Nina P. Hofmann

HMGB1 Is Associated with Atherosclerotic Plaque Composition and Burden in Patients with Stable Coronary Artery Disease

Objectives The role of inflammation in atherosclerosis is widely appreciated. High mobility group box 1 (HMGB1), an injury-associated molecular pattern molecule acting as a mediator of inflammation, has recently been implicated in the development of atherosclerosis. In this study, we sought to investigate the association of plasma HMGB1 with coronary plaque composition in patients with suspected or known coronary artery disease (CAD). Design HMGB1, high sensitive troponin T (hsTnT) and high sensitive C-reactive protein (hsCRP) were determined in 152 consecutive patients with suspected or known stable CAD who underwent clinically indicated 256-slice coronary computed tomography angiography (CCTA). Using CCTA, we assessed 1) coronary calcification, 2) non-calcified plaque burden and 3) the presence of vascular remodeling in areas of non-calcified plaques. Results Using univariate analysis, hsCRP, hsTnT and HMGB1 as well as age, and atherogenic risk factors were associated with non-calcified plaque burden (r = 0.21, p = 0.009; r = 0.48, p<0.001 and r = 0.34, p<0.001, respectively). By multivariate analysis, hsTnT and HMGB1 remained independent predictors of the non-calcified plaque burden (r = 0.48, p<0.01 and r = 0.34, p<0.001, respectively), whereas a non-significant trend was noticed for hs-CRP (r = 0.21, p = 0.07). By combining hsTnT and HMGB1, a high positive predictive value for the presence of non-calcified and remodeled plaque (96% and 77%, respectively) was noted in patients within the upper tertiles for both biomarkers, which surpassed the positive predictive value of each marker separately. Conclusions In addition to hs-TnT, a well-established cardiovascular risk marker, HMGB1 is independently associated with non-calcified plaque burden in patients with stable CAD, while the predictive value of hs-CRP is lower. Complementary value was observed for hs-TnT and HMGB1 for the prediction of complex coronary plaque.

A bi-center cardiovascular magnetic resonance prognosis study focusing on dobutamine wall motion and late gadolinium enhancement in 3,138 consecutive patients.

To the Editor: In the present study we sought to investigate the predictive value of resting and inducible wall motion abnormalities (WMA) and of late gadolinium enhancement (LGE) for hard cardiac outcomes and for revascularization procedures in 3,138 patients undergoing dobutamine cardiac magnetic

Prediction of functional recovery by cardiac magnetic resonance feature tracking imaging in first time ST-elevation myocardial infarction. Comparison to infarct size and transmurality by late gadolinium enhancement

PURPOSE To investigate whether myocardial deformation imaging, assessed by feature tracking cardiac magnetic resonance (FTI-CMR), would allow objective quantification of myocardial strain and estimation of functional recovery in patients with first time ST-elevation myocardial infarction (STEMI). METHODS Cardiac magnetic resonance (CMR) imaging was performed in 74 consecutive patients 2-4 days after successfully reperfused STEMI, using a 1.5T CMR scanner (Philips Achieva). Peak systolic circumferential and longitudinal strains were measured using the FTI applied to SSFP cine sequences and were compared to infarct size, determined by late gadolinium enhancement (LGE). Follow-up CMR at 6 months was performed in order to assess residual ejection fraction, which deemed as the reference standard for the estimation of functional recovery. RESULTS During the follow-up period 53 of 74 (72%) patients exhibited preserved residual ejection fraction ≥50%. A cut-off value of -19.3% for global circumferential strain identified patients with preserved ejection fraction ≥50% at follow-up with sensitivity of 76% and specificity of 85% (AUC=0.86, 95% CI=0.75-0.93, p<0.001), which was superior to that provided by longitudinal strain (ΔAUC=0.13, SE=0.05, z-statistic=2.5, p=0.01), and non-inferior to that provided by LGE (ΔAUC=0.07, p=NS). Multivariate analysis showed that global circumferential strain and LGE exhibited independent value for the prediction of preserved LV-function, surpassing that provided by age, diabetes and baseline ejection fraction (HR=1.4, 95% CI=1.0-1.9 and HR=1.4, 95% CI=1.1-1.7, respectively, p<0.05 for both). CONCLUSIONS Estimation of circumferential strain by FTI provides objective assessment of infarct size without the need for contrast agent administration and estimation of functional recovery with non-inferior accuracy compared to that provided by LGE.

