Catecholamines are tyrosine-derived neurotransmitters including dopamine, norepinephrine, and epinephrine [24, 25]. They also act as hormones regulating key physiological processes across nearly all body tissues, and thus are involved in the pathogenesis of many systemic diseases [24, 25, 26]. They are predominantly synthesised by the chromaffin cells of the adrenal medulla and sympathetic postganglionic neurons. The adrenal medulla releases epinephrine (80%) and norepinephrine (20%) in response to its sympathetic supply, commonly as part of an acute stress response. This release is in conjunction with norepinephrine secretion from sympathetic nerve terminals. The catecholamines have a short half-life of 1–3 minutes and are deaminated by monoamine oxidases or methylated by catechol-O-methyl transferases. These enzymes are also found in other tissues such as the liver [25].

The concentration and type of catecholamine determine the cardiovascular response to it. Acutely, catecholamines increase heart rate, systemic vascular resistance and myocardial contractility while reducing venous compliance [23]. They are considered the most potent positive inotropic agents in relation to the heart and are the main regulators of cardiac output. Epinephrine also acts as a bronchodilator and increases the rates of glycogenolysis, lipolysis and oxygen consumption [25]. In the heart, the norepinephrine that is released upon activation of sympathetic nervous system acts through $\alpha$${}_1$, $\beta$${}_1$ and $\beta$${}_2$ adrenoceptors to exert positive inotropic and chronotropic effects. In the blood vessels, the norepinephrine-mediated $\alpha$${}_1$ adrenoreceptor and $\beta$${}_1$ adrenoreceptor stimulation${}_{,}$ though the latter is less in number in blood vessels, promotes vasoconstriction, whereas the norepinephrine mediated $\beta$${}_2$ adrenoreceptor stimulation promotes vasodilation. As the $\alpha$${}_1$ adrenoreceptors predominate over $\beta$${}_2$ adrenoreceptors in the blood vessels, vasoconstriction remains the primary vascular response of norepinephrine. As the $\beta$${}_1$ adrenoreceptors (predominantly in the heart) and $\beta$${}_2$ adrenoreceptors (predominantly in the vascular tree) have greater affinity for epinephrine compared to norepinephrine, the $\beta$${}_2$ adrenoreceptor mediated vasodilatation remains the primary vascular response of epinephrine at lower doses [27]. However, at high doses, epinephrine may attach to the $\alpha$${}_1$ adrenoreceptors in the blood vessels resulting in vasoconstriction [21].

The $\beta$${}_1$ adrenoceptors are instrumental for autonomic regulation of the heart and are found in the sinoatrial (SAN) and atrioventricular (AVN) nodes as well as in both the atrial and the ventricular cardiomyocytes [21, 27]. They function through increasing the intracellular calcium concentration, calcium release from the sarcoplasmic reticulum, and by increasing the AVN conduction velocity. Concomitant $\beta$${}_1$ adrenoceptor-mediated renin release by the kidneys supports the blood pressure, plasma sodium levels and the blood volume [27].

Catecholamine excess states have been implicated in the pathogenesis of various types of cardiomyopathies including tachycardia-related cardiomyopathy, HCM, DCM, and TCM. The catecholamine excess may also aggravate pre-existing cardiac conditions in patients with phaeochromocytoma [28, 29, 30, 31]. Fig. 1 summarizes the major pathophysiological mechanisms of catecholamine-induced cardiomyopathy. Cardiomyocyte remodelling following sustained catecholamine excess leads to the development of different types of CICMPs. Acute excessive adrenergic stimulation may result in overstimulation of $\beta$${}_1$ adrenoceptors leading to an increase in oxygen demand in the heart leading to hypoxia in some areas [21]. Acute excessive adrenergic stimulation may also result in severe vasoconstriction including epicardial coronary artery vasospasm, myocardial ischaemia, and irreversible damage and necrosis [21, 32].

Fig. 1.

Major pathophysiological mechanisms of catecholamine-induced cardiomyopathy. Catecholamine excess states are associated with supply-demand imbalance, myocardial stunning ad cardiac dysfunction. Catecholamine excess states are associated with formation of oxidation products and reactive oxygen species resulting in cardiomyocyte apoptosis, necrosis, and cardiac remodelling by fibrosis. Finally, catecholamine excess states are also associated with impaired $\beta$ adrenoreceptor signalling and impaired myocardial contractility.

