Rare Metabolic and Endocrine Diseases with Cardiovascular Involvement: Insights from Cardiovascular Magnetic Resonance – A Review

Abstract

The identification of rare diseases with cardiovascular involvement poses significant diagnostic challenges due to the rarity of the diseases, but also due to the lack of knowledge and expertise. Most of them remain underrecognized and undiagnosed, leading to clinical mismanagement and affecting the patients’ prognosis, as these diseases are per definition life-threatening or chronic debilitating. This article reviews the cardiovascular involvement of the most well-known rare metabolic and endocrine diseases and their diagnostic approach through the lens of cardiovascular magnetic resonance (CMR) imaging and its prognostic role, highlighting its fundamental value compared to other imaging modalities.

Key words

cardiovascular magnetic resonance - rare endocrine and metabolic diseases - storage diseases - fabry disease - pheochromocytoma, hypertension - growth hormone

Introduction

A rare disease is defined as a condition that affects a small percentage of the population and is either life-threatening or chronic debilitating, and combined efforts are required to treat it. In terms of prevalence, there is no universal definition, as the numbers are affected by the size of each country’s population, and even after adjustment it varies from 1 to 8 in 10 000 people [1]. Thus, in the USA it is defined as a disease that affects less than 200 000 people, in Japan less than 50 000, and in Australia less than 2000 [2]. According to the European Public Health Commission, the prevalence of rare diseases is estimated at 1:2000 [3]. Rare diseases are more than 8000, while about 30 million people are affected in Europe and 300 million worldwide [4].

The rarity of the diseases, but also the lack of knowledge and expertise make them a special entity, the treatment of which requires combined action with wide cooperation of many specialties and diagnostic approaches of all nations, so that there is a coordination of treatment at European level. Data for rare diseases are limited, especially those derived from cardiovascular magnetic resonance (CMR) imaging, as investigators struggle with limited patient data and scarce funding for research. Besides, small sample sizes are inevitable, especially when the primary end point is also uncommon and heterogeneity in the natural history of the disease and geographic dispersion also play an important role.

The goals of this paper are to review the applications of CMR in the spectrum of cardiovascular involvement of the most well-known rare metabolic and endocrine diseases and to suggest further methodological approaches, which can contribute to an early diagnosis and treatment of the disease.

Main Body

1) Storage diseases

Fabry disease

The superiority of CMR in terms of accuracy in the evaluation of cardiac structure and function in relation to echocardiography is well known, but what makes it unique, especially in infiltrative cardiomyopathies, such as Fabry disease, is its ability to characterize myocardial tissue [5].

Left ventricular hypertrophy (LVH) remains a key feature in Fabry disease, which requires extensive characterization. Primarily, cine sequences allow accurate measurement of left ventricular wall and mass and papillary muscles, ventricular volumes, left and right ventricular ejection fraction, and assessment of wall motion abnormalities. Data from recent years have demonstrated the importance of accurately calculating the left ventricular and papillary muscle mass, as patients undergoing enzyme replacement therapy have had a smaller increase in left ventricular mass [6], and the presence of disproportionate papillary muscle hypertrophy is also characteristic of the disease [7] [8]. CMR can detect cardiac involvement in almost one-half of the genotype-positive patients, even when the LVH severity is mild [9]. In addition, patients with elevated left ventricular mass index (LVMi) are more likely to have ventricular arrhythmias, as shown by Deva et al. [10]. In a study by Vijapurapu et al., LVMi correlated with impairment of all systolic strain parameters as well [11].

Myocardial tissue is characterized mainly by the method of late gadolinium enhancement (LGE) following intravenous administration of gadolinium and typically presents midmyocardial fibrosis in the basal and midventricular inferior-lateral wall of the left ventricle [9] [12] [13] [14]. However, atypical patterns of late enhancement in the basal anteroseptal and apical segment have also been observed in patients with asymmetric hypertrophy of the interventricular septum or with apical hypertrophy respectively [10] [11]. In addition, cases of patients with intramural and subepicardial LGE have been reported [15]. Finally, in advanced stages of the disease, late enhancement may be extensive and diffuse [10]. Interestingly, Niemann et al. showed that the onset of late enhancement may precede hypertrophy, especially in women [16]. Another study from Taiwan demonstrated that severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations was also seen in a large portion of men with the IVS4 mutation, suggesting that it might be too late to start ERT after the occurrence of LVH or other significant cardiac manifestations in patients with late onset FD [17]. Furthermore, the prevalence of FD in patients with unexplained LGE has been reported as 2.5% [18]. Recently, a strong association between the amount of late enhancement and cardiovascular events (arrhythmias, severe heart failure, cardiac death) has been suggested, demonstrating the importance of CMR in risk stratification in patients with Fabry disease [19].

As far as the role of CMR in monitoring response to therapy in FD patients is concerned, LV mass regression has only been demonstrated in AFD patients with either baseline LVH [19] or little or no LGE at baseline [20] [21] [22] [23] [24]. These findings suggest that treatment of Fabry disease with ERT should be started early before the development of myocardial fibrosis. Besides, it has been shown that myocardial fibrosis in Fabry disease is progressive, and not modified by ERT [25].

The characterization of myocardial tissue, however, is complemented by the new parametric mapping techniques. These techniques allow the quantification of changes in the composition of the myocardium, based on the relaxation times T1, T2, T2*, and the extracellular volume by the addition of contrast agent [26]. Multiple studies have shown T1 mapping to be useful to differentiate patients with Fabry disease from other pathogeneses with increased wall thickness regardless of the sequence used [27] [28] [29] [30]. The relaxation time T1 is typically very low (6 standard deviations lower than normal), even in the absence of hypertrophy [28] [29] [31] [32] [33]. This is more prominent in female patients, as the disease manifests in later stages. Therefore, this method contributes significantly to the differential diagnosis, as other diseases that present with left ventricular hypertrophy have a high relaxation time T1, except for athletes’ heart. However, in this case there is a relatively small drop in T1 (up to only 2 standard deviations) [34]. Besides, the reduction of T1 relaxation time is not observed globally, since the basal posterior wall may have a high T1 time as part of the fibrosis and the surrounding segments may be normal. In any case, Deborde et al. demonstrated the importance of the value of T1 mapping for the identification of fibrosis foci, as it can be used in a large percentage of patients with Fabry disease and renal dysfunction without administration of gadolinium [35]. In addition, Réant et al. showed that T1 value along with other parameters was significantly predictive of occurrence of de novo atrial fibrillation or stroke in these patients [36]. A recent study by Nordin et al. demonstrated that, although T1 values remained within normal limits, the values decreased with increasing age, reflecting a subclinical increase in sphingolipid accumulation in the myocardium. Furthermore, males demonstrated a more rapid decrease in T1 with age, which was then seen to increase after the development of LVH; women had a less rapid decrease in T1 and on the development of LVH demonstrated stabilization of T1 values [37]. Finally, another study presented that native T1 values correlated stronger with LV mass than CMR-derived GLS, emphasizing the potential use of native T1-mapping in the early detection of cardiac involvement and guidance of therapy timing [38].

Of interest, however, is the increase in T2 relaxation time observed in the basal posterior wall, as a surrogate marker of inflammation [39] [40] [41], while a reduction in T2 relaxation time has been correlated with the reversal of left ventricular mass in patients undergoing enzyme replacement therapy, which makes the method useful for monitoring the course of treatment [6] [42]. Specifically, Augusto et al. showed that when LGE was present, there were significant associations between increased T2 values in the LGE segments, an increase of troponin and N-terminal pro-B-type natriuretic peptide, electrocardiographic changes, and GLS impairment, whereas persistent T2 and troponin elevation over 1 year suggested chronic myocardial edema and injury, with associated clinical deterioration [41]. In addition, in some patients, myocardial edema increased together with LVH [42]. Another study showed that in up to 56% of patients with Fabry disease myocarditis was detectable at histology. It was immune mediated, correlated with disease severity and contributed to disease progression and ERT resistance [43]. Finally, as the extracellular volume mainly reflects extracellular interstitial disease, it may miss intracellular lysosomal storage until diffuse fibrosis occurs [28].

Three stages of cardiac involvement have been proposed based on analysis of native T1 times, LVH, and LGE in a large cohort of patients with Fabry disease spanning all ages of life: 1) storage stage with normal or low native T1 times without LVH; 2) inflammation and myocyte hypertrophy with low native T1 times, presence of LGE with or without LVH; and 3) fibrosis and impairment with pseudonormalization of native T1 times and extensive LGE [39].