Comprehensive Bio-Imaging Using Myocardial Perfusion Reserve Index During Cardiac Magnetic Resonance Imaging and High-Sensitive Troponin T for the Prediction of Outcomes in Heart Transplant Recipients

We sought to determine the ability of quantitative myocardial perfusion reserve index (MPRI) by cardiac magnetic resonance (CMR) and high‐sensitive troponin T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant (HT) recipients. In 108 consecutive HT recipients (organ age 4.1 ± 4.7 years, 25 [23%] with diabetes mellitus) who underwent cardiac catheterization, CAV grade by International Society for Heart & Lung Transplantation (ISHLT) criteria, MPRI, late gadolinium enhancement (LGE) and hsTnT values were obtained. Outcome data including cardiac death and urgent revascularization (“hard cardiac events”) and revascularization procedures were prospectively collected. During a follow‐up duration of 4.2 ± 1.4 years, seven patients experienced hard cardiac events and 11 patients underwent elective revascularization procedures. By multivariable analysis, hsTnT and MPRI both independently predicted cardiac events, surpassing the value of LGE and CAV by ISHLT criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and low MPRI showed the highest rates of cardiac events (annual event rate = 14.5%), while those with low hsTnT and high MPRI exhibited excellent outcomes (annual event rate = 0%). In conclusion, comprehensive “bio‐imaging” using hsTnT, as a marker of myocardial microinjury, and CMR, as a marker of microvascular integrity and myocardial damage by LGE, may aid personalized risk‐stratification in HT recipients.

Quantitative analysis of left ventricular strain using cardiac computed tomography

OBJECTIVES To investigate whether cardiac computed tomography (CCT) can determine left ventricular (LV) radial, circumferential and longitudinal myocardial deformation in comparison to two-dimensional echocardiography in patients with congestive heart failure. BACKGROUND Echocardiography allows for accurate assessment of strain with high temporal resolution. A reduced strain is associated with a poor prognosis in cardiomyopathies. However, strain imaging is limited in patients with poor echogenic windows, so that, in selected cases, tomographic imaging techniques may be preferable for the evaluation of myocardial deformation. METHODS Consecutive patients (n=27) with congestive heart failure who underwent a clinically indicated ECG-gated contrast-enhanced 64-slice dual-source CCT for the evaluation of the cardiac veins prior to cardiac resynchronization therapy (CRT) were included. All patients underwent additional echocardiography. LV radial, circumferential and longitudinal strain and strain rates were analyzed in identical midventricular short axis, 4-, 2- and 3-chamber views for both modalities using the same prototype software algorithm (feature tracking). Time for analysis was assessed for both modalities. RESULTS Close correlations were observed for both techniques regarding global strain (r=0.93, r=0.87 and r=0.84 for radial, circumferential and longitudinal strain, respectively, p<0.001 for all). Similar trends were observed for regional radial, longitudinal and circumferential strain (r=0.88, r=0.84 and r=0.94, respectively, p<0.001 for all). The number of non-diagnostic myocardial segments was significantly higher with echocardiography than with CCT (9.6% versus 1.9%, p<0.001). In addition, the required time for complete quantitative strain analysis was significantly shorter for CCT compared to echocardiography (877±119 s per patient versus 1105±258 s per patient, p<0.001). CONCLUSION Quantitative assessment of LV strain is feasible using CCT. This technique may represent a valuable alternative for the assessment of myocardial deformation in selected patients with poor echogenic windows and general contraindications for magnetic resonance imaging.