Prolonged exposure to raised catecholamine levels leads to blunting of the $\beta$ adrenoceptor response to catecholamines, and consequently a desensitisation of the heart to further inotropic stimulation [21, 28]. Fig. 2 (Ref. [33]) displays the proposed mechanisms for $\beta$${}_1$ and $\beta$${}_2$ adrenergic receptor desensitisation. Desensitisation is mediated by adrenergic receptor phosphorylation via G protein coupled receptor kinases (GRKs), followed by binding to the protein $\beta$-arrestin2. GRK2/$\beta$-arrestin2 facilitate uncoupling of G protein from $\beta$${}_1$ adrenoreceptor and internalisation of $\beta$${}_1$ adrenoreceptor. Similarly, GRK2/$\beta$-arrestin2 facilitate uncoupling of G protein from $\beta$${}_2$ adrenoreceptor, internalisation of $\beta$${}_2$ adrenoreceptor, and a switch from Gs to Gi in $\beta$${}_2$ adrenoreceptor. The $\beta$${}_2$ adrenoreceptor-Gi coupling results in decreased cardiac contractility [33].

Fig. 2.

Proposed mechanism for $\beta {}_{\mathrm{𝟏}}$ and $\beta {}_{\mathrm{𝟐}}$ adrenergic receptor desensitisation (Left half physiological and right half pathological state) [33]. Binding of catecholamines to $\beta$${}_1$ and $\beta$${}_2$ adrenoreceptors results in GRK2 mediated phosphorylation and $\beta$-arrestin2 binding. GRK2/$\beta$-arrestin2 facilitate uncoupling of G protein from $\beta$${}_1$ adrenoreceptor and internalisation of $\beta$${}_1$ adrenoreceptor. GRK2/$\beta$-arrestin2 also facilitate uncoupling of G protein from $\beta$${}_2$ adrenoreceptor, internalisation of $\beta$${}_2$ adrenoreceptor, and a switch from Gs to Gi in $\beta$${}_2$ adrenoreceptor.

The Gs to Gi switch is described only with $\beta$${}_2$ adrenoreceptors, not with $\beta$${}_1$. Moreover, the switch happens only with epinephrine excess, not with norepinephrine excess [34]. Epinephrine activates both Gs and Gi pathways (Gs at lower and Gi at higher concentrations), whereas norepinephrine activates only the Gs pathway through $\beta$${}_2$ adrenoceptors [35]. Moreover, affinity of norepinephrine towards $\beta$${}_2$ adrenoceptor is 20-fold lower than towards $\beta$${}_1$ adrenoreceptor [35]. Catecholamine storms caused by epinephrine-secreting phaeochromocytomas are more commonly associated with TCM in comparison to norepinephrine-secreting and dopamine-secreting PPGLs [36]. Although the Gs to Gi switch via $\beta$${}_2$ adrenoreceptor is mechanically detrimental by impairing the cardiac contractility, it protects the heart against $\beta$${}_1$ adrenoreceptor mediated proapoptotic and proarrhythmogenic effect of catecholamine excess [37]. GRK2 and $\beta$-arrestin regulate the secretion of catecholamines in the adrenal medulla, suggesting a GRK2/$\beta$-arrestin-mediated crosstalk between adrenal and heart [38, 39]. Polymorphisms in $\beta$${}_1$ adrenergic receptors are implicated in causing heart failure, likely secondary to their effect on the sympathetic nervous system [40].