The technique of myocardial deformation, namely the newest feature tracking technique that does not require the acquisition of new sequences, but arises from the already obtained SSFP cine images, has also been proposed as a tool in the diagnostic quiver of Fabry disease. However, there is discrepancy regarding the strain values, maybe due to the different stages of the disease. Mathur et al. demonstrated that loss of base-to-apex circumferential strain gradient may be an early marker of cardiac involvement in Fabry disease, with independent and incremental value beyond native T1 [44]. Wilson et al. resulted in more positive CS values (CS) in patients with LVH [45], whereas Augusto et al. showed only a subtle impairment of GLS [46]. Recently, Zhao et al. presented that global longitudinal strain (GLS) was reduced significantly in all Fabry patients, while GCS was reduced only in patients with LVH or with LGE and heart failure [47]. The reduced GLS and global radial strain (GRS) were also confirmed in a recent study, which showed that GLS initially reduces with storage (low native T1 times and elevated LysoGb3 level, a specific biomarker of Fabry disease) and later with increasing LysoGb3 level and hypertrophy or scar (LGE) [48].

Regarding the myocardial perfusion imaging, positron emission tomography (PET) studies have showed coronary microvascular dysfunction, regardless of sex or the presence of left ventricular hypertrophy, with no improvement after enzyme replacement therapy [49] [50]. CMR data of recent years have shown a decrease in myocardial blood flow in the dynamic phase of the exam (myocardial blood flow) by the method of perfusion mapping, mainly subendocardial, with a greater reduction in patients with left ventricular hypertrophy, oedema and scar [51]. However, a reduction in perfusion was observed even in patients without left ventricular hypertrophy, thus making this sequence an early indicator of the disease [49] [51]. The same authors reported stress MBF to be lower in the endocardial than in the epicardial layers, but normal in controls. This was only in the subgroup with LVH. Indeed, in patients without any LVH, no difference between epicardial and endocardial stress MBF was detected. Besides, the presence of microvascular dysfunction before the onset of left ventricular hypertrophy has also been observed in hypertrophic cardiomyopathy [51] [52].

In conclusion, CMR with the new techniques it offers, plays a fundamental role in every stage of the course of Fabry disease, even in its early diagnosis.

Glucogen storage diseases (Pompe disease, Danon disease, Cori-Forbes disease, Anderson disease) and PRKAG2 syndrome

Given the rarity of the glucogen storage diseases, there is limited data regarding CMR. In the adult-form of Pompe disease (late-onset Pompe disease), a study has found that patients have normal ventricular dimensions and volumes in cine sequences, while a few have a non-ischemic late enhancement (LGE) or increased extracellular volume (ECV). The myocardial deformation feature tracking technique did not show any pathological changes in this group of patients. Therefore, the changes observed are mild and non-specific [53]. In a smaller study, CMR was performed in a subgroup of 12 patients with late-onset Pompe disease and no myocardial LGE was detected; how many patients underwent CMR, and cardiovascular comorbidities were not reported [54]. Otherwise, there are data from some case reports; a case of isolated severe nonischemic cardiomyopathy with an infiltrative process and heart failure [55], as well as a myocardial infiltration in a 54-year-old sportsman presented with syncope [56].

In contrast, patients with Danon’s disease and PSKAG2 syndrome appeared to have a higher T1 relaxation time and extracellular volume (ECV), as well as late gadolinium enhancement, compared to patients with hypertrophic cardiomyopathy [57]. In particular, the pattern of late gadolinium enhancement in patients with Danon’s disease is non-ischemic subendocardial or patchy and was observed mainly in the anterior/lateral/inferior wall of the midventricular or midventricular/apical myocardium or in the right ventricular insertion points, but not between them or in the interventricular septum [57] [58] [59] [60] [61] [62], whereas a patchy midmyocardial LGE was documented in a case report with Danon’s disease [63]. Case reports referred to the presence of apical hypertrophy with subendocardial patchy LGE, which was an atypical finding in apical HCM without an apical aneurysm or in an apical transmural pattern [60] [64]. Although data regarding the phenotype of Danon disease have disproportionately focused on the severe findings in men because women appear to be less severely affected, a study showed a severe arrhythmogenic phenotype in women that includes a high risk of sudden death [65]. Of great interest is also the presence of perfusion deficits in the resting first-pass perfusion in almost all segments, partially transmural in the lateral and anterior ones [59] [60].

In the case of PSKAG2 syndrome, diffuse, concentric left ventricular hypertrophy is characteristic. However, asymmetric and eccentric forms of hypertrophy have also been observed [66] [67]. In addition to the already mentioned higher T1 relaxation time and extracellular volume (ECV) that characterize PSKAG2 syndrome, late enhancement (LGE) is observed globally subendocardial, subepicardial, and midmyocardial or patchy [57] [66] [68] [69]. T2 relaxation time has not been reported to show any significant changes [66]. Patients with late gadolinium enhancement required pacemaker implantation or had myocardial infarction [56] [68] [70]. Besides, extensive LGE in patients with hypertrophic cardiomyopathy has been shown to be an independent prognostic indicator for sudden cardiac death or appropriate ICD discharges [71]. Therefore, it has been proposed to be used as risk marker for sudden cardiac death and other adverse outcomes in patients with PSKAG2 syndrome [69].

Regarding Anderson disease or glycogenosis IV, a recent case report was presented with biventricular failure and increased right ventricular trabeculation with the presence of thrombus without evidence of late gadolinium enhancement [72].

Mucopolysaccharidoses

Cardiac involvement has been reported in all seven types of mucopolysaccharidoses as a common and early manifestation, especially in patients with MPS I, II and VI [73]. Valve thickening with dysfunction mainly of the left-sided valves and hypertrophy are characteristic [74]. Conduction abnormalities, coronary artery stenosis or obstruction, and stenosis or dilatation of the ascending aorta may also occur [75]. Heart disease occurs silently and contributes significantly to early mortality. In a retrospective case study of children with various forms of the disease, left ventricular hypertrophy and diastolic dysfunction occurred at an early stage, while left ventricular dilatation and systolic dysfunction occurred at older ages and in later stages of the disease [76].

Although data are scarce, CMR has been suggested, as the coexisting Pectus excavatum does not allow for optimal echogenicity. In a case report, normal left ventricular ejection fraction with paradoxical septal motion and dilated right ventricle with reduced ejection fraction were observed in the cine sequences. Valve pathologies were also observed, such as stiffened posterior mitral leaflet, while valve diseases were further characterized in the flow sequences. No late enhancement was observed [77]. However, the use of stress perfusion in these patients is also applicable, as they present a diffuse pattern of coronary heart disease [75]. In addition, since the disease is characterized by pathologies of large vessels, the application of magnetic angiography may also provide important clinical information.

Gaucher Disease

The cardiovascular form of Gaucher disease is characterized mainly by the presence of calcifications in the aortic and mitral valve [78], whereas cases of recurrent pericarditis [79] and dilated cardiomyopathy with reduced ejection fraction have been reported as well [80].

Although cardiovascular involvement is rare, there are CMR references. In a study of nine patients no late gadolinium enhancement was observed [81], while in one case report biatrial dilatation and dilatation of the right ventricle with preserved ejection fraction were observed, while the dimensions of the left ventricle were normal with normal ejection fraction and without hypertrophy. In addition, thickening of mitral leaflets was observed. Late gadolinium enhancement (LGE) sequences showed patchy intra-myocardial hyperenhancement with multiple foci in the basal and middle LV inferior and inferolateral segments, consistent with interstitial infiltrative fibrosis [82]. In fact, following these findings, the patient’s enzyme replacement therapy was increased. The characteristic concomitant hepatosplenomegaly was also observed during the exam.

Therefore, CMR can play a role in the assessment of cardiac involvement in Gaucher disease and treatment, as high doses of enzyme replacement therapy have been shown to improve the symptoms of heart failure and left ventricular ejection fraction [83].

2) RASopathies

RASopathies are a group of genetic disorders caused by mutations in Ras/mitogen-activated protein kinase (RAS-MAPK) waterfall, including Noonan Syndrome, Noonan syndrome with multiple lentigines, capillary malformation–arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. In all diseases of this category, congenital heart defects mainly include hypertrophic cardiomyopathy and pulmonary valve stenosis. In particular, there is a higher degree of ventricular hypertrophy, and a more severe pattern of obstruction of the left ventricular outflow tract (LVOT) compared to non-syndromic forms [84]. Biventricular involvement is often described, due to the high prevalence of right ventricular hypertrophy. Myocardial ischemia is also common and is a major clinical problem in young adolescents [85]. Besides, coronary artery abnormalities have been reported in up to 30% of patients [86].

