Two-Layer Inkjet-Printed Microwave Split-Ring Resonators for Detecting Analyte Binding to the Gold Surface.

This work focuses on demonstrating the working principle of inkjet-printed Au nanoparticle (NP) two-layer Gigahertz (2.6 GHz) microwave split-ring resonators (SRRs) as a novel platform for the detection of analytes on flexible substrates. In contrast to the standard fabrication of split-ring resonator biosensors using printed circuit board technology, which results in a seven-layer system, the resonators in this work were fabricated using a two-layer system. A ground plane is embedded in the SRR measurement setup. In this method, a microwave electromagnetic wave is coupled into the Au SRR via an inkjet-printed Cu-NP stripline that is photonically sintered. This coupling mechanism facilitates the detection of analytes by inducing resonance shifts in the SRR. In this study, the functionality of the printed sensors was demonstrated using two different Au functionalization processes, firstly, with HS-PEG7500-COOH, and, secondly, with protein G with an N-terminal cysteine residue. The sensing capabilities of the printed structures are shown by the attachment of biomolecules to the SRR and the measurement of the resulting resonance shift. The experiments show a clear shift of the resonance frequency in the range of 20-30 MHz for both approaches. These results demonstrate the functionality of the simplified printed two-layer microwave split-ring resonator for use as a biosensor.

[Heart failure with reduced left ventricular ejection fraction (HFrEF, HFmrEF)].

INTRODUCTION: Heart failure is the final stage of most heart diseases and, with over 64 million people affected worldwide, is considered a global pandemic. The prevalence is expected to continue to rise. The prevention and treatment of cardiovascular diseases and the early detection of patients suffering from heart failure are essential. Different therapies are available depending on the extent of the reduction in left ventricular ejection fraction (LVEF). Optimal treatment prevents unnecessary admissions to hospital, reduces mortality and improves quality of life. In the following article, we discuss the diagnosis of heart failure and explain the various treatment options for heart failure with reduced LVEF (HFrEF, HFmrEF).

Modulation of Beta-Adrenergic Autoantibodies Over Time in Post-Viral ME/CFS is Related to Fatigue and Pain Symptoms.

BACKGROUND: Myalgic encephalomyelits/chronic fatigue syndrome (ME/CFS) is an acquired disease with symptoms of fatigue and pain. In pathogenesis, the induction of autoantibodies (AAB) against G-protein coupled receptors (GPCR), such as ß-adrenergic receptors (ß-AdR), has been suspected. GPCR-AAB correlate with symptom severity and autonomic dysfunction in ME/CFS. Objectives: To describe symptoms and treatment of a patient presenting with infection-triggered ME/CFS demonstrating that levels of ß-AdR-AAB underlie modulation over time, correlating with the severity of symptoms. METHODS: At T1 and T2, GPCR-AAB were measured and questionnaires assessing symptom severity were completed. TSHDS-IgM-AAB were tested, and SF density was analyzed via skin probe. RESULTS: At T2, elevated levels of ß-AdR-AAB were found, corresponding with an aggravation of fatigue and pain symptoms. Elevated TSHDS-IgM-AAB were found, which corresponded with reduced fiber density from the skin probe. CONCLUSIONS: The levels of ß-AdR-AAB in post-infectious ME/CFS can be modulated. Future studies might target interventions to reduce these AAB.

Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease.

BACKGROUND: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established. METHODS: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points. RESULTS: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P = 0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P = 0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P = 0.21). CONCLUSIONS: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.).

Real-world analysis of a Biolimus A9 polymer-free drug-coated stent with very short dual antiplatelet therapy in patients at high bleeding risk.