Catecholamines produce a direct toxic effect on the myocardium by increasing the sarcolemmal permeability and cellular calcium influx [28, 31]. These deleterious effects of catecholamine excess are mediated by the oxidation products of catecholamines rather than catecholamines per se [41]. Under physiological conditions catecholamines are metabolized mainly by catechol-O-methyl transferase and monoamine oxidase pathways. However, under conditions of catecholamine excess, these pathways are overwhelmed and the catecholamines (epinephrine released from adrenal medulla and norepinephrine released from sympathetic nerve endings) undergo oxidation to form aminochromes (active metabolite) and aminoleutins (inactive metabolite). The oxidation of catecholamines into aminochromes and aminoleutins are associated with the generation of reactive oxygen species (ROS) [41]. The oxidative stress resulting from the ROS molecules together with the aminochromes leads to calcium handling abnormalities inside the cardiomyocytes including high calcium permeability through the sarcolemma and low calcium uptake by the sarcoplasmic reticulum (SR) [42]. The resultant increase in myocardial cytosolic and mitochondrial calcium levels causes mitochondrial dysfunction, depletion of energy stores, and augments the ROS generation culminating in myocardial apoptosis, necrosis, with/without fibrosis. Similarly, the raised intracellular calcium levels mediated by the aminochromes inside the vascular smooth muscle cells results in coronary spasm, myocardial ischaemia, ventricular arrhythmias, and contractile dysfunction [43].

Catecholamine-mediated myocardial stunning has been implicated in the pathogenesis of TCM. The name TCM came from the shape of cardiac apex that resembles ‘takotsubo’, a conical Japanese pot used for catching octopus. Inverted TCM with apical sparing has also been described [44, 45]. In the mammalian left ventricle (LV), there is an apical-basal gradient for $\beta$ adrenoreceptors and sympathetic nerve density [46]. The LV apex has the highest $\beta$ adrenoreceptor density, and the lowest sympathetic nerve density. On the other hand, the LV base has the lowest $\beta$ adrenoreceptor density, which explains the hyperkinetic base that occurs in the classic TCM. The apical hypokinesia and ballooning is explained by the fact that the Gs to Gi switch of $\beta$${}_2$ adrenoceptors predominantly happen at LV apex leading to decreased contractility and myocardial stunning [46].

In contrast to the above theory of epinephrine mediated Gs to Gi switch, a systematic review and meta-analysis of 156 published case reports of TCM patients where the TCM was induced by exogenous epinephrine, exogenous norepinephrine, or endogenous catecholamine (PPGL) did not find any direct causal relation between epinephrine and TCM [47]. However, epinephrine excess was found to have an indirect effect via hyperactivation of the sympathetic nervous system (SNS) which in turn leads to disruption in cardiac sympathetic nerve terminals with norepinephrine spillover [48, 49]. This would explain the multifocal histological changes (contraction band necrosis) and patchy cardiac MRI changes seen in PPGL-related CICMPs [50]. Moreover, the SNS hyperactivation can explain the LV basal hypokinesia seen in inverted TCM.

Excess catecholamines that are released directly into the myocardium via sympathetic nerve terminals are more toxic in comparison to the excess catecholamines reaching the myocardium via blood stream [50]. Increased cardiac SNS activity, increased norepinephrine synthesis/release, decreased norepinephrine reuptake by the terminal nerve axons, increased sensitivity to catecholamines, myocardial ischaemia due to epicardial coronary artery spasm, and transient LV outflow tract obstruction have all been suggested as possible pathophysiologic mechanisms for TCM [51, 52, 53, 54]. Additionally, oestrogen-induced downregulation of the adrenergic receptors of the heart may also have a role, as TCM is more common in postmenopausal women [53, 55].

PPGLs are rare catecholamine-secreting neuroendocrine tumours arising from either the adrenal gland or the extra-adrenal chromaffin cells of autonomic neural ganglia. The annual incidence of phaeochromocytoma has been estimated as 3–8 cases per million per year in general population, and it occurs in less than 0.5% of patients with hypertension [56, 57]. The frequency can be higher in those with adrenal incidentalomas, where up to 4.2% can have PPGL [58]. Phaeochromocytomas can be sporadic or familial. Sporadic forms usually present between the ages of 40–50 years, whereas the hereditary forms including multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1), von Hippel-Lindau syndrome (VHL), and succinate dehydrogenase (SDH) subunit B, C and D mutations (SDHB, SDHC, and SDHD, respectively), usually present in childhood or early adulthood [59]. The hereditary PPGLs related to VHL mutations secrete norepinephrine, SDH mutations secrete dopamine and norepinephrine, whereas RET mutations (MEN2A) secrete norepinephrine and epinephrine [60].