Noonan syndrome typically presents with asymmetric septal hypertrophy, often obstructive, although isolated cases of apical hypertrophy have been reported [87] [88]. Also, pulmonary valve stenosis, and congenital heart disease such as atrial septal defect, atrioventricular canal, and rarely Fallot tetralogy, patent ductus arteriosus and mitral valve abnormalities are common [89]. Vascular abnormalities have been also described, mainly aortic dissection, aortic root dilatation and Valsalva sinus aneurysms [89].

In Noonan syndrome with multiple lentigines mitral valve prolapse is common, whereas atrial septal defect, non-compacted myocardium, and coronary artery anomalies have been reported [86]. Costello syndrome typically presents with subaortic septal hypertrophy, while concentric left ventricular hypertrophy and biventricular hypertrophy have been described [90]. In the case of cardio-facio-cutaneous syndrome, subaortic septal hypertrophy has also been observed in isolated cases.

Primarily, cine sequences demonstrate left ventricular hypertrophy with increased cardiac mass and any large atrial or atrioventricular septal defects. The presence of their hemodynamic importance, but also the assessment of valvular disease can be achieved with the flow sequences. In addition, important information can be extracted from the planimetry of the heart valve orifices.

In the late gadolinium enhancement (LGE) sequence, the presence of a patchy form of gadolinium enhancement in the anterior/anterior septal and lateral walls has been reported [91]. Another case report showed septal LVH, severe LA-dilatation secondary to severe mitral regurgitation and LGE in the antero- and infero-septal myocardial segments, as well as in the papillary muscles [92]. Finally, an 18-year-old girl presented with progressive ascending aortic aneurysm with histopathologically confirmed giant cell aortitis [93] and the reveal of double-chambered right ventricle in an adult patient with undiagnosed Noonan syndrome has also been reported [94]. Consequently, the use of angiography or whole heart sequences is recommended in order to rule out any coexisting congenital heart disease.

3) Endocrine disorders

Pheochromocytoma

Although the most common cardiovascular manifestation is hypertension, patients with pheochromocytoma may develop arrhythmias, hypotension, myocardial ischemia, cardiomyopathy, aortic dissection, peripheral ischemia, and shock [95]. In addition, excessive stimulation of catecholamines has been shown to lead to damage, manifested as Takotsubo or inverted Takotsubo cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and myocarditis [96] [97] [98] [99] [100] [101] [102] [103] [104] [105].

Specifically, left ventricular systolic function may be normal or reduced [101] [102] [103]. However, the reduced systolic function is transient, as improvement has been observed after surgical treatment of pheochromocytoma. Left ventricular hypertrophy is not bigger than that seen in hypertensive patients and resolves with surgery as well. Pericardial effusion is also observed. The sequence of myocardial deformation feature tracking is also interesting, as global circumferential strain (GCS) and diastolic strain are reduced in these patients, and they remain reduced even in operated patients with normal left ventricular ejection fraction [101].

The late gadolinium enhancement (LGE) method sometimes detects a small localized myocardial fibrosis in a non-ischemic pattern (midwall, subendocardial or patchy) with no increase in follow-up [101] [102].

Furthermore, the mapping technique can reveal myocardial lesions that are not seen in other sequences. Specifically, T1 relaxation time is increased compared to both healthy and hypertensive individuals [104], and in fact while it relapses with treatment [106], it sometimes remains high compared to normal [101]. Furthermore, basal, but not apical, circumferential strain was significantly higher in the patients with catecholamine-producing tumors compared to patients with essential hypertension [104]. In T2 mapping, there is an increase in T2 relaxation time, reflecting the presence of diffuse myocardial edema that subsides after surgery [102] [107].

As some patients present with symptoms of acute coronary syndrome without obstructive coronary artery disease findings on coronary angiography [108] [109], applying a stress perfusion sequence may rule out significant obstructive coronary heart disease, unless patients have significant risk factors for coronary heart disease or objective evidence of acute myocardial infarction [110]. In many cases, CMR plays a key role in order to eliminate other potential causes of regional LV systolic dysfunction, providing a comprehensive evaluation of both ventricles, and supporting the final diagnosis of the etiology. For example, in case reports, the presentation of phaeochromocytoma was as a biventricular Takotsubo cardiomyopathy [111] or Takotsubo cardiomyopathy and hypertrophic cardiomyopathy [112]. Two reports presented cases of myocarditis with T1 and T2 elevation with no evidence of LGE, where CMR revealed a pheochromocytoma [113] [114]. Another case report referred to the presence of asymptomatic pheochromocytoma in a patient with Holt – Oram syndrome, where CMR showed dilated right heart chambers with moderately severe RV systolic dysfunction, a patent RV-PA conduit with mild conduit regurgitation and extensive LGE of the RV myocardium and interventricular septum [115]. Finally, there is a report referring to a cardiac pheochromocytoma presenting during pregnancy; the tumor was in the right atrioventricular (AV) groove in the RCA (right coronary artery) territory, closely attached to the myocardium with LGE at its core [116].

Early recognition of different clinical symptoms that indicate this diagnosis is of great importance in the successful treatment of cardiomyopathy caused by pheochromocytoma. CMR allows an accurate diagnosis of cardiomyopathy and can monitor patients, as early recurrence of the disease can be detected even if patients are asymptomatic [110].

Growth hormone deficiency (GHD)

Growth hormone deficiency patients have been shown to have a normal or decreased left ventricular mass index (LVMi) [117] [118] [119] [120], which increases one year after replacement therapy [117] [118]. On the contrary, in another study LVM was greater than in normal subjects, even when corrected for the body surface area [121]. The authors explained this difference due to higher blood pressure in the patients with GHD than in the normal subjects. Decreased left right ventricular stroke volume index, LV end-diastolic volume index and end-systolic volume index, as well as reduced ascending aortic diameter have also been reported [117] [119]. Although cardiac fibrosis is not a typical feature of the disease, isolated cases of late gadolinium enhancement (LGE) have been reported, which nevertheless were eventually attributed to ischemic heart disease [117].

As subjects with growth hormone deficiency have high cholesterol levels and therefore a higher risk of cardiovascular disease [122] or myocardial ischemia [117], further investigation is possible with the application of the stress perfusion sequence.

Acromegaly

In patients with acromegaly, dilatation of heart cavities, hypertrophy, and normal or reduced ejection fraction [123] [124] [125] [126] [127] [128] are observed, while most of these changes are reversed with surgical treatment of the disease [124]. Interestingly, these changes are more pronounced in men than in women [125]. In this study right ventricle systolic dysfunction and mid-wall late gadolinium enhancement of the IVS and of the basal anterior LV myocardium were also demonstrated. Reported differences in the extent of LVMi or LVEF are maybe due to different degree of development and ethnicities of the enrolled patients (e. g., Asian vs. Caucasian). Another study showed that patients with acromegaly have increased myocardial T2 values, which decrease soon after treatment, reflecting reversible myocardial edema. The authors suggested that T2 value is more sensitive than left ventricular mass index in the detection of early reversal of acromegalic cardiomyopathy [129]. Finally, in a case report, acromegaly presented as dilatative cardiomyopathy with patchy LGE [130].

A tabular survey of studies of CMR in patients with rare metabolic and endocrine diseases with cardiovascular involvement is presented in [Table 1].

Table 1 Summary of studies of CMR in patients with rare metabolic and endocrine diseases with cardiovascular involvement.

