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Stressing the importance of cardiac assessment in pheochromocytoma TITLE Page 1 Stressing the importance of cardiac assessment in pheochromocytoma AUTHORS Andrew C. Morley-Smith1,2 MA MB BChir MRCP; and Alexander R. Lyon1,2 MA BM BCh PhD FRCP AFFILIATIONS 1. National Institute for Health Research Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust 2. National Heart & Lung Institute, Imperial College London BRIEF TITLE Cardiac assessment in pheochromocytoma CORRESPONDING Alexander R. Lyon MA BM BCh PhD FRCP AUTHOR NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK Telephone +44 (0) 207 351 8164 Fax +44 (0) 207 351 8776 Email [email protected] DISCLOSURES AND CONFLICTS None to declare Stressing the importance of cardiac assessment in pheochromocytoma Page 2 The complexities of catecholamine physiology have intrigued physicians and the public alike for centuries. Epinephrine was isolated in 1897 by John Jacob Abel1, and in parallel in 1901 by the Japanese scientist Jokichi Takamine who called it adrenaline2. Quickly the positive inotropic and chronotropic effects of catecholamines were appreciated and exploited, but by the second half of the twentieth century the adverse effects of chronic exposure were increasingly recognised, including their roles in hypertension and heart failure, eventually yielding -adrenoceptor blockers as heart failure therapy. More recently the notion that short term effects of catecholamines are temporary and reversible has also been challenged. Acute heart failure in the context of adrenergic ‘storms’, including Takotsubo syndrome3, 4 (TTS) and neurocardiogenic stunning following subarachnoid haemorrhage, has highlighted that high circulating catecholamine levels can either be toxic, or cause acute negative inotropic effects. However the long term effects of these acute surges in endogenous or exogenous catecholamines and associated acute adrenergic crises are poorly understood. One patient cohort characterised by high circulating catecholamine levels, including sudden surges with adrenergic crises, are patients with a pheochromocytoma5. Pheochromocytoma is a syndrome of catecholamine excess consequent to neoplastic growth of chromaffin cells of the sympathetic nervous system, classically in the adrenal medulla (pheochromocytoma) but sometimes occurring in extra-adrenal chromaffin tissue (paragangliomas). The precise biochemistry depends on the cell lineage, and tumours can release combinations of norepinephrine, epinephrine or dopamine alongside an array of other hormones. Diagnosis is challenging because the intermittent secretion of catecholamines by tumour cells makes single point-of-care testing of plasma or urine for catecholamines or their breakdown products unreliable. Collection of urine over 24 hours for urinary metanephrines increases sensitivity, but corroboration from other techniques (including suppression testing, Stressing the importance of cardiac assessment in pheochromocytoma Page 3 functional nuclear imaging with 123I-metaiodobenzylguanidine (MIBG), or cross-sectional anatomical imaging in combination with positron emission tomography) is required for accurate diagnosis. Traditional thinking is that surgery is curative for the majority of patients and their cardiovascular physiology returns to normal after tumour resection, with long term follow up targeted to detecting recurrence, metastatic disease or tumours in the contralateral adrenal gland. However, Ferreira and colleagues challenge this standard view in this issue of JACC. The authors recognise that catecholamine toxicity is known to cause histopathological evidence of acute and chronic myocardial inflammatory change6, and hypothesise that there is significant unrecognised cardiac toxicity from pheochromocytoma, both acutely and more importantly at long term follow up after surgical ‘cure’. They applied advanced cardiac magnetic resonance (CMR) imaging to assess cardiac function in a cohort of patients before or following surgical resection of pheochromocytoma. The authors recruited 125 patients in three study groups. The pheochromocytoma group (n=60) comprises 29 patients in whom the tumour was recently diagnosed, scanned 2 (IQR 1-4) months after diagnosis (referred to here as the ‘new diagnosis’ cases), and a further 31 historic cases studied 51 (IQR 27-83) months after surgical resection (the ‘previous diagnosis’ cases). Eighteen patients (62%) in the new diagnosis group and 5 patients (16%) in the old diagnosis group attended for a second scan respectively at 12±5 and 25±10 months after the initial examination. These cohorts are used to characterise acute and chronic cardiac phenotypes in pheochromocytoma, in comparison to healthy (n=51) and hypertensive (n=14) controls. The authors report CMR cardiac phenotypes from cine images in standard planes for left ventricular ejection fraction (LVEF) and ventricular