Right Ventricular Endocardial Thermography in Transplanted and Coronary Artery Disease Patients: First Human Application

ABSTRACT: Background. We sought to evaluate for the first time in humans the safety and feasibility of right ventricular (RV) thermography in patients with coronary artery disease (CAD) and in patients after heart transplantation (Tx), in comparison to subjects without structural heart disease (controls). Methods. Ninety-one RV thermography procedures were performed in 16 patients with CAD, 19 heart-transplant recipients and 6 patients without structural heart disease. We recorded the temperature of the RV intracavitary blood and RV endocardial septum, and calculated their difference using a dedicated commercially available thermography catheter. Results. No complications were observed. CAD patients had a significantly higher temperature difference (0.19 ± 0.11 ºC) compared to both Tx patients (0.10 ± 0.06 ºC) and controls (0.07 ± 0.04 ºC) (p

J INVASIVE CARDIOL 2010;22:400–404

Key words: coronary artery disease, temperature, transplantation

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Intravascular temperature measurement (thermography) is a novel method to assess thermal heterogeneity in blood and tissues. It has been previously used to detect temperature differences in coronary atheromatous plaques and coronary sinus blood. Increased thermal heterogeneity has been documented in the culprit^1-4 and non-culprit5 lesions of patients with acute coronary syndromes, in the coronary sinus blood of patients with coronary artery disease (CAD)6,7 and in patients with congestive heart failure due to dilated cardiomyopathy.⁸ Very recently, a significant temperature difference was reported in the aortic leaflets of patients with non-rheumatic aortic stenosis and correlated with tissue markers of inflammation and neoangiogenesis.⁹ In this study we hypothesized that CAD patients may have increased right ventricular (RV) endocardial heterogeneity, using as an endpoint the difference between RV endocardial and RV blood temperatures. Rather than the intracoronary temperature measurements, we chose to use RV endocardial thermography to avoid obvious safety issues related to coronary manipulations, especially in patients with documented CAD. As a result, we sought to investigate the safety and feasibility of RV endocardial surface temperature measurement in patients with CAD and in patients after heart transplantation (Tx) in comparison to subjects without structural heart disease.