BACKGROUND: Patients at high risk of bleeding requiring percutaneous coronary intervention (PCI) need careful evaluation of both their thrombotic and their bleeding risks. In these patients, a polymer-free metallic stent coated with biolimus-A9 (BA9-DCS) followed by 1­month dual antiplatelet therapy (DAPT) could be a safe option; however, real-world data are still lacking. We analyzed the performance of the device in a real-world scenario. METHODS: Patients assessed as being at high risk of bleeding with an indication for PCI were treated with BA9-DCS and DAPT consisting of aspirin (100 mg/day) and clopidogrel (75 mg/day) for at least 1 month, followed by either oral anticoagulation or single antiplatelet therapy. No exclusion criteria were used. The primary endpoint was the occurrence of an adverse event after PCI, i.e. severe bleeding requiring hospitalization, ischemic or hemorrhagic stroke, clinically driven stent thrombosis, myocardial infarction or cardiac death. RESULTS: Overall, 89 patients were enrolled in this study [median age 75 (66-81) years; 27 females (30%)] and 171 interventions were performed. During a median follow-up of 203 (145-273) days the primary endpoint occurred in 20 patients (23%): 12 (13%) had clinically significant bleeding, four (5%) ischemic stroke and four (5%) died from cardiac causes related neither to stent thrombosis nor to acute myocardial infarction. Female gender emerged as the only statistically significant predictor of an adverse event (adjusted hazard ratio (HR) 3.3; 95% confidence interval (CI): 1.2-8.7, p = 0.017). CONCLUSION: In real-world patients at high risk of bleeding, implantation of the polymer-free metallic stent coated with Biolimus-A9 (Biofreedom®; Biosensors Europe, Morges, Switzerland) followed by 1 -month DAPT showed encouraging results without any stent thrombosis.

Arrhythmogenic right ventricular cardiomyopathy : Evolving from unique clinical features to a complex pathophysiological concept.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart muscle disease, is characterized by a progressive replacement of viable, in its classic form predominantly right ventricular myocardium by fibro-fatty tissue. These pathological alterations may provide the substrate for the occurrence of life-threatening ventricular tachyarrhythmias, heart failure, and sudden cardiac death. The clinical course in this young patient population is highly variable, diagnostic algorithms complex, and individualized treatment strategies yet to be refined. Molecular genetic analyses have revealed both heterozygous and compound mutations in genes encoding for desmosomal proteins that are an integral part of the intercellular architecture. However, its diagnostic and prognostic impact remains to be elucidated. Over time, other genetic (i.e., non-desmosomal) and non-genetic causes (phenocopies) have been identified, and biventricular and left dominant manifestations (ALVC) are known. Based on a qualitative scoring system, initially published in 1994, diagnostic criteria were revised and substantiated by quantitative criteria in 2010 followed by a critical appraisal 9 years later. In 1995, ARVC was included in the classification of cardiomyopathies of the World Health Organization but was recently proposed to be subsumed in a broader concept termed "arrhythmogenic cardiomyopathy" (AC). This review provides an update on the clinical diagnosis and differential diagnoses of ARVC as well as our current understanding of the underlying pathogenesis, and it sheds light on new efforts in risk stratification.

Reconfigurable frequency coding of triggered single photons in the telecom C-band.

In this work, we demonstrate reconfigurable frequency manipulation of quantum states of light in the telecom C-band. Triggered single photons are encoded in a superposition state of three channels using sidebands up to 53 GHz created by an off-the-shelf phase modulator. The single photons are emitted by an InAs/GaAs quantum dot grown by metal-organic vapor-phase epitaxy within the transparency window of the backbone fiber optical network. A cross-correlation measurement of the sidebands demonstrates the preservation of the single photon nature; an important prerequisite for future quantum technology applications using the existing telecommunication fiber network.

Imprints of the Molecular Electronic Structure in the Photoelectron Spectra of Strong-Field Ionized Asymmetric Triatomic Model Molecules.

We examine the circular dichroism in the angular distribution of photoelectrons of triatomic model systems ionized by strong-field ionization. Following our recent work on this effect [Paul, Yue, and Gräfe, J. Mod. Opt. 64, 1104 (2017)JMOPEW0950-034010.1080/09500340.2017.1299883], we demonstrate how the symmetry and electronic structure of the system is imprinted into the photoelectron momentum distribution. We use classical trajectories to reveal the origin of the threefolded pattern in the photoelectron momentum distribution, and show how an asymmetric nuclear configuration of the triatomic system effects the photoelectron spectra.

Generation, guiding and splitting of triggered single photons from a resonantly excited quantum dot in a photonic circuit.