mass; tagged cine sequences for Stressing the importance of cardiac assessment in pheochromocytoma Page 4 strain and strain rate; and myocardial tissue characterisation using late gadolinium enhancement (LGE) and native (pre-contrast) T1 mapping. In the ‘new diagnosis’ group, acutely there is evidence of systolic (reduced global LVEF and impaired peak systolic circumferential strain) and diastolic (diastolic strain rate) impairment. These functional changes are accompanied by focal LGE in a non-ischaemic pattern in 59% of patients, and elevated myocardial T1 compared with healthy and hypertensive controls, assessed both as mean T1 and proportion of myocardium with T1 meeting established criteria for myocarditis. The global LVEF improves by the second scan (median 12 months), while the deformation parameters show no significant change, suggesting a persistent, sub-clinical abnormality of myocardial function. The observed LGE is persistent but non-progressive. The total area of abnormal T1 reduces at late follow up but remained elevated compared to healthy controls, whereas the reduction in mean T1, a more subtle parameter, was not significant. The ‘previous diagnosis’ group have preserved global systolic function (LVEF 67±5%) comparable to controls, but persistent, subtle abnormalities of systolic and diastolic function by deformation parameters. Nineteen percent have LGE which may reflect persistent fibrosis from the previous catecholamine exposure, given the absence of other confounding cardiovascular diseases. In this group there is a larger area of myocardium with abnormal T1 compared to normal and hypertensive controls, though again mean T1 shows no difference. Considering these findings together, the authors conclude that pheochromocytoma cases an acute catecholaminergic myocarditis, with elevated T1 and patchy subendocardial LGE accompanied by global LV dysfunction, which partially resolves after tumour resection but leaves chronic LGE indicating focal replacement fibrosis and a T1 abnormality which Stressing the importance of cardiac assessment in pheochromocytoma Page 5 may represent diffuse interstitial fibrosis, with subclinical abnormalities of LV function. It is interesting that left ventricular hypertrophy is not seen in these patients, distinguishing these findings from those of hypertension alone. This is the first systematic report of long term cardiac effects of this rare tumour, and we congratulate the authors on their success in seeing the study to completion. Five years’ recruitment across 3 centres to recruit 60 pheochromocytoma patients underpins the rarity of the condition and difficulty studying it. The application of state-of-the-art CMR techniques provides unique insight to the long term cardiac sequelae of this illness. This article raises questions. Firstly, we should consider what these CMR findings actually represent. There is a continuum of myocardial changes in response to high catecholamine exposure (from acute cardiomyocyte swelling, contraction band necrosis, inflammatory infiltrate, through reactive interstitial fibrosis to chronic replacement fibrotic change), and neither the native T1 mapping nor the LGE defines specifically any of these as distinct categories. In the acute and chronic phases the signals from either technique could represent myocardial inflammation (leaky capillaries and increased myocardial water content) or fibrosis (expanded extracellular volume). Based on a prior histopathological study6 and preclinical insights from acute catecholamine challenges, the LGE and T1 changes seen acutely predominantly represent active catecholaminergic myocarditis (perhaps with some fibrosis developing depending on chronicity), whereas late after tumour resection they represent focal (LGE) or diffuse (T1) fibrosis. Novel CMR techniques including post-contrast T1 mapping and extracellular volume mapping could be informative, but ultimately biopsy or post mortem specimens are required to confirm the underlying histopathology and what these CMR signals represent. Stressing the importance of cardiac assessment in pheochromocytoma Page 6 Secondly, the specific biochemical nature of the catecholamine excess may be relevant and is not explored in this study. Pheochromocytomas can secrete an array of hormones, of which the most common are epinephrine, norepinephrine and dopamine, usually with one the dominant catecholamine. The authors do not report the biochemical results for the patients, and it would be interesting to compare the cardiac effects of different catecholamines separately. Endogenous catecholamines have differing effects on the heart and circulatory system due to differing relative potencies for α- and β-adrenoceptors, and also can activate different subcellular signalling pathways depending on their concentrations. This is particularly relevant at high concentrations, and sudden surges in circulating concentration have a