Methods

All study participants gave written informed consent and the ethics committee of our institution approved the study protocol. We studied 16 consecutive patients with stable CAD scheduled for elective percutaneous coronary intervention (PCI) of at least one significant coronary stenosis > 70% in an epicardial vessel of at least 2.0 mm diameter (Group I). We also studied 19 consecutive transplant recipients undergoing routine RV myocardial biopsy as part of their clinical follow up (Group II), of whom 14 had a history of dilated cardiomyopathy and 5 had a history of ischemic cardiomyopathy. Six patients with a structurally normal heart undergoing radiofrequency ablation for atrioventricular nodal reentrant tachycardia, served as controls. Patients with active infection, known neoplastic disease or chronic inflammatory disorders of any kind were excluded. RV thermography was performed with the Epiphany thermography catheter (3 Fr, Medispes SW, Switzerland), which is a well-validated system.^1–3,5–8 The temperature accuracy is 0.05˚C and the time constant is 300 ms. This is a monorail catheter with a tip thermistor and its software is commercially available. All procedures were performed by a single operator (A.M.) and before the scheduled coronary angioplasty, RV biopsy or atrioventricular node reentry tachycardia ablation, respectively. The temperature of RV intracavitary blood and the RV endocardial septum were recorded and their difference was calculated by subtraction. In further detail, the study protocol was as follows: the area of interest was depicted in two orthogonal views and the right internal jugular or right femoral vein was catheterized; a 7 Fr long sheath was introduced into the RV and stabilized close to the RV apical-septal region. The temperature catheter was then advanced through the introducer sheath. Multiple^2–5 real-time paired measurements were obtained from intracavitary blood without contact (at 3–5 mm distance) with the endocardium, and from the RV endocardial septum in contact with the endocardial surface. From each pair, a temperature difference was automatically recorded and stored in the dedicated computer software (Figure 1). For each patient, a single temperature difference was used as a mean of all temperatures obtained. In Group II patients, the biopsy specimens were obtained from exactly the same endocardial point as the temperature measurement (Figure 2). Statistical analysis. One-way ANOVA was used for statistical analysis between all three Groups and the Scheffe test was used for post hoc paired comparisons when the ANOVA p-value was Results Baseline characteristics are reported in Table 1. Patients in Group I were 15 males and 1 female, and their age was 60.5 ± 15.9 years. Ten patients suffered from single-vessel and 6 from multivessel CAD. Similarly, 10 patients had significant left anterior descending disease, and 6 had stenoses in the other coronary arteries. In Group II there were 16 males and 3 females aged 41 ± 12.8 years. The three groups were different in their ages (p = 0.002). Patients in Group II were younger (p = 0.002 compared to Group I) and their orthotopic heart transplant was performed 563 ± 695 days before the index procedure. Our controls were all males, 45.7 ± 19.4 years of age (p = 0.8 and p = 0.14 compared to Group I and Group II, respectively). As expected, Group II patients had a more frequent history of risk factors for CAD. A total of 91 consecutive procedures were performed, 16 in Group I, 69 in Group II (as part of their clinically indicated RV biopsy program) and 6 in Group III, respectively. No complications were noted during RV thermography. Three procedures in Group II were unsuccessful due to technical reasons and were excluded from analysis. In addition, in this Group, 2 patients presented mild cellular rejection on biopsy, but without increased RV temperature heterogeneity. Results from 88 successfully completed procedures are reported as mean ± standard deviation (min-max). There was a significant difference in temperature difference among the three clinical groups; in the CAD group, the temperature difference was 0.19 ± 0.11˚C (0.03–0.40˚C), in Tx patients it was 0.10 ± 0.06˚C (0.01–0.31˚C), and in controls it was 0.07 ± 0.04˚C (0.02–0.14˚C) (p Discussion This is the first study to show that RV endocardial thermography in humans, using a commercially available dedicated catheter is feasible and safe. In addition, we have shown that patients with stable CAD have a significantly higher temperature difference in the RV endocardium compared to control subjects, whereas clinically stable transplant recipients have temperatures similar to the controls. Inflammation plays a key role in the development of CAD; inflammatory mechanisms are present in all stages of atherosclerosis progression, from the initial formation to the eventual erosion or rupture of the plaque, including endothelial dysfunction, leukocyte migration, extracellular matrix degradation and platelet activation.^10,11 The presence of inflammatory activation has been mainly documented in acute coronary syndrome patients, whereas data on stable CAD are limited. Coronary thermography has been proposed as a novel method to detect vulnerable coronary plaques. Thermal heterogeneity has been mainly detected in culprit lesions of patients with acute coronary syndromes,¹² especially in association with rupture or positive arterial remodeling.³ A temperature difference > 0.5ºC has been reported to predict worse prognosis after PCI.¹² However, an increased temperature difference can also be observed in non-culprit plaques in acute coronary syndrome patients, as well as in stable coronary stenoses.