Disease	Investigators [Ref] and Study Design	Number of cases	Comparator	Findings
Fabry Disease (FD)	Imbriaco M et al. [6], Prospective observational study	11	None	LV mass and LV wall thickness were significantly reduced after 45 months of ERT, no significant change in LVEF
	Kozor R et al. [7], Prospective observational study	20	20 healthy control individuals	Inclusion of papillary muscles & trabeculations in LV mass contributed to a greater percentage of LVM in Fabry subjects
	Kozor R et al. [8], Retrospective observational study	478	125 Fabry disease, 85 hypertrophic cardiomyopathy (HCM), 67 amyloid, 82 aortic stenosis (AS), 40 hypertension, 79 controls	Disproportionate hypertrophy of LVPMs in FD, regardless of LVH. Low T1 not always present
	Kozor R et al. [9], Prospective observational study	50	39 healthy control individuals	Detection of cardiac involvement in 48% of the FD cohort, despite the overall mild disease phenotype. Of those not on ERT, 21% were reclassified as having cardiac involvement allowing improved risk stratification and targeting of therapy
	Deva DP et al. [10], Retrospective observational study	39	None	Concentric LVH, inferolateral mid-myocardial scar the most common manifestations of FD, but apical and asymmetrical of forms of LVH having more apical and mid-ventricular LV scar than cases with concentric thickening also observed. Patients with elevated LVMi had a greater incidence of ventricular arrhythmia
	Vijapurapu R et al. [11],Cross-sectional, international multicenter study	166	None	Low T1 in LVH patients, no significant correlation between LVEF – LVMi; LVMi correlated with impairment of all systolic strain parameters
	Moon J et al. [12], Prospective observational study	26	None	In 92% of the patients, LGE was seen in the basal infero-lateral wall and was not sub-endocardial. 50% of the male patients had LGE and its percentage was related to LVMi but not to EF or LV volumes
	De Cobelli F et al. [13], Retrospective observational study	13	10 patients with symmetric HCM, matched for age (7 males)	FD patients with LVH consistently showed LGE in the inferolateral basal or mid basal segments in a mesocardial distribution sparing the subendocardium
	Nojiri A et al. [14], Prospective observational study	26	None	LGE localized at the mid-wall in the infero-lateral area of LV. LGE-positive patients were older, and tended to have a larger LVMi
	Weidemann F et al. [15], Clinical cross-sectional study	39	25 healthy control individuals	31% (2 females, 10 males) of the FD patients had LGE in the inferolateral wall, two of them showed additional LGE in antero-septal segments. 23% had intramural and 7.7% had subepicardial LGE
	Niemann M et al. [16], Prospective observational study	104	None	LGE and loss of myocardial function can occur without LVH in females
	Hsu TR et al. [17], Prospective observational study	129	None	Severe, irreversible cardiac fibrosis before development of LVH was seen in a large portion of men with the IVS4 mutation
	Moonen A et al. [18], Retrospective observational study	79 patients with unexplained LGE	None	Prevalence of FD in patients with unexplained LGE was 2.5%; patchy mid-wall pattern in the inferoseptum
	Hanneman K et al. [19], Retrospective observational study	90	None	LVH and LGE were independent predictors of adverse cardiac events; patients with extensive LGE were at highest risk
	Arends M et al. [20], Retrospective observational study	73	None	Increased cardiac mass at baseline was associated with decrease in cardiac mass during treatment; presence of cardiac fibrosis predicted a stronger increase in cardiac mass
	Koeppe S et al. [21], Prospective observational study	25	43 healthy control individuals	Highest degree of hypertrophy and hypokinesia if LGE was detectable. Significant decrease of the EDWT under ERT in LGE negative patients and decline of hypokinesia with regional differences
	Weidemann F et al. [22], Prospective observational study	32	20 healthy control individuals	FD patients with mild or severe fibrosis showed a minor reduction in LVH despite ERT
	Beer M et al. [23], Prospective observational study	17	None	LGE was associated with increased LVM, failure of significant regression of LVH during ERT and worse segmental myocardial function
	Hughes DA et al. [24], Randomized, controlled study	15	None	ERT resulted in regression of LVH
	Krämer J et al. [25], Prospective observational study	57	None	In patients with established fibrosis, there is an increase in the degree of fibrosis despite ERT, as the only independent predictor of ventricular arrhythmias
	Walter TC et al. [27], Prospective observational study	25	14 patients with HCM, 21 healthy control individuals	T1 shortening in FD patients in a varying degree, segment-specific
	Thompson RB et al. [28], Prospective observational study	31	21 subjects with concentric remodeling or hypertrophy and 23 healthy controls	Reduced myocardial T1 values are the most sensitive and specific cardiovascular MRI parameter in patients with FD irrespective of sex and LV morphology and function
	Sado DM et al. [29], Prospective observational study	44	67 healthy volunteers, 41 patients with hypertension, 34 patients with HCM, 21 with severe aortic stenosis and 20 patients with definite amyloid light-chain (AL) cardiac amyloidosis	Septal T1 was lower in FD and higher in other diseases. Pseudonormalization or elevation of T1 was showed in the left ventricular inferolateral wall, correlating with the presence or absence of LGE
	Karur GR et al. [30], Prospective observational study	30	30 patients with HCM	Significantly lower native T1 values at 3.0 T in patients with FD compared with those with HCM - independent and incremental diagnostic value beyond age, sex, and conventional imaging features
	Pica S et al. [31], Prospective observational study	63	None	T1 reduction in FD happens prior to the onset of LVH and is associated with early diastolic and systolic changes measured by echocardiography
	Camporeale A et al. [32], Prospective observational study	44	None	In prehypertrophic FD, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but not associated with functional abnormalities
	Deborde E et al. [35], Prospective observational study	17	36 patients with HCM, 70 healthy control individuals	Significantly lower native T1 values in patients with FD in comparison with those with HCM and healthy volunteers
	Réant P et al. [36], Prospective observational study	35	20 healthy control individuals	T1 value was significantly predictive of occurrence of de novo atrial fibrillation or stroke in FD patients
	Nordin S et al. [37], Prospective observational study	182 (15 children)	None	T1 values remained within normal limits, but decreased with increasing age; more rapid decrease in T1 with age, which was then seen to increase after the development of LVH in males; less rapid decrease in T1 and stabilization of T1 values on the development of LVH in females
	Reid AB et al. [38], Prospective observational study	66	None	T1 values correlated stronger with LV mass than CMR-derived GLS
	Nordin S et al. [39], Prospective observational study	47	28 patients with HCM, 30 patients with chronic myocardial infarction, 60 healthy control individuals	Lower T1 values and lesser T1 elevation in LGE in FD patients, normal remote area T2, but elevated LGE T2
	Augusto JB et al. [41], Prospective observational multicenter study	186	29 patients with HCM, 30 patients with chronic myocardial infarction, 59 healthy control individuals	Chronic local T2 elevation in LGE in FD, strongly associated with chronic troponin elevation; slight global T2 elevation. Association with ECG and mechanical changes and clinical worsening over 1 year
	Messalli G et al. [42], Prospective observational study	16	None	ERT leads to significant reduction in T2, maximal myocardial thickness and total LV mass
	Frustaci A et al. [43], Retrospective observational study	78	None	Myocarditis histologically detectable in 56% of patients with FD, immune mediated, correlated with disease severity and contributed to disease progression and ERT resistance
	Mathur S et al. [44], Prospective observational study	38	8 healthy control individuals	Loss of base-to-apex CS gradient is an early marker of cardiac involvement in FD, with independent and incremental value beyond native T1
	Wilson HC et al. [45], Retrospective observational study	18	None	FD patients with LVH have reduced native T1 and more positive circumferential strain compared to those without
	Augusto JB et al. [46], Prospective observational study	114	76 healthy control individuals	Pre-LVH FD with normal T1 had reduced GLS, microvascular changes, subtle T2 elevation, limited LGE
	Zhao L et al. [47], Prospective observational study	20	20 healthy control individuals	GLS was reduced significantly in all Fabry patients, GCS was reduced only in patients with LVH or with LGE and heart failure
	Roller FC et al. [48], Prospective observational study	28	28 healthy control individuals	T1, GLS, and GRS were significantly reduced in FD patients. T1 and GLS were significantly lower in Lyso-Gb3 positive FD patients
	Elliott PM et al. [49], Prospective observational study	10	24 healthy control individuals	Resting and hyperemic MBF and CFR were reduced in FD patients compared with controls
	Knott KD et al. [50], Prospective observational study	44	27 healthy control individuals	FD patients have reduced perfusion, particularly in the subendocardium with greater reductions with LVH, storage, edema, and scar