different impact than a chronic moderate elevation. Supra-physiological serum catecholamine concentrations are seen in TTS, and indeed several cases of TTS have been reported in patients with pheochromocytomas. Preclinical pharmacological studies demonstrate that high concentrations of epinephrine, but not norepinephrine, can activate the β2-adrenoceptor, switching coupling from the Gs to Gi secondary messenger pathway7, 8. This stimulus trafficking to Gi results in a profound negative inotropic effect, in particular in the cardiac apex where the density of -2 receptors is greatest, but importantly is cardioprotective limiting apoptosis. In contrast there is no such protective effect for norepinephrine excess. Therefore the acute and chronic cardiac effects of a pheochromocytoma may vary depending on the precise cocktail of catecholamine exposure and its pattern of release by the tumour. Further studies are needed to compare their relative effects on regional as well as global abnormalities in the myocardium, and those with versus without persisting LGE and higher levels of T1 abnormalities. Finally, and most importantly, the clinical significance of these findings remains to be determined. Abnormal CMR findings are surrogate biomarkers and raise the question of the Stressing the importance of cardiac assessment in pheochromocytoma Page 7 relevance of current and future functional pathophysiological abnormalities. It would be interesting to correlate these imaging findings with other established biochemical cardiac biomarkers (brain natriuretic peptide or cardiac troponin) and with functional assessment such as cardiopulmonary exercise testing to unmask limitations in cardiac performance. But most important is the impact on morbidity and mortality. Abnormalities during the acute phase may have an impact on acute complications, and cardiovascular risks during surgery and postoperative recovery. Persisting abnormalities could lower the threshold for developing heart failure or arrhythmias in the context of future myocardial stressors (for example hypertension, myocardial infarction or cardiotoxic cancer therapy). Long term clinical outcomes for this and future cohorts of phaeochromocytoma patients is needed to clarify if heightened morbidity or mortality is associated with these structural and functional cardiac abnormalities seen on CMR, and to guide the optimal clinical management to patients post resection. In summary, Ferreira and colleagues provide a detailed account of the myocardial CMR phenotype in patients with pheochromocytoma before and after tumour resection, and highlight an unrecognised complication of this condition, preponderant in patients previously thought to be cured. Further studies are required to relate the observed CMR phenotypes to myocardial histopathology, subgroups determined by biochemical catecholamine signatures, and long term cardiovascular outcomes of these patients to help guide the optimal acute and long term clinical approach. Even in 2016 we continue to understand more about the impact of these fundamental stress hormones upon cardiovascular pathophysiology, and no doubt there is still more to learn. Stressing the importance of cardiac assessment in pheochromocytoma Page 8 ACKNOWLEDGEMENTS A.C.M.S. is a British Heart Foundation Clinical Research Training Fellow (FS/13/34/30173) and A.R.L. is a British Heart Foundation Intermediate Clinical Research Fellow (FS/11/67/28954). Both authors are supported by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation Trust. REFERENCES 1. Abel J.J., On epinephrin, the active constituent of the suprarenal capsule and its compounds. Proceedings of the American Physiological Society, 1899: p. iii-xxi. 2. Takamine J., Adrenalin, the active principle of the suprarenal glands and its mode of preparation. American Journal of Pharmacy, 1901. 73: p. 523-531. 3. Lyon A.R., Bossone E., Schneider B., et al., Current state of knowledge on Takotsubo syndrome: a Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail, 2016. 18(1): p. 8-27. 4. Wittstein I.S., Thiemann D.R., Lima J.A., et al., Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med, 2005. 352(6): p. 539-48. 5. Fishbein L., Pheochromocytoma and Paraganglioma: Genetics, Diagnosis, and Treatment. Hematol Oncol Clin North Am, 2016. 30(1): p. 135-50. 6. Van Vliet P.D., Burchell H.B., and Titus J.L., Focal myocarditis associated with pheochromocytoma. N Engl J Med, 1966. 274(20): p. 1102-8. Stressing the importance of cardiac assessment in pheochromocytoma 7. Page 9 Lyon A.R., Rees P.S., Prasad S., Poole-Wilson P.A., and Harding S.E., Stress (Takotsubo) cardiomyopathy--a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med, 2008. 5(1): p. 22-9. 8. Paur H., Wright P.T., Sikkel M.B., et al., High levels of circulating epinephrine trigger apical cardiodepression in a beta2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation, 2012. 126(6): p. 697-706.