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BACKGROUND: After heart transplantation (HTx), invasive coronary angiography is gold standard for surveillance of cardiac allograft vasculopathy (CAV). Non-invasive CAV surveillance is desirable.PURPOSE: We examined left ventricular global longitudinal strain (LVGLS) and non-invasive coronary flow velocity reserve (CFVR) related to CAV and prognosis after heart transplantation (HTx).METHODS: Echocardiographic Doppler coronary flow velocity reserve (CFVR) and left ventricular global longitudinal strain (LVGLS) were evaluated in 98 HTx patients. All-cause mortality and major adverse cardiac events (MACE) including hospitalization due to heart failure, cardiovascular death and significant CAV progression, were recorded.RESULTS: Median follow-up was 3.3 (range 1.7-5.4) years. Patients with low CFVR (CONCLUSIONS: In HTx patients with severe CAV, a higher prevalence of low CFVR and worsened LVGLS was observed. Both measurements were strong independent predictors of MACE and all-cause mortality in HTx-patients. Combined CFVR and LVGLS provided incremental prognostic value and showed an excellent ability to rule out significant CAV and may be considered as part of routine CAV surveillance of HTx-patients.

Aims: We aim to evaluate changes in invasive haemodynamics, right ventricular (RV) function, and perfusion during the first year after heart transplantation (HTx) and to determine the relation between RV function and myocardial perfusion. Methods and results: Thirty patients were prospectively enrolled at the time of HTx. Right heart catheterization (RHC), comprehensive 2D and 3D echocardiography and cardiac biomarkers were performed at baseline (≤2 weeks after HTx) and at follow-up 1, 3, 6, and 12 months after HTx. At 12 months, HTx patients were subjected to an exercise stress test with assessment of maximal oxygen consumption (VO 2max). RV myocardial perfusion reserve was evaluated by 15O-H 2O positron emission tomography at baseline and at 3 and 12 months after HTx. A group of 43 healthy subjects served as echocardiographic controls and a subgroup comprising 16 healthy controls underwent exercise stress test with simultaneous RHC. At baseline, HTx patients had higher pulmonary artery wedge pressure (PAWP) and right atrial pressure (RAP) and pulmonary vascular resistance (PVR) than healthy controls whereas cardiac index (CI) was reduced (PAWP; 14 mmHg [8;17] vs. 8 mmHg [7;10]; RAP: 7 mmHg [4;11] vs. 5 mmHg [4;6]; PVR: 1.9 wood units [1.3;2.6] vs. 1.1 wood units [1.0;1.4]; CI 2.4 L/min/m 2 [2.2;2.8] vs. 3.3 L/min/m 2 [2.8;.3.6], all P 2max 12 months after HTx (r = 0.75, P

Background: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx), and the pathogenesis is not fully clarified. We aimed to investigate a wide range of biomarkers and their correlation with micro- and macrovascular CAV and major adverse cardiac events in HTx patients. Methods: We evaluated 91 cardiovascular disease-related proteins in 48 HTx patients using a novel proteomic panel. Patients were dichotomized according to micro- and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and 15O-H 2O positron emission tomography imaging. Major adverse cardiac events included significant CAV progression, heart failure, treated rejection, and cardiovascular death. Results: We found consistent differences in two proteins involved in cholesterol homeostasis: significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) (p

BACKGROUND: Long-term survival after heart transplantation (HTx) is compromised by cardiac allograft vasculopathy (CAV) characterized by coronary macro- and microvascular disease. The pathogenesis of CAV is unclear and may involve coronary thrombosis. We investigated whether HTx patients with CAV had higher platelet aggregation and turnover than HTx patients without CAV and healthy controls. Furthermore, we investigated the anti-platelet effect of low-dose aspirin in HTx patients.METHODS: We included 57 patients who had undergone HTx (median 8.3 years from HTx) and 57 healthy controls. Platelet aggregation was measured on-aspirin and off-aspirin using impedance aggregometry with adenosine diphosphate (ADP) and arachidonic acid (AA). We evaluated platelet turnover by flow cytometry, CAV burden by coronary angiography and echocardiography, and microvascular function by echocardiographic coronary flow velocity reserve (CFVR).RESULTS: Off-aspirin, HTx patients with CAV (n = 21) had higher ADP-induced platelet aggregation than healthy controls (p < 0.01) and HTx patients without CAV (n = 36) (p < 0.05). Aspirin treatment reduced AA-induced platelet aggregation in both HTx groups, but HTx patients with CAV had higher platelet aggregation on-aspirin than HTx patients without CAV (p < 0.05). Platelet turnover did not differ between HTx patients with CAV and HTx patients without CAV (p > 0.34). HTx patients with lower CFVR values had higher platelet aggregation than HTx patients with higher CFVR values (p < 0.05).CONCLUSIONS: Off-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV and healthy controls. On-aspirin, platelet aggregation was higher in HTx patients with CAV than in HTx patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx patients with CAV.