We demonstrate resonance fluorescence from single In-GaAs/GaAs quantum dots embedded in a rib waveguide beamsplitter structure operated under pulsed laser excitation. A systematic study on the excitation laser pulse duration depicts that a sufficiently small laser linewidth enables a substantial improved single-photon-to-laser-background ratio inside a waveguide chip. This manifests in the observation of clear Rabi oscillations over two periods of the quantum dot emission as a function of laser excitation power. A photon cross-correlation measurement between the two output arms of an on-chip beamsplitter results in a g(2)(0)=0.18, demonstrating the generation, guiding and splitting of triggered single photons under resonant excitation in an on-chip device. The present results open new perspectives for the implementation of photonic quantum circuits with integrated quantum dots as resonantly-pumped deterministic single-photon sources.

Perfusion cardiovascular magnetic resonance and fractional flow reserve in patients with angiographic multi-vessel coronary artery disease.

BACKGROUND: Perfusion cardiovascular magnetic resonance (CMR) and fractional flow reserve (FFR) are emerging as the most accurate tools for the assessment of myocardial ischemia noninvasively or in the catheter laboratory. However, there is limited data comparing CMR and FFR in patients with multi-vessel disease. This study aims to evaluate the correlation between myocardial ischemia detected by CMR with FFR in patients with multivessel coronary disease at angiography. METHODS AND RESULTS: Forty-one patients (123 vascular territories) with angiographic 2- or 3-vessel coronary artery disease (visual stenosis >50 %) underwent high-resolution adenosine stress perfusion CMR at 1.5 T and FFR measurement. An FFR value of <0.75 was considered significant. On a per patient basis, CMR and FFR detected identical ischemic territories in 19 patients (46 %) (mean number of territories 0.7+/-0.7 in both (p = 1.0)). On a per vessel basis, 89 out of 123 territories demonstrated concordance between the CMR and FFR results (72 %). In 34 % of the study population, CMR resulted in fewer ischemic territories than FFR; in 12 % CMR resulted in more ischemic territories than FFR. There was good concordance between the two methods to detect myocardial ischemia on a per-patient (k =0.658 95 % CI 0.383-0.933) level and moderate concordance on a per-vessel (k = 0.453 95 % CI 0.294-0.612) basis. CONCLUSIONS: There is good concordance between perfusion CMR and FFR for the identification of myocardial ischemia in patients with multi-vessel disease. However, some discrepancy remains and at this stage it is unclear whether CMR underestimates or FFR overestimates the number of ischemic segments in multi-vessel disease.

Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking.

BACKGROUND: Fibrofatty degeneration of myocardium in ARVC is associated with wall motion abnormalities. The aim of this study was to examine whether Cardiovascular Magnetic Resonance (CMR) based strain analysis using feature tracking (FT) can serve as a quantifiable measure to confirm global and regional ventricular dysfunction in ARVC patients and support the early detection of ARVC. METHODS: We enrolled 20 patients with ARVC, 30 with borderline ARVC and 22 subjects with a positive family history but no clinical signs of a manifest ARVC. 10 healthy volunteers (HV) served as controls. 15 ARVC patients received genotyping for Plakophilin-2 mutation (PKP-2), of which 7 were found to be positive. Cine MR datasets of all subjects were assessed for myocardial strain using FT (TomTec Diogenes Software). Global strain and strain rate in radial, circumferential and longitudinal mode were assessed for the right and left ventricle. In addition strain analysis at a segmental level was performed for the right ventricular free wall. RESULTS: RV global longitudinal strain rates in ARVC (-0.68 ± 0.36 sec⁻¹) and borderline ARVC (-0.85 ± 0.36 sec⁻¹) were significantly reduced in comparison with HV (-1.38 ± 0.52 sec⁻¹, p ≤ 0.05). Furthermore, in ARVC patients RV global circumferential strain and strain rates at the basal level were significantly reduced compared with HV (strain: -5.1 ± 2.7 vs. -9.2 ± 3.6%; strain rate: -0.31 ± 0.13 sec(-1) vs. -0.61 ± 0.21 sec⁻¹). Even for patients with ARVC or borderline ARVC and normal RV ejection fraction (n=30) global longitudinal strain rate proved to be significantly reduced compared with HV (-0.9 ± 0.3 vs. -1.4 ± 0.5 sec(-1); p < 0.005). In ARVC patients with PKP-2 mutation there was a clear trend towards a more pronounced impairment in RV global longitudinal strain rate. On ROC analysis RV global longitudinal strain rate and circumferential strain rate at the basal level proved to be the best discriminators between ARVC patients and HV (AUC: 0.9 and 0.92, respectively). CONCLUSION: CMR based strain analysis using FT is an objective and useful measure for quantification of wall motion abnormalities in ARVC. It allows differentiation between manifest or borderline ARVC and HV, even if ejection fraction is still normal.