These tumours secrete catecholamines including epinephrine, norepinephrine, and dopamine. Phaeochromocytomas arising from the adrenal medulla accounts for nearly 80–85%, whereas the paragangliomas arising from autonomic neural ganglia account for 15–20% of PPGL [60]. While normal adrenals predominantly secrete epinephrine, majority of PPGLs predominantly secrete norepinephrine with only about 15% secreting predominantly epinephrine [61]. The PPGLs predominantly secreting dopamine are rare and these are malignant PPGLs in which the dopamine decarboxylase enzyme is missing [62]. Usual presenting features of PPGL include the classical triad (headache, hyperhidrosis, and palpitation), tachycardia, tremor, anxiety, pallor, chest pain, dyspnea, and sometimes local tumoral symptoms like abdominal pain, although many patients can be asymptomatic. Hypertension is present in nearly 95% of patients with PPGL, with sustained hypertension noted in 55% and episodic hypertension in 45% [63].

The PPGLs predominantly secreting norepinephrine presents with sustained hypertension, those predominantly secreting epinephrine presents with episodic hypertension, and those predominantly secreting dopamine presents with no hypertension [61]. Fluctuating hypertension with cyclic bouts of hypertension and hypotension is well described in phaeochromocytoma patients possibly due to spontaneous infarction of the tumour during the phaeochromocytoma crisis [64, 65, 66, 67]. The proposed mechanisms for spontaneous necrosis include catecholamine-induced vasoconstriction, embolic infarction, haemorrhage into the tumour, high intracapsular pressure, or antihypertensive therapy induced hypotension [67]. Hypertension can be absent in PPGL patients, and the various proposed mechanisms include secretion of dopamine as the predominant catecholamine, conversion of catecholamines into inactive metabolites within the tumour itself, secretion of other molecules together with catecholamines - including vascular endothelial growth factor that suppresses catecholamine action, reduction in sensitivity of receptors to catecholamine, or significant reduction in cardiac function due to CICMP [68].

Cardiovascular complications of phaeochromocytomas include left ventricular hypertrophy, ACS including myocardial infarction, acute pulmonary oedema, myocarditis, cardiac arrythmias, cardiomyopathies, thromboembolism, and shock [21, 57, 69]. Based on the cardiac remodelling in response to the endogenous catecholamine excess, PPGL patients might present with either one of the three types of CICMPs, including DCM, HCM, or TCM [70]. DCM characterised by congestive cardiac failure, pulmonary oedema or cardiogenic shock associated with diffuse left ventricular or even biventricular dysfunction can be one of the presenting manifestations of PPGL [71]. DCM can occur spontaneously or can occur after initiation of $\beta$ blockade [71, 72]. The DCM can be transient in most cases with early detection/appropriate resection [73] or can be chronic/progressive with late detection [74]. Obstructive HCM can be another presenting manifestation in cases of undiagnosed PPGL due to long standing hypertension [30, 75]. Furthermore, a picture of apical HCM of the Japanese type (in electrocardiography and echocardiography) is also described in PPGL patients [76]. HCM improves after surgical resection of the PPGL [75, 76].

TCM patients often present with acute chest pain, acute severe heart failure, dynamic ST-T changes, elevated cardiac biomarkers, and left ventricular regional wall motion abnormalities (RWMA) in a circumferential apical, midventricular, or basal distribution, without evidence of significant CAD on coronary angiographic studies [77]. Thus, TCM closely mimics ACS and hence these patients are often misdiagnosed and treated as ACS. Nearly 1–3% of all patients presenting with suspected ST-segment elevation myocardial infarction has in fact TCM [77]. The diagnostic hallmark of TCM is the reversibility of cardio depression occurring within weeks of initial presentation [57].