⁵ Increased heat production at sites of arterial plaques has been attributed to inflammatory responses. Following the initial ex vivo observation by Casscells et al in human carotid endarterectomy specimens,¹³ several reports have documented the association between thermal heterogeneity and systemic/local inflammatory activation. Specifically, the presence and proximity of macrophages, and not smooth muscle cells, was directly related to temperature heterogeneity in experimental vascular lesions.^14,15 In CAD patients, Stefanadis et al observed a close association between temperature difference and systemic inflammatory markers.^6,7,16,17 Moreover, hypolipedemic diet and statins tend to attenuate thermal heterogeneity.^2,7,14,16 Our finding of a significant difference in RV thermal heterogeneity between stable CAD and control patients corroborates previous observations from coronary artery and coronary sinus thermographies,^1,6,17 representing possibly one more method of invasive detection of vulnerable coronary circulation. Athero-thrombosis is currently viewed as a disorder characterized by low-grade vascular inflammation, and in stable CAD patients, compared to healthy individuals, several inflammatory markers have been reported at significantly higher concentrations.^18,19 Patients with stable CAD present with higher C-reactive protein levels compared to controls,²⁰ and higher concentrations in patients with stable angina is associated with rapid CAD progression.²¹ In addition, raised C-reactive protein is a strong predictor of coronary events in patients with stable angina.²² Increased heat production in patients with stable CAD compared to normal subjects has been previously described, with the same catheter system, in a study measuring coronary sinus blood temperature in relation to right atrium blood temperature (0.18 ± 0.04˚C vs. 0.14 ± 0.07˚C, respectively);⁶ in addition, in that study there was no statistical difference in temperature measurements between patients with stable CAD versus those with acute coronary syndromes. Interestingly, the RV endocardial temperature difference in stable CAD patients in our study was identical to the DT measured between the right atrium and coronary sinus in similar patients in that study. If confirmed by other investigators, RV thermography, like coronary sinus thermography, may be used to detect a more global thermal myocardial heterogeneity, rather than a site-specific coronary plaque examination (intracoronary thermography). In addition, it is relatively simple, avoiding cannulation of the coronary sinus and potential intracoronary complications, such as coronary spasm or endothelial denudation.²³ At the same time, it is independent of blood flow alterations that may lead to falsely elevated measurements of thermal heterogeneity due to other energy expenditure unrelated to the presence of vulnerable plaque.²⁴ Our post-heart Tx patients underwent RV thermography just prior to routine surveillance RV endocardial biopsy in an attempt to detect a local inflammatory process, which in the event of a cellular-mediated rejection episode, is mainly attributed to the action of cytokines. Macrophage and T-lymphocyte-produced cytokines are well known mediators and effectors of the cellular rejection process in transplanted hearts and it has been reported that the cardiac allograft is a major source of cytokines, at least as shown by studies measuring cytokine levels in the coronary sinus.²⁵ However, peripheral blood cytokine levels do not consistently correlate with cellular rejection,^26–28 particularly since their action constitutes a major target of the administered immunosuppressive schemes. Therefore, it is becoming increasingly clear that the current immunological approach to diagnose early rejection episodes is rather inadequate and measurement of a combination of protein- and gene-based biomarkers, possibly incorporated into an algorithm, may be necessary to guide immunosuppression and serve as a noninvasive tool to detect graft rejection.²⁹ Our transplanted patient group consisted of patients with stable clinical status and a very low incidence of cellular rejection, and in these patients, the RV endocardial temperature difference was similar to subjects without structural heart disease. This lack of thermal heterogeneity between the two groups possibly indicates the absence of local inflammatory activation in the transplanted group and the effectiveness of the administered immunosuppression, but these assumptions need to be confirmed by the finding of thermal heterogeneity in cases with severe cellular rejection. Study limitations. This study sought to examine the safety and feasibility of RV endocardial thermography and should be viewed in the context of several important limitations. The number of patients included was small, thus our findings, although adequate for a feasibility study, should be confirmed by larger series before a conclusion on the prognostic implication of thermal heterogeneity in the CAD group can be drawn. The inclusion of the group undergoing catheter ablation for atrio-ventricular nodal reentrant tachycardia is far from defining a healthy control group (such participation was considered unethical). However, these patients had no detectable structural heart disease, as they had no signs of coronary atherosclerosis, including history, elctrocardiogram and echocardiogram. A noteworthy limitation was that we did not perform RV thermography in acute coronary syndrome patients, thus we could not confirm potential differences in endocardial heat measurements between different CAD groups for the purpose of vulnerability detection. Finally, inflammatory markers were not measured in order to correlate thermography and inflammatory activation.

