to hyperemic MBF in a normal perfused area. The aim of this study was to assess the value of RFR in the detection of significant coronary artery disease.

Methods And Results: From a clinical population of patients with suspected coronary artery disease who underwent oxygen-15-labeled water cardiac positron emission tomography and invasive coronary angiography, 92 patients with single- or 2-vessel disease were included. Intermediate lesions (diameter stenosis, 30%-90%; n=75) were interrogated by FFR. Thirty-eight (41%) vessels were deemed hemodynamically significant (>90% stenosis or FFR≤0.80). Hyperemic MBF, coronary flow reserve, and RFR were lower for vessels with a hemodynamically significant lesion (2.01±0.78 versus 2.90±1.16 mL·min(-1)·g(-1); P<0.001, 2.27±1.03 versus 3.10±1.29; P<0.001, and 0.67±0.23 versus 0.93±0.15; P<0.001, respectively). The correlation between RFR and FFR was moderate (r=0.54; P<0.01). Receiver operator characteristic curve analysis showed an area under the curve of 0.82 for RFR, which was not significantly higher compared with that for hyperemic MBF and coronary flow reserve (0.76; P=0.32 and 0.72; P=0.08, respectively).

Conclusions: Noninvasive estimation of FFR by quantitative perfusion positron emission tomography by calculating RFR is feasible, yet only a trend toward a slight improvement of diagnostic accuracy compared with hyperemic MBF assessment was determined.
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http://dx.doi.org/10.1161/CIRCIMAGING.114.002400DOI Listing
January 2015

Impaired hyperemic myocardial blood flow is associated with inducibility of ventricular arrhythmia in ischemic cardiomyopathy.

Circ Cardiovasc Imaging 2014 Jan 16;7(1):20-30. Epub 2013 Dec 16.

Department of Cardiology and Institute for Cardiovascular Research, Departments of Radiology and Nuclear Medicine, Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.

Background: Risk stratification for ventricular arrhythmias (VAs) is important to refine selection criteria for primary prevention implantable cardioverter defibrillator therapy. Impaired hyperemic myocardial blood flow (MBF) is associated with increased mortality rate in ischemic and nonischemic cardiomyopathy, which may be attributed to electric instability inducing VAs. The aim of this pilot study was to assess whether hyperemic MBF impairment may be related with VA inducibility in patients with ischemic cardiomyopathy.

Methods And Results: Thirty patients with ischemic cardiomyopathy referred for primary prevention implantable cardioverter defibrillator implantation were prospectively included (26 men; 65±8 years old; left ventricular ejection fraction, 29±6%). [15O]H2O positron-emission tomography was performed to quantify resting MBF, hyperemic MBF, and coronary flow reserve. Left ventricular dimensions, function, and scar burden were assessed with cardiovascular magnetic resonance imaging. An electrophysiological study was performed to test VA inducibility. Positive electrophysiological study patients (n=12) showed reduced hyperemic MBF (1.25±0.30 versus 1.66±0.38 mL·min(-1)·g(-1); P<0.01) and coronary flow reserve (1.59±0.49 versus 2.12±0.48; P<0.01) compared with electrophysiological study negative patients (n=18). In electrophysiological study positive patients, the number of scar segments>75% transmurality was higher (P<0.05), although scar size and border zone did not differ. Receiver-operating characteristic curve analysis indicated that impaired hyperemic MBF (area under the curve, 0.84; 95% confidence intervals [0.69-0.99]) and coronary flow reserve (area under the curve, 0.77; 95% confidence intervals [0.57-0.96]) were associated with VA inducibility.

Conclusions: In this pilot study, impaired hyperemic MBF and coronary flow reserve were associated with VA inducibility in patients with ischemic cardiomyopathy. These results are hypothesis generating for a potential role of quantitative positron-emission tomography perfusion imaging in risk stratification for VAs.
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http://dx.doi.org/10.1161/CIRCIMAGING.113.001158DOI Listing
January 2014
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