Autonomic dysfunction in patients with arrhythmogenic right ventricular cardiomyopathy: biochemical evidence of altered signaling pathways.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC. METHODS: During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns). RESULTS: Among the proteins analyzed, only tissue levels of norepinephrine (NE; P < 0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P < 0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls. CONCLUSIONS: The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of ß-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.

Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Predicted heart rate effect of inhaled PF-00610355, a long acting ß-adrenoceptor agonist, in volunteers and patients with chronic obstructive pulmonary disease.

AIM: To assess the cardiovascular effects of a new inhaled long-acting ß-adrenoceptor agonist PF-00610355 in COPD patients. METHODS: Thirteen thousand and sixty-two heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma and COPD patients were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics and concomitant medication was evaluated using non-linear mixed-effects models. The median heart rate increase in COPD patients for doses of PF-00610355 up to 280 µg once daily was simulated with the final pharmacokinetic/pharmacodynamic (PKPD) model. RESULTS: An Emax model accounting for delayed on-and off-set of the PF-00610355-induced change in heart rate was developed. The predicted potency in COPD patients was three-fold lower compared with healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo-corrected increase of 2.7 (0.90-4.82) beats min(-1) in COPD patients for a PF-00610355 dose of 280 µg once daily, with 19% subjects experiencing a heart rate increase of more than 20 beats min(-1) compared with 8% in the placebo group. CONCLUSIONS: This PKPD analysis supports the clinical observation that no relevant effects of PF-00610355 on heart rate in COPD patients should be expected for doses up to 280 µg once daily.

T-wave integral: an electrocardiographic marker discriminating patients with arrhythmogenic right ventricular cardiomyopathy from patients with right ventricular outflow tract tachycardia.

AIMS: Clinical and electrocardiographic (ECG) presentation of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow-tract tachycardia (RVOT) may be similar. The aim of the study was to assess the validity and utility of T-wave integral measurement as an ECG discriminator of patients with ARVC and RVOT using a body surface mapping (BSM). METHODS AND RESULTS: A 120-channel BSM with quantitative signal analysis of the T-wave integral was performed in 10 patients with ARVC. Results were compared with those obtained from 13 patients with RVOT and a control group of 12 healthy subjects (controls). Age, body mass index, and QRS-axis on surface ECG were not significantly different between the groups. Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly negative T-wave integral in the right lower anterior region of the torso when compared with RVOT (P < 0.001). There was no statistically significant difference between RVOT patients and controls. At a cut-off level of -0.3 mV ms, sensitivity and specificity were 83% [area under curve (AUC) 0.85 ± 0.04 for the comparison of ARVC and RVOT]. These differences were pronounced in ARVC patients with a plakophlin-2 mutation (P < 0.001). CONCLUSION: Quantitative analysis of the BSM T-wave integral in distinct anatomical regions discriminates ARVC patients from RVOT patients and controls and may serve as an additional diagnostic tool.

Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.

Understanding the Vicious Circle of Pain, Physical Activity, and Mental Health in Lipedema Patients-A Response Surface Analysis.

Lipedema is a widespread disease with painful accumulations of subcutaneous fat in the legs and arms. Often, obesity co-occurs. Many patients suffer from impairment in mobility and mental health. Obesity and mental health in turn can be positively influenced by physical activity. In this study, we aimed to examine the interrelations between pain and physical activity on mental health in lipedema patients. In total, 511 female lipedema patients (age M = 40.16 ± 12.45 years, BMI M = 33.86 ± 7.80 kg/m2) filled in questionnaires measuring pain, physical activity, and mental health (PHQ-9; WHOQOL-BREF with subscales mental, physical, social, environmental, and overall health). Response surface analyses were calculated via R statistics. The explained variance was high for the model predicting depression severity (R2 = 0.18, p < 0.001) and physical health (R2 = 0.30, p < 0.001). Additive incongruence effects of pain and physical activity on depression severity, mental, physical, and overall health were found (all p < 0.001). In our study, physical activity and pain synergistically influenced physical, mental, and overall health. The pain not only led to low mental health but also interfered with the valuable potential of engaging in physical activity in lipedema patients.