The clinical picture of TCM associated with PPGL and that not associated with PPGL are quite divergent. Nearly two-thirds of TCM patients associated with PPGL develop cardiac complications in comparison to only one-fifth of TCM patients without PPGL. The TCM-PPGL patients are associated with higher recurrence rate (17.7% vs 3.26%). These patients are younger (fourth or fifth decade). The TCM localisation pattern was different in TCM-PPGL patients, with the basal pattern contributed to almost 1/3 of cases and global pattern contributed to 1/5 of the cases [78]. The contributions of TCM-PPGL to apical, mid-ventricular, basal, and global TCM patterns were 43.9%, 5.6%, 26.2%, and 20.6%, whereas the corresponding contributions of TCM cases in general were 81.7%, 14.6%, 2.2%, and 0% respectively [47]. When compared to the classical TCM pattern, the inverted TCM that was commonly seen in TCM-PPGL was associated with higher complication rates, including, cardiogenic shock, heart failure, acute renal failure, and arrhythmias. This higher complication rates could be related to the higher levels of circulating catecholamines in TCM-PPGL patients. Moreover, the precipitating factors are often not clear in TCM-PPGL patients [79].

A catecholamine crisis or phaeochromocytoma multisystem crisis is a rare, acute, severe complication of catecholamine-induced haemodynamic compromise and collapse [80]. The term ‘type A crisis’ is used to describe a more limited crisis without sustained hypotension, whereas ‘type B crisis’ is used to describe a severe presentation with sustained hypotension, shock and multi-organ dysfunction [45]. Fever can be present in a minority of cases without a focus of sepsis, possibly related to secretion of interleukin-6 by the tumour [81, 82, 83]. Phaeochromocytoma crisis can mimic other conditions leading to misdiagnosis and phaeochromocytomas are often found as an incidental finding on imaging performed for an alternative diagnosis [44, 84]. Nearly 11% of phaeochromocytoma patients required in-hospital treatment on intensive care units due to complications caused by unsuspected phaeochromocytomas [85]. Phaeochromocytoma-crisis is associated with an overall mortality of 15%, with a higher (28%) mortality in those developing ‘type B crisis’ compared to those developing ‘type A crisis’ (6%) [45].

The diagnosis of CICMP is often delayed due to atypical presentations. In a study on 163 PPGL patients with CICMP, hypertension was the presenting symptom only in 65% of patients [86]. Among the various CICMP subgroups, hypertension was common with DCM (83%), and HCM (80%), compared to TCM. The classical PPGL triad of headache, sweating, and palpitation was present in only 4% of patients. Among the subgroups, the classical triad was common in HCM patients, whereas the DCM patients commonly presented with congestive heart failure [86]. Hence, CICMP should be suspected in all cardiomyopathy patients that is non-ischaemic, and non-valvular, even in those without definite features of catecholamine excess. Similarly, PPGL associated TCM should be suspected in all ACS patients exhibiting pronounced blood pressure variability with no culprit lesions on coronary angiography. The diagnosis is important as surgical removal of PPGL would improve CICMP in 96% of cases. Moreover, if not undergoing surgical resection, the disease would lead to mortality or cardiac transplantation in 44% of cases [86].

Consider possibility of catecholamine-induced cardiomyopathy when a known PPGL patient presents with symptoms of heart failure, hypotension, and multisystem crisis [21]. However, the diagnosis of CICMP can often be missed initially in patients who are not already known to have a phaeochromocytoma [87]. Fig. 3 (Ref. [60]) shows an algorithm for the diagnostic workup of PPGL. In asymptomatic patients, the phaeochromocytoma often comes to light whilst investigating for an adrenal incidentaloma with non-contrast computed tomography (CT) with an attenuation value of more than 10 Hounsfield units ($>$10 HU). Elevated levels of plasma free metanephrines, and urinary fractionated metanephrines are required for biochemical confirmation, as outlined in the 2014 Endocrine Society Clinical Practice Guidelines [87]. Urinary fractionated metanephrines has a comparable sensitivity to that of plasma free metanephrines (97% vs 99%), but the specificity of urinary fractionated metanephrines is lower than that of plasma free metanephrines [88].

Fig. 3.