PURPOSE: Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality following heart transplantation (HTx). The pathogenesis is multifactorial and involves inflammation, thrombosis, endothelial dysfunction and immunological factors. Non-invasive biomarkers for the diagnosis of CAV have not yet been identified. We aimed to investigate the relation between micro and macrovascular CAV and a wide range of cardiovascular protein biomarkers. METHODS: Using a novel proximity extension assay (Olink® CARDIOVASCULAR III), blood samples from 48 HTx patients (median 9.1 years after HTx) were analyzed for 92 biomarkers reflecting inflammation, immune response, cell adhesion, hemostasis, fibrinolysis, tissue remodeling, and proteolysis. Patients were dichotomized according to micro and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and coronary flow reserve by (15)O-H2O positron emission tomographic imaging. RESULTS: Twenty-seven patients had angiographic CAV. A total of 13 biomarkers differed significantly between groups (Table 1). In particular, N-terminal prohormone brain natriuretic peptide (NT-proBNP), proprotein convertase subtilisin/kexin type 9 (PCSK9), and paraoxonase 3 (PON3) differed consistently between groups. However, after correcting for multiple testing with Bonferroni correction (p

Purpose Cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) affects the epicardial arteries and veins and also the coronary microcirculation. In the absence of proximal epicardial artery stenosis, coronary flow velocity reserve (CFVR) reflects the function of the myocardial microcirculation. We aimed to determine the prognostic value of 1) CFVR and 2) a combination of CFVR and left ventricular global longitudinal strain (LVGLS) in HTx patients. Methods CFVR was evaluated using pulsed wave Doppler echocardiography in 98 HTx patients (median 6.9 years from HTx) examined with coronary angiography. Patients were enrolled from 2013 to 2018 and prospectively followed until June 1st 2020. All-cause mortality and major adverse cardiac events (MACE) including heart failure, significant CAV progression, coronary intervention or cardiovascular death, were recorded. Results Median follow-up was 3.2 [interquartile range 1.9-5.1] years. Patients with low CFVR ( -15.5%), we obtained a strong predictive model for MACE (HR 10.5, 95% CI 4.5-24.5, p Conclusion CFVR strongly predicts MACE and all-cause mortality in HTx-patients. A model combining low CFVR and low LVGLS magnitude was a strong model for MACE and all-cause mortality prediction and could be considered as a non-invasive method for routine CAV surveillance.

Background Following heart transplantation (HTx), long-term survival is reduced mainly due to development of a specific form of coronary artery disease, coronary allograft vasculopathy (CAV). Using optical coherence tomography to visualize the coronary artery wall, we have recently shown that layered fibrotic plaques resembling organized clots are the dominant plaque component in CAV. Thus, thrombosis is suggested as a possible mechanism contributing to development and progression of CAV. Aspirin is widely used after HTx despite limited evidence and lack of specific guidelines. The antiplatelet effect of aspirin has not been thoroughly examined in HTx-patients. Purpose To investigate baseline platelet aggregation and the antiplatelet effect of aspirin in HTx-patients with and without CAV. Methods We included 68 HTx-patients (median 8.6 years from HTx). In 66 patients taking 75 mg aspirin for a minimum of 7 days, platelet aggregation was measured in whole blood using impedance aggregometry with the following agonists: Adenosine diphosphate (ADP) stimulating ADP-receptors and arachidonic acid (AA) for monitoring of aspirin treatment. Aspirin compliance was confirmed by measuring serum-thromboxane B2. Platelet aggregation prior to aspirin therapy was measured in 59 patients as it was not considered clinically safe to interrupt ongoing aspirin treatment for one week prior to blood sampling in 9 patients mainly due to previous coronary stenting. CAV burden was determined by coronary angiography and echocardiography based on international classification. Patients were divided into two groups; no CAV (n=37) and CAV (n=29). Results In HTx-patients not treated with aspirin, we found significantly increased ADP-induced platelet aggregation in patients with CAV vs. patients without CAV (904 (95% CI 813–995) vs. 786 (95% CI 728–843) AU*min, P=0.02). Baseline AA-induced aggregation was also higher in patients with CAV vs. patients without CAV, though non-significant (994 (95% CI 907–1081) vs. 905 (95% CI 839–972) AU*min, P=0.10). Even though aspirin reduced AA-induced platelet aggregation in both groups, patients with CAV had significantly increased AA-induced platelet aggregation compared with patients without CAV on aspirin treatment (380 (95% CI 295–465) vs. 286 (95% CI 239–334) AU*min, P=0.04) (Fig. 1). Conclusions HTx-patients with CAV have increased platelet aggregation before and after aspirin treatment compared with HTx-patients without CAV. Aspirin monotherapy may not provide sufficient platelet inhibition in HTx-patients with CAV. Acknowledgement/Funding Aarhus University (PhD-salary)

Purpose Sudden cardiac death (SCD) is a frequent and unexplained complication in relation to heart transplantation (HTx). The mechanism is expectedly multifactorial and Cardiac Allograft Vasculopathy (CAV) is possibly related to SCD. We aimed to investigate the relation between CAV and arrhythmias and silent ischemia in long-term HTx patients. Methods CAV was classified in accordance with the International Society of Heart and Lung Transplantation guideline by coronary angiography and echocardiography . Patients were divided into three CAV groups (CAV 0, 1 and 2+3). Incidence of arrhythmias and silent ischemia were detected by 48-hour electrocardiogram monitoring , and analyzed blinded to CAV status. Results We included 49 HTx patients transplanted a median of 9 years ago [4-14]. We saw a higher incidence of nonsustained ventricular tachycardia (NSVT) in CAV 2+3 patients than in CAV 0 and 1 patients (p=0.01). Also, isolated premature ventricular contractions (PVC) were more frequently observed in this group than in CAV 0 and 1 patients (p=0.01). No difference in incidence of isolated premature atrial contractions (p=0.67) and supraventricular tachycardia (p=0.13) was observed between the CAV groups. Silent ischemia was only observed in CAV 2+3 patients (p=0.04), all patients with silent ischemia (n=3) died within 12 months. The PQ-interval was increased in CAV patients compared with patients without CAV (p=0.01) but no episodes of advanced AV-block were detected. Conclusion Patients with substantial CAV showed a higher incidence of PVCs and NSVT. However, the burden of ventricular rhythm-disturbances was modest and not clearly indicating an increased risk of SCD. In contrast, presence of silent ischemia in patients with severe CAV was associated with high mortality.