Glucogen Storage Disease
Late-onset Pompe Disease	Boentert M et al. [53], Prospective observational study	17	18 healthy control individuals	Mild, non-specific cardiac abnormalities can be detected by CMR only in a small proportion of patients with late-onset Pompe disease
	Morris DA et al. [54], Prospective observational study	subgroup of 12 (not reported)	187 healthy control individuals	No evidence of myocardial fibrosis in late-onset Pompe disease
	Mori M et al. [55], Case report			Isolated severe nonischemic cardiomyopathy with infiltrative process and heart failure
	Walczak-Galezewska M [5], Case report			Isolated infiltrative cardiomyopathy with syncope
Danon Disease & PSKAG2 syndrome	Fang T et al. [57], Prospective observational study	2	None	Higher T1, ECV, and LGE in patients with Danon’s disease and PSKAG2 syndrome, compared to patients with HCM
	Dara BS et al. [58], Case reports	2	None	Patchy LGE in the lateral wall, and one or both RV insertion points in Danon’s disease
	Piotrowska-Kownacka D et al. [59], Case report			LGE in the anterior/lateral/apical segments, and RF inferior insertion point; first pass perfusion defects in Danon’s disease
	Tada H et al. [60], Case report			Subendocardial inferior LGE, intramyocardial lateral LGE and RF inferior insertion point
	Nucifora G et al. [61], Case reports	2		Subendocardial anterior, lateral, posterior LGE, transmural apical, IVS and RF inferior insertion point
	Rigolli M et al. [62], Prospective observational study	12	None	In males, LVH was typically concentric with normal LVEF. Females had impaired LVEF, asymmetrical LVH, RVH, and 2 different phenotypes: HCM or DCM. 3 patients showed no LGE. Various LGE patterns and distributions but always sparing the mid-septum. Extensive LGE consistently sparing the mid-septum may represent a specific sign of DD cardiomyopathy
	Vago H et al. [63], Case report			Patchy midmyocardial LGE in Danon’s disease
	Yu L. et al. [64], Case report			Apical hypertrophy with subendocardial patchy LGE in Danon’s disease
	Miani D et al. [65], Prospective comperative study	5 female patients	2 male patients	Severe arrhythmogenic phenotype in women with high risk of sudden death in Danon’s disease
	Pöyhönen P et al. [66], Prospective comperative study	6		At earlier stages of PSKAG2 syndrome, without LGE, T1 values may be reduced, while in the advanced disease stage T1 values are higher. Patchy LGE
	Fabris E et al. [67], Case report			Asymmetric LVH in PSKAG2 syndrome
	Yogasundaram H et al. [68], Case report			Patchy, subepicardial, midmyocardial LGE in PSKAG2 syndrome
	Yang KQ et al. [69], Prospective comparative study	6		Concentric LVH, subendocardial or transmural LGE in PSKAG2 syndrome
	Sternick EB et al. [70], Case report			Myocardial infraction in a teenager with PRKAG2 gene mutation
	Lyo S et al. [72], Case report			Severe biventricular failure with presence of intraventricular thrombi with increased RV-trabeculation and no LGE in heterozygous glycogen storage disease type IV
Mucopolysaccharidoses	Mostefa-Kara Μ et al. [77], Case report			Normal LVEF, paradoxical septal motion, dilated RV with reduced EF; valve pathologies, no LGE
Gaucher Disease	Roghi A et al. [81], Prospective observational study	9		Two patients with valvular disease, three patients with mild LA-enlargement, no LGE
	Solanich X. et al. [82], Case report			Biatrial dilatation,RV-dilatation with preserved EF, normal LV-dimensions and LVEF, no LVH; Patchy intra-myocardial LGE with multiple foci in the basal and middle LV inferior/inferolateral segments
Rasopathies	Hudsmith LE et al. [91], Case report			Patchy LGE in the anterior/anterior septal and lateral segments in a patient with Noonan syndrome
	O’Neill AC et al. [92], Case report			Septal LVH, severe LA-dilatation secondary to severe MR;LGE in the antero- and infero-septal myocardial segments and papillary muscles in Noonan syndorme
	Menon S et al. [93], Case report			Progressive aneurysmal dilatation of the ascending aorta with histopathologically confirmed giant cell aortitis in an 18-year old girl with Noonan syndrome
	Patel AM et al. (94), Case report			Reveal of double-chambered RV in an adult patient with Noonan syndrome
Pheochromocytoma	Ferrerira VM et al. [101], Prospective observational study	29	31 patients with previously surgically cured pheochromocytoma, 51 healthy control subjects and 14 hypertensive control subjects	In newly diagnosed pheochromocytoma impaired LVEF, peak systolic CS, diastolic strain rate, higher T1, areas of myocarditis and focal fibrosis (nonischemic LGE)
	Roghi A et al. [102], Case report			Myocardial edema and intramyocardial LGE in a middle-aged woman with non-specific clinical presentation suggesting ACS or subacute myocarditis. Resolution of both after surgical excision.
	De Lazzari M et al. [103], Case report			Heart failure (normal LV-dimensions and mild LVSD with akinesia of mid inferolateral wall and hypokinesia of mid anterolateral and inferior walls). Myocardial edema and midwall LGE in the inferolateral wall
	Higuchi S et al. [104], Retrospective observational study	16	16 patients with essential hypertension	Native T1 values and basal, but not apical, circumferential strain were significantly higher in the CPT than the EH patients
	Gervais MK et al. [105], Case report			Pheochromocytoma presenting as inverted Takotsubo cardiomyopathy and DCM
	Nam MCY et al. [106], Case report			Transient regional myocardial edema in endocrinopathy-Induced Takotsubo cardiomyopathy
	de Miguel V et al. [107], Case report			Catecholamine-induced myocarditis (increased LV wall thickness and diffuse intramyocardial edema with focal midwall LGE)
	Martínez A et al. [111], Case report			Biventricular Takotsubo Cardiomyopathy as the Initial Manifestation of a Pheochromocytoma
	Gravina M et al. [112], Case report			Pheochromocytoma mimicking Takotsubo cardiomyopathy and HCM
	Khattak S et al. [113], Case report			Myocarditis (T1 and T2 elevation, no evidence of LGE), where CMR revealed a pheochromocytoma
	Wong TS et al. (114), Case report			Catecholamine-mediated myocarditis complicated by LV thrombus
	Ng P et al. [115], Case report			Asymptomatic pheochromocytoma in a patient with Holt–Oram syndrome: dilated right heart chambers, moderately severe RVSD, patent RV-PA conduit with mild conduit regurgitation, extensive LGE of the RV myocardium and IVS
	Fraser LA et al. [116], Case report			Cardiac pheochromocytoma presenting during pregnancy; tumor located in the right atrioventricular groove in the right coronary artery territory, closely attached to the myocardium with LGE at its core
Growth hormone deficiency (GHD)	Thomas JD et al. [117], Prospective observational study	10	10 healthy control subjects	Trend towards reduced LVMi and significantly reduced aortic area observed in GHD patients at baseline; lost by 1 year of GH treatment. Fibrosis and ischemia in some patients
	Dattani A et al. [118], Prospective observational study	10	6 healthy control subjects	Patients with adult-onset GHD have an LVMi at or below the lower limit of normal, which improves with one year of GH replacement
	Andreassen M et al. [119], Prospective observational study	16	16 healthy control subjects	Patients had significantly smaller LVEDVi & LVESVi; GHD not associated with LVSD or reduced LVMI
	De Cobelli F et al. [120], Prospective observational study	15	15 healthy control subjects	Reduced LVM in patients with GHD without major structural/metabolic alterations
	Gonzalez S et al. [121], Double-blind, placebo-controlled randomized, cross-over trial	17	16 healthy control subjects	Patients with GHD had significantly higher systolic BP, EF, LVMi than the control group; treatment with rGH normalized the insulin-like growth factor 1 concentration failed to normalize the functional and structural cardiac differences
Acromegaly	Guo X et al. [124], Prospective observational study	50	None	LV and RV EF of acromegaly patients were higher than the healthy reference values. Male patients had thicker LV myocardia, wider ventricular diameters and more dilated pulmonary artery roots than female patients. Postoperative cardiac reversibility was observed in male but not in all female patients.
	Guo X et al. [125], Prospective observational study	61	None	LVH, LV, and RV systolic dysfunction and mid-wall LGE of the IVS and of the basal anterior LV myocardium. Gender might influence cardiac parameters via its impact on BMI
	Bogazzi F et al. [126], Prospective observational study	14	None	LVH present in 72% of the patients, which was only detected in 36% patients by echocardiography. Cardiac fibrosis was absent in all patients
	dos Santos Silva CM et al. [127], Prospective observational study	40	None	No clinically relevant differences in cardiac variables were observed before and after treatment, no difference in LVMi and LVEF among patients with and without disease control
	Warszawski L et al. [128], Prospective observational study	36	None	No sustained arrhythmias and lack of arrhythmia-related symptoms in a contemporary cohort of acromegaly patients with low frequency of structural heart changes
	Gouya H et al. [129], Prospective observational study	15	None	Increased T2 values in patients with acromegaly, which decrease soon after treatment, reflecting reversible myocardial edema. T2 value is more sensitive than LVMi in the detection of early reversal of acromegalic cardiomyopathy
	Kim MS et al. [130], Case report			Acromegaly presenting as dilatative cardiomyopathy with patchy LGE