Conclusions

This is the first study to show that RV endocardial thermography in humans is feasible and safe. In addition, patients with stable CAD present a significantly higher temperature difference in the RV endocardium compared to control subjects, whereas clinically stable transplant recipients have temperatures similar to controls. Further studies are needed to establish the potential role of RV endocardial thermography in CAD patients.

References

1. Stefanadis C, Diamantopoulos L, Tsiamis E, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965–1971. 2. Toutouzas K, Vaina S, Tsiamis E, et al. Detection of increased temperature of the culprit lesion after myocardial infarction: The favourable effect of statins. Am Heart J 2004;148:783–788. 3. Toutouzas K, Synetos A, Stefanadi E, et al. Correlation between morphologic characteristics and local temperature differences in culprit lesions of patients with symptomatic coronary artery disease. J Am Coll Cardiol 2007;49:2264–2271. 4. Takumi T, Lee S, Hamasaki S, et al. Limitation of angiography to identify the culprit plaque in acute myocardial infarction with coronary total occlusion utility of coronary plaque temperature measurement to identify the culprit plaque. J Am Coll Cardiol 2007;50:2197–2203. 5. Toutouzas K, Drakopoulou M, Mitropoulos J, et al. Elevated plaque temperature in non-culprit de novo atheromatous lesions of patients with acute coronary syndromes. J Am Coll Cardiol 2006;17:301–306. 6. Toutouzas K, Drakopoulou M, Markou V, et al. Increased coronary sinus temperature: Correlation with systemic inflammation. Eur J Clin Invest 2006;36:218–223. 7. Toutouzas K, Drakopoulou M, Markou V, et al. Correlation of systemic inflammation with local inflammatory activity in non-culprit lesions: Beneficial effect of statins. Int J Cardiol 2007;119:368–373. 8. Toutouzas K, Stougiannos P, Drakopoulou M, et al. Coronary sinus thermography in idiopathic dilated cardiomyopathy: Correlation with systemic inflammation and left ventricular contractility. Eur J Heart Fail 2007;9:168–172. 9. Toutouzas K, Drakopoulou M, Synetos A, et al. In vivo aortic valve thermal heterogeneity in patients with nonrheumatic aortic valve stenosis : The first in vivo experience in humans. J Am Coll Cardiol 2008;52:758–763. 10. Hanson G. Inflammation, Atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352:1685–1695. 11. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–874. 12. Stefanadis C, Toutouzas K, Tsiamis E, et al. Increased local temperature in human coronary atherosclerotic plaques: An independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention. J Am Coll Cardiol 2001;37:1277–1283. 13. Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: Possible implications for plaque rupture and thrombosis. Lancet 1996;347:1422–1423. 14. Verheye S, De Meyer GR, Van Langenhove G, et al. In vivo temperature heterogeneity of atherosclerotic plaques is determined by plaque composition. Circulation 2002;105:1596–1601. 15. Madjid M, Naghavi M, Malik BA, et al. Thermal detection of vulnerable plaque. Am J Cardiol 2002;90:36L–39L. 16. Stefanadis C, Toutouzas K, Tsiamis E, et al. Relation between local temperature and C-reactive protein levels in patients with coronary artery disease: Effects of atorvastatin treatment. Atherosclerosis 2007;192:396–400. 17. Stefanadis C, Diamantopoulos L, Dernellis J, et al. Heat production of atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes. J Mol Cell Cardiol 2000;32:43–52. 18. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–1143. 19. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid-a protein in severe unstable angina. N Engl J Med 1994;331:417–419. 20. Taniguchi H, Momiyama Y, Ohmori R, et al. Associations of plasma C-reactive protein levels with the presence and extent of coronary stenosis in patients with stable coronary artery disease. Atheroscerosis 2004;178:173–177. 21. Zouridakis E, Avanzas P, Espliguero RA, et al. Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris. Circulation 2004;110:1747–1753. 22. Haverkate F, Thompson SG, Pyke SDM, et al, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet 1997;349:462–466. 23. Verheye S, De Meyer GR, Krams R, et al. Intravascular thermography: Immediate functional and morphological vascular findings. Eur Heart J 2004;25:158–165. 24. Stefanadis C, Toutouzas K, Tsiamis E, et al. Thermal heterogeneity in stable human coronary atherosclerotic plaques is underestimated in vivo: The “cooling effect” of blood flow. J Am Coll Cardiol 2003;41:403–408. 25. Fyfe A, Daly P, Galligan L, et al. Coronary sinus sampling of cytokines after transplantation: Evidence for macrophage activation and interleukin-4 production within the graft. J Am Coll Cardiol 1993;21:171–176. 26. George JF, Kirklin JK, Naftel DC, et al. Serial measurements of interleukin-6, interleukin-8, tumor necrosis factor-alpha, and soluble vascular cell adhesion molecule-1 in the peripheral blood plasma of human cardiac allograft recipients. J Heart Lung Transplant 1997;16:1046–1053. 27. Deng MC, Erren M, Kammerling L, et al. The relation of interleukin-6, tumor necrosis factor-alpha, IL-2, and IL-2 receptor levels to cellular rejection, allograft dysfunction and clinical events early after cardiac transplantation. Transplantation 1995;60:1118–1124. 28. Jordan SC, Czer L, Toyoda M, et al. Serum cytokine levels in heart allograft recipients: Correlation with findings on endomyocardial biopsy. J Heart Lung Transplant 1993;12:333–337. 29. Mehra MR, Feller E, Rosenberg S. The promise of protein-based and gene-based clinical markers in heart transplantation: From bench to bedside. Nat Clin Pract Cardiovasc Med 2006;3:136–143.

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Athanassios Manginas, MD*, Elias Andreanides, MD*, Εvangelos Leontiadis, MD*, Petros Sfyrakis, MD§, Themistocles Maounis, MD*, Dimitrios Degiannis, MD£, Petros A. Alivizatos, MD§, Dennis V. Cokkinos, MD* From the Departments of *Cardiology, §Cardiothoracic Surgery and Heart Transplantation and Molecular, and the £Immunopathology and Histocompatibility Laboratory at the Onassis Cardiac Surgery Center, Athens, Greece. The authors report no conflicts of interest regarding the content herein. Manuscript submitted April 30, 2010, provisional acceptance given May 25, 2010, final version accepted June 10, 2010. Address for correspondence: Athanassios Manginas, MD, FACC, FESC, Department of Cardiology, Onassis Cardiac Surgery Center, 356 Syngrou Ave, Kallithea, Athens, 176 74, Greece. E-mail: esbarouni@yahoo.gr