An algorithm for the diagnostic workup of phaeochromocytoma and paraganglioma [60]. This algorithm should be used in the evaluation of people who are either symptomatic for PPGL or who are asymptomatic, but with presence of adrenal incidentaloma, hypertension in young non-obese people, or hereditary predisposition for PPGL. Abbreviations: PPGL, Phaeochromocytoma and Paraganglioma; ULN, Upper Limit of Normal; CT, Computed Tomography; ${}^{123}$I-MIBG, ${}^{123}$I metaiodobenzylguanidine; ${}^{18}$F-FDOPA, ${}^{18}$F-fluorodihydroxyphenylalanine; ${}^{18}$F-FDG, ${}^{18}$F-fluorodeoxyglucose; ${}^{68}$Ga-DOTA-SSA, ${}^{68}$Gallium-labeled somatostatin analog.

The 2016 European Endocrine Society guidelines recommend the addition of 3-methoxytyramine (the dopamine metabolite) in the initial screening panel for the diagnosis and follow-up of patients with PPGLs [89]. The addition of 3-methoxytyramine along with free metanephrines would improve the sensitivity (97.2% vs 98.6%) but reduce the specificity (95.9% vs 95.1%) [90]. The dopamine producing malignant PPGLs are not missed with this addition. The 2016 European Endocrine Society guidelines also recommend using plasma chromogranin as a screening tool in cases with a clinical probability for PPGL once plasma free metanephrines and 3-methoxytyramine are negative [89]. Plasma and urinary catecholamines and urine vanillylmandelic acid (VMA) are less often used currently because of suboptimal sensitivities and specificities [60].

Cardiac failure due to any cause would be associated with catecholamine release, with a likely consequent rise in plasma metanephrine levels. As metanephrine levels are not yet validated in patients with cardiac failure, routine use of serum fractionated metanephrines or urinary free metanephrines in all cardiomyopathy patients would result in significantly high false-positive results [91]. These tests should be used only when the pre-test probability of CICMP is high. The factors that increase the pre-test probability of CICMP include younger age at diagnosis of cardiomyopathy; genetic diseases associated with PPGL (MEN2, NF1, VHL, SDH); patients with symptoms suggestive of PPGL including classical PPGL triad; blood pressure (sustained, episodic, or fluctuating blood pressure); inverted TCM (with higher risk for cardiogenic shock, heart failure, acute renal failure, and arrhythmias); and adrenal incidentalomas with radiological features of phaeochromocytoma [91].

These patients with clinical features suggestive of PPGL or CICMP should undergo anatomical localisation studies using computed tomography (CT) or magnetic resonance imaging (MRI) after the initial step of biochemical confirmation. CT should be the first-choice imaging modality because of its excellent spatial resolution for thorax, abdomen, and pelvis. However, MRI is recommended in patients with residual/recurrent/metastatic PPGL, for detection of skull base and neck paragangliomas, in patients with surgical clips that could cause artifacts when using CT, in patients with an allergy to CT contrast, and in patients in whom radiation exposure should be limited (children, pregnant women, those with known germline mutations, and those with recent excessive radiation exposure) [87].

The anatomical imaging should be followed by functional imaging. The Iodine-123-tagged MIBG (metaiodobenzylguanidine) scintigraphy can detect tumours that were undetected by CT or MRI and is useful to establish the diagnosis of PPGL in cases where tumours were already detected on anatomical imaging [92]. The ${}^{123}$I-MIBG scintigraphy is not useful in subjects with SDH mutations. On the other hand, 18F-fluorodeoxyglucose positron emission tomography CT scanning (${}^{18}$F-FDG PET/CT) is very useful due to Warburg effect: impairment of mitochondrial function due to loss of SDH function causes the tumour cells to shift from oxidative phosphorylation to aerobic glycolysis [93]. Similarly, the ${}^{18}$F-FDG PET/CT is the preferred functional imaging over ${}^{123}$I-MIBG scintigraphy in patients with metastatic PPGL. Genetic testing is recommended in all patients with phaeochromocytoma [87].