Conclusion

Cardiovascular magnetic resonance through its ability to assess with great accuracy the anatomy, function, inflammation, (dynamic) perfusion of the myocardium, fibrosis, vascular structures, iron and/or fat deposition plays a key role in the early diagnosis of cardiac involvement, risk stratification, treatment evaluation, and long-term follow-up of patients with metabolic cardiomyopathy [131]. In the case of rare diseases specifically, its role should be considered fundamental, as it allows an early diagnosis of cardiovascular involvement, leading to the determination of the therapeutic strategy and affecting the patients’ prognosis.

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Aronson JK. Rare diseases and orphan drugs. Br J Clin Pharmacol 2006; 61: 243-245
• 2 Lavandeira A. Orphan drugs: legal aspects, current situation. Haemophilia 2002; 8: 194-198
• 3 Baldovino S, Moliner AM, Taruscio D. et al. Rare diseases in Europe: from a wide to a local perspective. Isr Med Assoc J 2016; 18: 359-363
• 4 Nguengang Wakap S, Lambert DM, Olry A. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020; 28: 165-173
• 5 Esposito R, Santoro C, Mandoli GE. et al. Cardiac imaging in Anderson-Fabry disease: past, present and future. J Clin Med 2021; 10: 1994
• 6 Imbriaco M, Pisani A, Spinelli L. et al. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: A prospective long-term cardiac magnetic resonance imaging study. Heart 2009; 95: 1103-1107
• 7 Kozor R, Callaghan F, Tchan M. et al. A disproportionate contribution of papillary muscles and trabeculations to total left ventricular mass makes choice of cardiovascular magnetic resonance analysis technique critical in Fabry disease. J Cardiovasc Magn Reson 2015; 17: 22
• 8 Kozor R, Nordin S, Treibel TA. et al. Insight into hypertrophied hearts: a cardiovascular magnetic resonance study of papillary muscle mass and T1 mapping. Eur Heart J Cardiovasc Imaging 2017; 18: 1034-1040
• 9 Kozor R, Grieve SM, Tchan MC. et al. Cardiac involvement in genotype-positive Fabry disease patients assessed by cardiovascular MR. Heart 2016; 102: 298-302
• 10 Deva DP, Hanneman K, Li Q. et al. Cardiovascular magnetic resonance demonstration of the spectrum of morphological phenotypes and patterns of myocardial scarring in Anderson-Fabry disease. J Cardiovasc Magn Reson 2016; 18: 14
• 11 Vijapurapu R, Nordin S, Baig S. et al. Characterisation of systolic myocardial strain in patients with fabry disease. Heart 2018; 104: 50
• 12 Moon JC, Sachdev B, Elkington AG. et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003; 24: 2151-2155
• 13 De Cobelli F, Esposito A, Belloni E. et al. Delayed-enhanced cardiac MRI for differentiation of Fabry’s disease from symmetric hypertrophic cardiomyopathy. AJR Am J Roentgenol 2009; 192: 97-102
• 14 Nojiri A, Anan I, Morimoto S. et al. Clinical findings of gadolinium-enhanced cardiac magnetic resonance in Fabry patients. J Cardiol 2020; 75: 27-33
• 15 Weidemann F, Breunig F, Beer M. et al. The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J 2005; 26: 1221-1227
• 16 Niemann M, Herrmann S, Hu K. et al. Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment. JACC Cardiovasc Imaging 2011; 4: 592-601
• 17 Hsu TR, Hung SC, Chang FP. et al. Later onset Fabry disease, cardiac damage progress in silence: experience with a highly prevalent mutation. J Am Coll Cardiol 2016; 68: 2554-2563
• 18 Moonen A, Lal S, Ingles J. et al. Prevalence of Anderson-Fabry disease in a cohort with unexplained late gadolinium enhancement on cardiac MRI. Int J Cardiol 2020; 304: 122-124
• 19 Hanneman K, Karur GR, Wasim S. et al. Left ventricular hypertrophy and late gadolinium enhancement at cardiac MRI are associated with adverse cardiac events in Fabry disease. Radiology 2020; 294: 42-49
• 20 Arends M, Biegstraaten M, Hughes DA. et al. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: analysis of prognostic factors. PLoS One 2017; 8: e0182379
• 21 Koeppe S, Neubauer H, Breunig F. et al. MR-based analysis of regional cardiac function in relation to cellular integrity in Fabry disease. Int J Cardiol 2012; 160: 53-58
• 22 Weidemann F, Niemann M, Breunig F. et al. Long-term effects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation 2009; 119: 524-529
• 23 Beer M, Weidemann F, Breunig F. et al. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry’s cardiomyopathy. Am J Cardiol 2006; 97: 1515-1518
• 24 Hughes DA, Elliott PM, Shah J. et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart 2008; 94: 153-158
• 25 Krämer J, Niemann M, Störk S. et al. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am J Cardiol 2014; 114: 895-900
• 26 Messroghli DR, Moon JC, Ferreira VM. et al. Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2*  and extracellular volume: a consensus statement by the society for cardiovascular magnetic resonance (SCMR) endorsed by the european association for cardiovascular imaging (EACVI). J Cardiovasc Magn Reson 2017; 19: 75
• 27 Walter TC, Knobloch G, Canaan-Kuehl S. et al. Segment-by-segment assessment of left ventricular myocardial affection in Anderson-Fabry disease by non-enhanced T1-mapping. Acta Radiologica 2017; 58: 914-921
• 28 Thompson RB, Chow K, Khan A. et al. T1 mapping with cardiovascular MRI is highly sensitive for Fabry disease independent of hypertrophy and sex. Circ Cardiovasc Imaging 2013; 6: 637-645
• 29 Sado DM, White SK, Piechnik SK. et al. Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 2013; 6: 392-398
• 30 Karur GR, Robison S, Iwanochko RM. et al. Use of myocardial T1 mapping at 3.0 T to differentiate Anderson-Fabry disease from hypertrophic cardiomyopathy. Radiology 2018; 288: 398-406
• 31 Pica S, Sado DM, Maestrini V. et al. Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2014; 16: 99
• 32 Camporeale A, Pieroni M, Pieruzzi F. et al. Predictors of clinical evolution in prehypertrophic Fabry disease. Circ Cardiovasc Imaging 2019; 12: e008424
• 33 Hagège A, Réant P, Habib G. et al. Fabry disease in cardiology practice: literature review and expert point of view. Arch Cardiovasc Dis 2019; 112: 278-287
• 34 Swoboda PP, McDiarmid AK, Erhayiem B. et al. Assessing myocardial extracellular volume by T1 mapping to distinguish hypertrophic cardiomyopathy from athlete’s heart. J Am Coll Cardiol 2016; 67: 2189-2190
• 35 Deborde E, Dubourg B, Bejar S. et al. Differentiation between Fabry disease and hypertrophic cardiomyopathy with cardiac T1 mapping. Diagn Interv Imaging 2020; 101: 59-67
• 36 Réant P, Testet E, Reynaud A. et al. Characterization of Fabry disease cardiac involvement according to longitudinal strain, cardiometabolic exercise test, and T1 mapping. Int J Cardiovasc Imaging 2020; 36: 1333-1342
• 37 Nordin S, Kozor R, Medina-Menacho K. et al. Proposed stages of myocardial phenotype development in Fabry disease. JACC Cardiovasc Imaging 2019; 12: 1673-1683
• 38 Reid AB, Miller CA, Jovanovic A. et al. Native T1 mapping versus CMR Feature Tracking (FT) derived strain analysis for the assessment of cardiac disease manifestation in Anderson Fabry. J Cardiovasc Magn Reson 2016; 18: 422
• 39 Nordin S, Kozor R, Bulluck H. et al. Cardiac Fabry disease with late gadolinium enhancement is a chronic inflammatory cardiomyopathy – evidence from multi parametric mapping by cardiovascular magnetic resonance. J Am Coll Cardiol 2016; 68: 1707-1708
• 40 Perry R, Shah R, Saiedi M. et al. The role of cardiac imaging in the diagnosis and management of Anderson-Fabry disease. JACC Cardiovasc Imaging 2019; 12: 1230-1242
• 41 Augusto JB, Nordin S, Vijapurapu R. et al. Myocardial edema, myocyte injury, and disease severity in Fabry disease. Circ Cardiovasc Imaging 2020; 13: e010171
• 42 Messalli G, Imbriaco M, Avitabile G. et al. Role of cardiac MRI in evaluating patients with Anderson-Fabry disease: assessing cardiac effects of long-term enzyme replacement therapy. Radiol Med 2012; 117: 19-28
