Download TITLE Stressing the importance of cardiac assessment in

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
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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
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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
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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
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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.
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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
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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
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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.
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