Combined Assessment of High-Sensitivity Troponin T and Noninvasive Coronary Plaque Composition for the Prediction of Cardiac Outcomes

PURPOSE To determine the risk-stratification ability of plaque volume and composition assessment with cardiac computed tomographic (CT) angiography and high-sensitivity troponin T (hsTnT) in patients at intermediate risk for coronary artery disease (CAD). MATERIALS AND METHODS The study complied with the Declaration of Helsinki and was approved by the local ethics committee. All patients gave written informed consent. Five hundred twenty-one consecutive patients (mean age ± standard deviation, 62 years ± 10; 256 men and 265 women) were included in this prospective, observational, longitudinal, single-center study. Quantitative cardiac CT angiography analysis was performed in all patients (for 7690 coronary segments), whereas biomarkers (hsTnT and high-sensitivity C-reactive protein) were available in 408 patients (78%). To evaluate the incremental value of cardiac CT angiography and hsTnT for the prediction of cardiovascular events, multivariate Cox regression and integrated discrimination improvement analysis were applied. RESULTS In 521 patients, 13 hard cardiac events occurred during a mean follow-up period of 2.3 years ± 1.1 (median, 2.4 years; range, 0.5-4.5 years), while 23 patients underwent late coronary revascularization. The Duke clinical score was 51% ± 30, indicating intermediate risk. The presence of no plaques or purely calcified versus noncalcified plaques, plaque volume according to tertiles, and increased hsTnT (≥14 pg/mL) was independently associated with hard cardiac events (hazard ratio [HR] = 26.08, 95% confidence interval [CI]: 2.78, 244.99; HR = 12.14, 95% CI: 1.87, 78.74; and HR = 10.31, 95% CI: 2.72, 39.0, respectively; P < .01 for all). Patients with increased hsTnT and plaque burden (n = 53) showed the highest incidence for hard cardiac events (annual rate, 12.7%), followed by those with either increased hsTnT or plaque burden (n = 145; annual rate = 0.44%, P < .03), while those with lower hsTnT and plaque burden exhibited excellent outcomes and no hard event during the follow-up duration (n = 210; annual rate = 0%, P < .001). CONCLUSION Use of hsTnT as a marker of myocardial microinjury and cardiac CT angiography as a marker of the total atherosclerotic burden improves the prediction of cardiac outcome in patients with presumably stable CAD and may aid in personalized risk stratification in patients at intermediate risk.

When do we really need coronary calcium scoring prior to contrast-enhanced coronary computed tomography angiography? Analysis by age, gender and coronary risk factors.

Aims To investigate the value of coronary calcium scoring (CCS) as a filter scan prior to coronary computed tomography angiography (CCTA). Methods and Results Between February 2008 and April 2011, 732 consecutive patients underwent clinically indicated CCTA. During this ‘control phase’, CCS was performed in all patients. In patients with CCS≥800, CCTA was not performed. During a subsequent ‘CCTA phase’ (May 2011–May 2012) another 200 consecutive patients underwent CCTA, and CCS was performed only in patients with increased probability for severe calcification according to age, gender and atherogenic risk factors. In patients where CCS was not performed, calcium scoring was performed in contrast-enhanced CCTA images. Significant associations were noted between CCS and age (r = 0.30, p<0.001) and coronary risk factors (χ2 = 37.9; HR = 2.2; 95%CI = 1.7–2.9, p<0.001). Based on these associations, a ≤3% pre-test probability for CCS≥800 was observed for males <61 yrs. and females <79 yrs. According to these criteria, CCS was not performed in 106 of 200 (53%) patients during the ‘CCTA phase’, including 47 (42%) males and 59 (67%) females. This resulted in absolute radiation saving of ∼1 mSv in 75% of patients younger than 60 yrs. Of 106 patients where CCS was not performed, estimated calcium scoring was indeed <800 in 101 (95%) cases. Non-diagnostic image quality due to calcification was similar between the ‘control phase’ and the ‘CCTA’ group (0.25% versus 0.40%, p = NS). Conclusion The value of CCS as a filter for identification of a high calcium score is limited in younger patients with intermediate risk profile. Omitting CCS in such patients can contribute to further dose reduction with cardiac CT studies.