• 43 Frustaci A, Verardo R, Grande C. et al. Immune-mediated myocarditis in Fabry disease cardiomyopathy. J Am Heart Assoc 2018; 7: e009052
• 44 Mathur S, Dreisbach JG, Karur GR. et al. Loss of base-to-apex circumferential strain gradient assessed by cardiovascular magnetic resonance in Fabry disease: Relationship to T1 mapping, late gadolinium enhancement and hypertrophy. J Cardiovasc Magn Reson 2019; 21(1): 45
• 45 Wilson HC, Ambach S, Madueme PC. et al. Comparison of native T1, strain, and traditional measures of cardiovascular structure and function by cardiac magnetic resonance imaging in patients with Anderson-Fabry disease. Am J Cardiol 2018; 122: 1074-1078
• 46 Augusto JB, Johner N, Shah D. et al. The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage. Eur Heart J Cardiovasc Imaging 2021; 790-799
• 47 Zhao L, Zhang C, Tian J. et al. Quantification of myocardial deformation in patients with Fabry disease by cardiovascular magnetic resonance feature tracking imaging. Cardiovasc Diagn Ther 2021; 11: 91-101
• 48 Roller FC, Brose A, Richter M. et al. Value of left ventricular feature tracking strain analysis for detection of early cardiac involvement in Fabry disease (FD). J Clin Med 2021; 10: 3734
• 49 Elliott PM, Kindler H, Shah JS. et al. Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A. Heart 2006; 92: 357-360
• 50 Knott KD, Augusto JB, Nordin S. et al. Quantitative myocardial perfusion in Fabry disease. Circ Cardiovasc Imaging 2019; 12: e008872
• 51 Tomberli B, Cecchi F, Sciagrà R. et al. Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. Eur J Heart Fail 2013; 15: 1363-1373
• 52 Petersen SE, Jerosch-Herold M, Hudsmith LE. et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation 2007; 115: 2418-2425
• 53 Boentert M, Florian A, Dräger B. et al. Pattern and prognostic value of cardiac involvement in patients with late-onset pompe disease: a comprehensive cardiovascular magnetic resonance approach. J Cardiovasc Magn Reson 2016; 18: 91
• 54 Morris DA, Blaschke D, Krebs A. et al. Structural and functional cardiac analyses using modern and sensitive myocardial techniques in adult Pompe disease. Int J Cardiovasc Imaging 2015; 31: 947-956
• 55 Mori M, Bailey LA, Estrada J. et al. Severe cardiomyopathy as the isolated presenting feature in an adult with late-onset Pompe disease: A Case Report. JIMD Rep 2017; 31: 79-83
• 56 Walczak-Galezewska M, Skrypnik D, Szulinska M. et al. Late-onset Pompe disease in a 54 year-old sportsman with an episode of syncope: a case report. Eur Rev Med Pharmacol Sci 2017; 21: 3665-3667
• 57 Fang T, Wang J, Kang Y. et al. The value of cardiac magnetic resonance imaging in identification of rare diseases mimicking hypertrophic cardiomyopathy. J Clin Med 2021; 10: 3339
• 58 Dara BS, Rusconi PG, Fishman JE. Danon disease: characteristic late gadolinium enhancement pattern on cardiac magnetic resonance imaging. Cardiol Young 2011; 21: 707-709
• 59 Piotrowska-Kownacka D, Kownacki L, Kuch M. et al. Cardiovascular magnetic resonance findings in a case of Danon disease. J Cardiovasc Magn Reson 2009; 11(1): 12
• 60 Tada H, Harimura Y, Yamasaki H. et al. Utility of real-time 3-dimensional echocardiography and magnetic resonance imaging for evaluation of Danon disease. Circulation 2010; 121: 390-392
• 61 Nucifora G, Miani D, Piccoli G. et al. Cardiac magnetic resonance imaging in Danon disease. Cardiology 2012; 121: 27-30
• 62 Rigolli M, Kahn AM, Brambatti M. et al. Cardiac magnetic resonance imaging in Danon disease cardiomyopathy. JACC Cardiovasc Imaging 2021; 14: 514-516
• 63 Vago H, Somloi M, Toth A. et al. Danon disease: a rare cause of left ventricular hypertrophy with cardiac magnetic resonance follow-up. Eur Heart J 2016; 37: 1703
• 64 Yu L, Wan K, Han Y. et al. A rare phenotype of heterozygous Danon disease mimicking apical hypertrophic cardiomyopathy. Eur Heart J 2018; 39: 3263-3264
• 65 Miani D, Taylor M, Mestroni L. et al. Sudden death associated with danon disease in women. Am J Cardiol 2012; 109: 406-411
• 66 Pöyhönen P, Hiippala A, Ollila L. et al. Cardiovascular magnetic resonance findings in patients with PRKAG2 gene mutations. J Cardiovasc Magn Reson 2015; 17: 89
• 67 Fabris E, Brun F, Porto AG. et al. Cardiac hypertrophy, accessory pathway, and conduction system disease in an adolescent: the PRKAG2 cardiac syndrome. J Am Coll Cardiol 2013; 62: e17
• 68 Yogasundaram H, Paterson ID, Graham M. et al. Glycogen storage disease because of a PRKAG2 mutation causing severe biventricular hypertrophy and high-grade atrio-ventricular block. Circ Heart Fail 2016; 9: e003367
• 69 Yang KQ, Lu CX, Zhang Y. et al. A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular pre-excitation. Sci Rep 2017; 7: 2407
• 70 Sternick EB, de Almeida Araújo S, Rocha C. et al. Myocardial infarction in a teenager. Eur Heart J 2014; 35: 1558
• 71 Chan RH, Maron BJ, Olivotto I. et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014; 130: 484-495
• 72 Lyo S, Miles J, Meisner J. et al. Case report: adult-onset manifesting heterozygous glycogen storage disease type IV with dilated cardiomyopathy and absent late gadolinium enhancement on cardiac magnetic resonance imaging. Eur Heart J Case Rep 2020; 4: 1-6
• 73 Zhou J, Lin J, Leung WT. et al. A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management. Intractable Rare Dis Res 2020; 9: 1-9
• 74 Fesslová V, Corti P, Sersale G. et al. The natural course and the impact of therapies of cardiac involvement in the mucopolysaccharidoses. Cardiol Young 2009; 19: 170-178
• 75 Braunlin EA, Harmatz PR, Scarpa M. et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis 2011; 34: 1183-1197
• 76 Leal GN, de Paula AC, Leone C. et al. Echocardiographic study of paediatric patients with mucopolysaccharidosis. Cardiol Young 2010; 20: 254-261
• 77 Mostefa-Kara Μ, Groote P, Abboud G. et al. Cardiac magnetic resonance imaging of mucopolysaccharidosis type II cardiomyopathy. Intern J Cardiol 2011; 147: 170-171
• 78 Abrahamov A, Elstein D, Gross-Tsur V. et al. Gaucher’s disease variant characterised by progressive calcification of heart valves and unique genotype. Lancet 1995; 346: 1000-1003
• 79 Benbassat J, Bassan H, Milwidsky H. et al. Constrictive pericarditis in Gaucher’s disease. Am J Med 1968; 44: 647-652
• 80 Smith RL, Hutchins GM, Sack GH. et al. Unusual cardiac, renal and pulmonary involvement in Gaucher’s disease. Intersitial glucocerebroside accumulation, pulmonary hypertension and fatal bone marrow embolization. Am J Med 1978; 65: 352-360
• 81 Roghi A, Poggiali E, Cassinerio E. et al. The role of cardiac magnetic resonance in assessing the cardiac involvement in Gaucher type 1 patients: morphological and functional evaluations. J Cardiovasc Med (Hagerstown) 2017; 18: 244-248
• 82 Solanich X, Claver E, Carreras F. et al. Myocardial infiltration in Gaucher’s disease detected by cardiac MRI. Int J Cardiol 2012; 155: 5-6
• 83 Spada M, Chiappa E, Ponzone A. Cardiac response to enzyme-replacement therapy in Gaucher’s disease. N Engl J Med 1998; 339: 1165-1166
• 84 Cerrato F, Pacileo G, Limongelli G. et al. A standard echocardiographic and tissue Doppler study of morphological and functional findings in children with hypertrophic cardiomyopathy compared to those with left ventricular hypertrophy in the setting of Noonan and LEOPARD syndromes. Cardiol Young 2008; 18: 575-580
• 85 Limongelli G, Pacileo G, Marino B. et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol 2007; 100: 736-741
• 86 Calcagni G, Gagliostro G, Limongelli G. et al. Atypical cardiac defects in patients with RASopathies: updated data on CARNET study. Birth Defects Res 2020; 112: 725-731
• 87 Monda E, Rubino M, Lioncino M. et al. Hypertrophic cardiomyopathy in children: pathophysiology, diagnosis, and treatment of non-sarcomeric causes. Front Pediatr 2021; 9: 632293