Electrocardiogram (ECG) and 2-dimensional echocardiogram should be performed in all cases of suspected or confirmed PPGL/CICMP. Electrocardiographic changes range from unremarkable, sinus tachycardia, wandering pacemaker, and repolarisation ECG changes. The latter include ST-segment elevation, ST-segment depression, peaked T-waves, or giant inverted T-waves. The ST-segment elevation with giant inverted T-waves is seen in apical TCM, whereas ST-segment depression with peaked T-waves is seen in basal TCM [69]. The echocardiographic features of different CICMPs are given in Table 1 [21, 94]. In TCM, echocardiography helps to identify the pattern and extent of disease. In other CICMPs, echocardiography helps to assess mechanical complications including dynamic LV outflow tract obstruction, with or without systolic anterior motion of the anterior mitral leaflets, and/or functional mitral valve regurgitation.

Coronary angiogram and cardiac MRI should be performed in selected cases with cardiovascular involvement [87]. Left ventriculography performed during coronary angiogram should not be considered as the sole investigation to assess the myocardial function, as right ventricle (RV) could be involved in one-fourth of the TCM cases [95]. Cardiac Magnetic Resonance (CMR) can differentiate TCM from myocarditis and ischaemic cardiomyopathy. CMR in patients with TCM exhibits high-intensity signal on T2-weighted images in a transmural distribution, without significant late gadolinium enhancement, in regions with wall motion abnormalities. Occasionally, the CMR in TCM patients might show areas of myocarditis, focal fibrosis as small foci of late gadolinium enhancement [96].

PPGL was one of the exclusion criteria for the diagnosis of TCM as per the Mayo Clinic criteria that has been used historically [97]. However, in 2018 the Heart Failure Association-European Society of Cardiology (HFA-ESC) TCM task force developed an international takotsubo diagnostic criteria, which is also known as InterTAK Diagnostic Criteria, wherein PPGL was included as the secondary cause of TCM [77]. An InterTAK diagnostic score can be calculated as given in Table 2. Patients with symptoms suggestive for an ACS, however, with no ST-elevations in the ECG, but with high probability of TCM should undergo screening using the InterTAK Diagnostic Score. If the score is positive with $>$70 points, echocardiography should be done. If echocardiographic features are suggestive of TCM, a CT coronary angiography should be done. On the other hand, patients achieving $\le$70 points should undergo coronary angiography with left ventriculography [98]. These recommendations from HFA-ESC TCM task force is displayed in Fig. 4.

Fig. 4.

Algorithm for the diagnosis of Takotsubo cardiomyopathy as per HFA-ESC TCM task force [98].

High index of suspicion and prompt diagnosis is important for a favourable outcome from this potentially fatal condition. The diagnosis should be considered in all patients presenting with acute cardiomyopathy and cardiogenic shock without a clear ischaemic or valvular aetiology [99]. The diagnosis should be confirmed immediately as several medications including dopamine D2 receptor antagonists, $\beta$ adrenergic receptor blockers, sympathomimetics, opioid analgesics, tricyclic antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, corticosteroids, peptides and neuromuscular blocking agents are implicated in adverse reactions in patients with phaeochromocytoma and can precipitate or worsen a crisis [87, 100, 101].

The initial management of phaeochromocytoma crisis should be in a setting where expertise and access to mechanical circulatory support is available. Stabilisation of blood pressure with $\alpha$ adrenoceptor blockers followed by $\beta$ adrenoceptor blockers and surgical resection of the phaeochromocytoma is the cornerstone of treatment. Retrospective studies have shown that selective $\alpha$${}_1$ adrenergic receptor blockers were associated with lower preoperative diastolic pressure, a lower intraoperative heart rate, better postoperative haemodynamic recovery, and fewer adverse effects such as reactive tachycardia and sustained postoperative hypotension than nonselective adrenergic blockers. In patients presenting with phaeochromocytoma crisis, use of $\alpha$ adrenoceptor blockade is associated with significantly lesser mortality of 40% compared to 99% in those without use of $\alpha$ adrenoceptor blockade [44].

The $\beta$ adrenoceptor blockers should be added after appropriate $\alpha$ adrenoceptor blockade to control the tachycardia [87, 102]. Failure to optimise $\alpha$ adrenoceptor blockade prior to $\beta$ adrenoceptor blocker initiation can result in hypertensive crisis (due to unopposed $\alpha$ receptor stimulation) and worsening of the haemodynamic instability. Patients should have medical treatment for 7–14 days to allow adequate time to normalize blood pressure and heart rate prior to surgery [94]. An algorithm for the management of PPGL is given in Fig. 5.