Effects of oral valganciclovir prophylaxis for cytomegalovirus infection in heart transplant patients

Background Cytomegalovirus (CMV) infection is a serious complication following heart transplantation. This study (June 2003–January 2010) retrospectively assessed the effects of oral valganciclovir prophylaxis in adult heart transplant recipients during the first year after transplantation. Methods In patients with normal renal function, 900 mg of oral valganciclovir was administered twice daily for 14 days after heart transplant followed by 900 mg per day for following 6 months. In the event of renal insufficiency, valganciclovir was adjusted according to the manufacturer’s recommendations. Antigenemia testing for pp65 antigen and simultaneous polymerase chain reaction (PCR) were used to document exposure to CMV. From 2003 to 2010, 146 patients (74.0% men) of mean age 50.7 ± 10.3 years at the time of heart transplant were included. Results A total of 16 patients (11.0% of total, 75.0% male) had a positive pp65 and PCR result (ie, CMV infection) during the year following heart transplant; three of these patients had discontinued valganciclovir prophylaxis within the first 6 months following transplant because of leukopenia, including one patient developed CMV colitis. Two further patients developed CMV pneumonia during prophylactic valganciclovir therapy. Eight patients had positive pp65 and PCR tests in the 6–12 months after heart transplant following cessation of routine prophylaxis. One of these patients developed CMV pneumonia and another developed CMV colitis and CMV pneumonia. Thirty-seven of the 146 (25.3%) patients were CMV donor-seropositive/recipient-seronegative, and seven (18.9% of this subgroup) had a positive CMV test. In patients who were CMV donor-seropositive/recipient-seronegative, the risk of a positive CMV test (ie, CMV infection) was significantly elevated (P = 0.023). Conclusion CMV prophylaxis with oral valganciclovir for 6 months following heart transplant is clinically feasible. In line with previous studies, CMV donor-seropositive/recipient-seronegative patients have a significantly elevated risk of CMV infection. In patients who prematurely discontinue valganciclovir, close monitoring of CMV antigenemia appears warranted. No significantly elevated rate of CMV infection was observed after 6 months of valganciclovir prophylaxis.

Myocardial Perfusion Reserve and Strain-Encoded CMR for Evaluation of Cardiac Allograft Microvasculopathy.

OBJECTIVES This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy. BACKGROUND Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. METHODS Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. RESULTS Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). CONCLUSIONS CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.

Long‐Term Outcome After Heart Transplantation Predicted by Quantitative Myocardial Blush Grade in Coronary Angiography

The purpose of our study was to investigate whether the quantification of myocardial blush grade (MBG) during surveillance coronary angiography can predict long‐term outcome after heart transplantation (HT). In 105 HT recipients who underwent cardiac catheterization, cardiac allograft vasculopathy (CAV) was assessed visually using the ISHLT grading scale (prospective cohort study). MBG was quantified by dividing the plateau of contrast agent gray‐level intensity (Gmax) by the time‐to‐peak intensity (Tmax). In a subgroup (n = 72), myocardial perfusion index by cardiac magnetic resonance imaging (CMR) was assessed. During a mean follow‐up duration of 2.7 (standard deviation [SD] 1.0) years, 26 patients experienced cardiac events, including 7 with cardiac death and 19 who underwent coronary revascularization. Gmax/Tmax was related to CAV by ISHLT criteria and to subsequent cardiac events. By univariate analysis, patient age, organ age, CAV, MBG and myocardial perfusion index by CMR were all predictive for cardiac events. Multivariable analysis demonstrated that Gmax/Tmax provided the most robust prediction of cardiac death (hazard ratio [HR] = 0.2, 95% confidence interval [CI] = 0.06–0.64, p < 0.01) and cardiac events (HR = 0.52, 95% CI = 0.32–0.84, p < 0.01), beyond clinical parameters and the presence of CAV. Gmax/Tmax is a valuable surrogate parameter of microvascular integrity, which is associated with cardiac death and revascularization procedures after HT.