• 88 Nishikawa T, Ishiyama S, Shimojo T. et al. Hypertrophic cardiomyopathy in Noonan syndrome. Acta Paediatr Jpn 1996; 38: 91-98
• 89 Roberts AE, Allanson JE, Tartaglia M. et al. Noonan syndrome. Lancet 2013; 381: 333-342
• 90 Gripp KW, Lin AE. Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations. Genet Med 2012; 14: 285-292
• 91 Hudsmith LE, Petersen SE, Francis JM. et al. Hypertrophic cardiomyopathy in Noonan syndrome closely mimics familial hypertrophic cardiomyopathy due to sarcomeric mutations. Int J Cardiovasc Imaging 2006; 22: 493-495
• 92 O’Neill AC, McDermott S, Ridge CA. et al. Investigation of cardiomyopathy using cardiac magnetic resonance imaging part 2: Rare phenotypes. World J Cardiol 2012; 4: 173-182
• 93 Menon S, Pierpont ME, Driscoll D. Giant cell aortitis and Noonan syndrome. Congenit Heart Dis 2008; 3: 291-294
• 94 Patel AM, Kim JB, Roberts AE. et al. Double-chambered right ventricle in an adult with Noonan syndrome. Cardiol Rev 2006; 14: 16-20
• 95 Gu YW, Poste J, Kunal M. et al. Cardiovascular manifestations of pheochromocytoma. Cardiol Rev 2017; 25: 215-222
• 96 Zhang R, Gupta D, Albert SG. Pheochromocytoma as a reversible cause of cardiomyopathy: analysis and review of the literature. Int J Cardiol 2017; 249: 319-323
• 97 Y-Hassan S. Clinical features and outcome of pheochromocytoma-induced Takotsubo syndrome: analysis of 80 Published Cases. Am J Cardiol 2016; 117: 1836-1844
• 98 Di Valentino M, Balestra GM, Christ M. et al. Inverted Takotsubo cardiomyopathy due to pheochromocytoma. Eur Heart J 2008; 29: 830
• 99 Huddle KR, Kalliatakis B, Skoularigis J. Pheochromocytoma associated with clinical and echocardiographic features simulating hypertrophic obstructive cardiomyopathy. Chest 1996; 109: 1394-1397
• 100 Park JH, Kim KS, Sul JY. et al. Prevalence and patterns of left ventricular dysfunction in patients with pheochromocytoma. J Cardiovasc Ultrasound 2011; 19: 76-82
• 101 Ferreira VM, Marcelino M, Piechnik SK. et al. Pheochromocytoma Is characterized by catecholamine-mediated myocarditis, focal and diffuse myocardial fibrosis, and myocardial dysfunction. J Am Coll Cardiol 2016; 67: 2364-2374
• 102 Roghi A, Pedrotti P, Milazzo A. et al. Adrenergic myocarditis in pheochromocytoma. J Cardiovasc Magn Reson 2011; 13(1): 4
• 103 De Lazzari M, Cipriani A, Marra MP. et al. Heart failure due to adrenergic myocardial toxicity from a pheochromocytoma. Circ Heart Fail 2015; 8: 646-648
• 104 Higuchi S, Ota H, Ueda T. et al. 3T MRI evaluation of regional catecholamine-producing tumor-induced myocardial injury. Endocr Connect 2019; 8: 454-461
• 105 Gervais MK, Gagnon A, Henri M. et al. Pheochromocytoma presenting as inverted Takotsubo cardiomyopathy: a case report and review of the literature. J Cardiovasc Med (Hagerstown) 2015; 16: 113-117
• 106 Nam MCY, Di Marco A, Ausami A. et al. Demarcation of transient regional myocardial edema in endocrinopathy-induced Takotsubo cardiomyopathy on cardiac magnetic resonance T1 mapping. Can J Cardiol 2020; 36: 968
• 107 de Miguel V, Arias A, Paissan A. et al. Catecholamine-induced myocarditis in pheochromocytoma. Circulation 2014; 129: 1348-1349
• 108 Sanna GD, Talanas G, Fiore G. et al. Pheochromocytoma presenting as an acute coronary syndrome complicated by acute heart failure: The challenge of a great mimic. J Saudi Heart Assoc 2016; 28: 278-282
• 109 De Backer TL, De Buyzere ML, Taeymans Y. et al. Cardiac involvement in pheochromocytoma. J Hum Hypertens 2000; 14: 469-471
• 110 Santos JRU, Brofferio A, Viana B. et al. Catecholamine-induced cardiomyopathy in pheochromocytoma: how to manage a rare complication in a rare disease?. Horm Metab Res 2019; 51: 458-469
• 111 Martínez A, Gallo-Bernal S, Acosta SC. et al. Biventricular Takotsubo cardiomyopathy as the initial manifestation of a pheochromocytoma. CASE (Phila) 2021; 5: 363-367
• 112 Gravina M, Casavecchia G, D’Alonzo N. et al. Pheochromocytoma mimicking Takotsubo cardiomyopathy and hypertrophic cardiomyopathy: a cardiac magnetic resonance study. Am J Emerg Med 2017; 35: 353-355
• 113 Khattak S, Sim I, Dancy L. et al. Phaeochromocytoma found on cardiovascular magnetic resonance in a patient presenting with acute myocarditis: an unusual association. BMJ Case Rep. 2018 bcr2017222621
• 114 Wong TS, Bejar S, Michelin P. et al. MR imaging of catecholamine-mediated myocarditis complicated by left ventricular thrombus. Diagn Interv Imaging 2018; 99: 337-338
• 115 Ng P, Deepak D, Teo L. et al. Asymptomatic phaeochromocytoma in a patient with Holt-Oram syndrome: a case report. Eur Heart J Case Rep 2019; 3: 1-5
• 116 Fraser LA, Kiaii B, Shaban J. et al. Cardiac pheochromocytoma presenting during pregnancy. BMJ Case Rep. 2010 bcr0420102890
• 117 Thomas JD, Dattani A, Zemrak F. et al. Characterisation of myocardial structure and function in adult-onset growth hormone deficiency using cardiac magnetic resonance. Endocrine 2016; 54: 778-787
• 118 Dattani A, Thomas J, Zemrak F. et al. Cardiovascular changes in patients with adult-onset growth hormone deficiency assessed by CMR. J Cardiovasc Magn Reson 2012; 14: 192
• 119 Andreassen M, Faber J, Kjaer A. et al. Cardiac function in growth hormone deficient patients before and after 1 year with replacement therapy: a magnetic resonance imaging study. Pituitary 2011; 14: 1-10
• 120 De Cobelli F, Rossini A, Esposito A. et al. Short-term evaluation of cardiac morphology, function, metabolism and structure following diagnosis of adult-onset growth hormone deficiency. Growth Horm IGF Res 2019; 46-47: 50-54
• 121 Gonzalez S, Windram JD, Sathyapalan T. et al. Effects of human recombinant growth hormone on exercise capacity, cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency. J Int Med Res 2017; 45: 1708-1719
• 122 de Boer H, Blok GJ, Voerman HJ. et al. Serum lipid levels in growth hormone-deficient men. Metabolism 1994; 43: 199-203
• 123 Ramos-Leví AM, Marazuela M. Cardiovascular comorbidities in acromegaly: an update on their diagnosis and management. Endocrine 2017; 55: 346-359
• 124 Guo X, Cao Y, Cao J. et al. Reversibility of cardiac involvement in acromegaly patients after surgery: 12-month follow-up using cardiovascular magnetic resonance. Front Endocrinol (Lausanne) 2020; 11: 598948
• 125 Guo X, Cao J, Liu P. et al. Cardiac abnormalities in acromegaly patients: a cardiac magnetic resonance study. Int J Endocrinol 2020; 2018464
• 126 Bogazzi F, Lombardi M, Strata E. et al. High prevalence of cardiac hypertophy without detectable signs of fibrosis in patients with untreated active acromegaly: an in vivo study using magnetic resonance imaging. Clin Endocrinol (Oxf) 2008; 68: 361-368
• 127 dos Santos Silva CM, Gottlieb I, Volschan I. et al. Low frequency of cardiomyopathy using cardiac magnetic resonance imaging in an acromegaly contemporary cohort. J Clin Endocrinol Metab 2015; 100: 4447-4455
• 128 Warszawski L, Kasuki L, Sá R. et al. Low frequency of cardiac arrhythmias and lack of structural heart disease in medically-naïve acromegaly patients: a prospective study at baseline and after 1 year of somatostatin analogs treatment. Pituitary 2016; 19: 582-589
• 129 Gouya H, Vignaux O, Le Roux P. et al. Rapidly reversible myocardial edema in patients with acromegaly: assessment with ultrafast T2 mapping in a single-breath-hold MRI sequence. AJR Am J Roentgenol 2008; 190: 1576-1582
• 130 Kim MS, Choi HW, Seo YS. et al. Dilated cardiomyopathy in acromegaly: a case report with cardiac MR findings. Investig Magn Reson Imaging 2019; 23: 395-400
• 131 Mavrogeni S, Markousis-Mavrogenis G, Markussis V. et al. The emerging role of cardiovascular magnetic resonance imaging in the evaluation of metabolic cardiomyopathies. Horm Metab Res 2015; 47: 623-632

Publication History

Received: 16 February 2022

Accepted after revision: 08 May 2022

Accepted Manuscript online:
08 May 2022

Article published online:
13 June 2022