Fig. 5.

An algorithm for the management of phaeochromocytoma and paraganglioma [60]. Laparoscopic adrenalectomy, either conventional or robot-assisted, is the gold standard technique for adrenalectomy in tumors 6 cm. However, open adrenalectomy is the preferred technique I those with tumors $\ge$6 cm, for multifocal PPGL, those with high risk of malignancy including PGL. Abbreviations: ${}^{131}$I-MIBG, ${}^{131}$I metaiodobenzylguanidine; PRRT, Peptide Receptor Radionuclide Therapy; TACE, Transarterial Chemoembolisation; PEI, Percutaneous Ethanol Injection.

In patients with acute decompensated cardiomyopathy, phentolamine given as intravenous bolus or infusion is preferred because of its short half-life and rapid reversal of adverse effects. Phenoxybenzamine, which has a half-life of 24 hours, can be started once haemodynamic stability has been achieved [94]. Doxazosin is a competitive $\alpha$${}_1$ selective blocker and is therefore theoretically less appropriate than phenoxybenzamine. However, a sequential study of 35 patients with phaeochromocytoma reported that doxazosin (2–16 mg/day) provided safe, efficacious preoperative/perioperative control of arterial pressure, causing fewer side-effects, and allowing more rapid postoperative recovery of adrenoceptor function versus phenoxybenzamine. Co-administration of $\beta$ adrenoceptor antagonists to control the heart rate was not required except in patients with known epinephrine-secreting tumours [103]. Calcium channel blockers can be added to optimise blood pressure control if $\alpha$ adrenoceptor blockers alone are not adequate. However, monotherapy with calcium channel blockers is not recommended unless patients have very mild preoperative hypertension or have severe orthostatic hypotension with $\alpha$ adrenergic receptor blockers [87].

Management of patients presenting with acute heart failure requires adequate diuretics, but this is often complicated by hypotension due to intravascular volume depletion or systolic heart failure [21]. Indiscriminate use of inotropes and vasopressors should be avoided as they precipitate a phaeochromocytoma-crisis and may cause cardiogenic shock by causing LV outflow tract obstruction. Hence these drugs should be initiated judiciously, utilizing the lowest possible dose in patients with CICMP and hypotension. Fluid status needs to be monitored carefully and intra-arterial balloon counter-pulsation, the Impella system, the TandemHeart device or veno-arterial extra-corporeal membrane oxygenation (VA ECMO) can be considered in refractory cases of catecholamine crisis associated with hypotension [44, 104, 105, 106, 107, 108]. Severe hypotension may occur once the tumour is resected, which might result from the abrupt cessation of catecholamine secretion and depleted blood volume.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers may have a role in managing heart failure in patients with phaeochromocytoma. Clinical signs of congestive heart failure may resolve within two weeks following treatment with captopril. Myocardial performance can also become normal within two weeks of medical therapy, with one week with captopril monotherapy and with another week with captopril-phenoxybenzamine combination therapy [109]. Proposed mechanisms include the inhibition of the cardiac renin-angiotensin axis and inhibition of free radicals from long chain fatty acids described in phaeochromocytoma [110, 111]. Orthostatic hypotension in combination with sustained hypertension has been reported to be a feature in 10–50% of the individuals with phaeochromocytoma [112]. Treatment should primarily focus on restoring circulating volume. Mineralocorticoids should not be administered in patients with phaeochromocytoma [100, 101].

In summary, there is no specific treatment approach for the management of patients with CICMP. The preoperative management of CICMP should include control of blood pressure variability by lowering sympathetic activation with the help of $\alpha$ and $\beta$ adrenergic blockade, maintenance of adequate blood volume, diuretics administration in case of volume overload, and the use of left ventricular assist devices in refractory cases of catecholamine crisis related with hypotension [113]. These preoperative management together with optimal anaesthetic techniques can minimise the perioperative haemodynamic instability (modifiable). However, factors like size of the tumour, location of the tumour, association with genetic syndromes, and secretory activity of the tumour are the nonmodifiable factors that can result in perioperative haemodynamic instability [114].