Population Pharmacokinetics of Mivavotinib (TAK-659), a Dual Spleen Tyrosine Kinase and FMS-Like Tyrosine Kinase 3 Inhibitor, in Patients With Advanced Solid Tumors or Hematologic Malignancies.

Mivavotinib (TAK-659), an orally administered, small-molecule, dual inhibitor of spleen tyrosine kinase and FMS-like tyrosine kinase 3 (SYK/FLT3), is under development for the treatment of patients with advanced malignancies. In this analysis, we evaluated the population pharmacokinetics (PK) of mivavotinib and its sources of variability (covariates) in adult patients with advanced solid tumors, or relapsed/refractory B-cell lymphomas or acute myeloid leukemia, using pooled data from 159 patients enrolled in 2 phase 1/2 clinical studies. A 2-compartment model with first-order linear elimination and a first-order absorption rate (and associated lag time) adequately described the PK of mivavotinib in this patient population. The population estimates of apparent clearance (CL/F) and apparent central compartment volume (Vc /F) were 31.6 L/h and 893 L, respectively, resulting in a half-life of ≈20 hours. In the final model, creatinine clearance was included as a covariate of CL/F, and sex as a covariate of Vc /F. Simulations showed that steady-state exposure to mivavotinib increased with decreasing renal function. Expanding eligibility by enrolling patients with moderate renal impairment in phase 1 increased the diversity of patients in early trials and allowed the model to inform dose adjustment in patients with moderate renal impairment in future trials. In addition, simulations showed median steady-state trough concentration of mivavotinib following 70 mg twice daily and 160 mg daily dosing to be commensurate with 100 ng/mL, the level leading to >90% FLT3 inhibition per ex vivo plasma immune assays and considered a potential exposure threshold required for FLT3-driven efficacy.

Microvascular dysfunction in nonfailing arrhythmogenic right ventricular cardiomyopathy.

PURPOSE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a nonischaemic cardiomyopathy and leading cause of sudden death in the young. It has been shown that microvascular dysfunction reflected by an impaired myocardial blood flow (MBF) response to stress is present in patients with other forms of nonischaemic cardiomyopathy, e.g. dilated cardiomyopathy, and that the reduced MBF may be related to a poor prognosis. Therefore, we quantified MBF, coronary flow reserve and coronary vascular resistance in patients with nonfailing ARVC using H(2)(15)O and PET. METHODS: In ten male patients with ARVC (mean age 49 ± 14 years), MBF was quantified at rest and during adenosine-induced hyperaemia using H(2)(15)O PET. Results were compared with those obtained in 20 age-matched healthy male control subjects (mean age 46 ± 14 years). RESULTS: Resting MBF was not significantly different between patients with ARVC and controls (MBF(rest) 1.19 ± 0.29 vs. 1.12 ± 0.20 ml/min/ml). However, hyperaemic MBF was significantly lower in patients with ARVC than in controls (2.60 ± 0.96 vs. 3.68 ± 0.84 ml/min/ml; p = 0.005). Consequently, patients with ARVC had a significantly lower coronary flow reserve than control subjects (2.41 ± 1.34 vs. 3.39 ± 0.93; p = 0.030). In addition, hyperaemic coronary vascular resistance was increased in patients with ARVC (36.79 ± 12.91 vs. 26.31 ± 6.49 mmHg × ml(-1) × min × ml; p = 0.007), but was found to be unchanged at rest. CONCLUSION: In this small well-characterized cohort of patients with nonfailing ARVC, we found a significantly reduced hyperaemic MBF and increased coronary vascular resistance. Further studies are necessary to corroborate this potential new functional aspect of the pathophysiological mechanisms underlying ARVC.