Intramyocardial calcification in apical hypertrophic cardiomyopathy assessed using multimodality imaging: a case series

Abstract

Apical hypertrophic cardiomyopathy (ApHCM) is an HCM variant, affecting frequently males in midlife. It is characterized by apical obliteration and persistent diastolic contraction, often resulting in microvascular ischaemia. We report five cases of ApHCM, with evidence of intramyocardial calcification on echocardiogram. On cardiac magnetic imaging (MRI), a hypointense component at early gadolinium enhancement (EGE) sequences, compatible with calcium, and a deep layer, with hyperintensity at late gadolinium enhancement (LGE) sequences, referable to fibrosis, suggest an endomyocardial fibrosis (EMF) diagnosis. EMF pathologic hallmark is endocardium and myocardium scarring, evolving to dystrophic calcification. It is found only in few ApHCM patients. Our series is the largest one described until now. Analysing patients' history, coexistent inflammatory triggers were evident in all of them, so their co‐morbidities could represent a further cause of small vessel disease, in the context of ischaemic microvascular stress due to hypertrophy, leading to fibrosis and dystrophic calcification. This series could demonstrate the relation between apical fibrosis/calcification and microvascular ischaemia due to hypertrophy and inflammatory triggers.

Introduction

Apical hypertrophic cardiomiopathy (ApHCM) is an HCM variant, first described by Sakamoto et al. in 1976, accounting for up to 25% of HCM in Asian population and 1–10% in non-Asian one and affects frequently males in midlife.¹ It is more sporadic and less sarcomere mutation associated,¹ than classic HCM. Three phenotypes are described: (i) with isolated apical hypertrophy; (ii) ‘mixed’, with apical and septal hypertrophy, but with the apex thickest; (iii) ‘relative’, an early ApHCM phenotype.² Recent data suggest annual cardiac death rates of 0.5% to 4%.² Mixed ApHCM, younger age,¹ cavity obliteration, and apical asynergy represent negative prognostic predictors.^2,3 No authoritative ApHCM-specific recommendations exist. HCM sudden cardiac death (SCD) risk stratification and then implantable cardioverter defibrillator (ICD) implantation indications are available, including family history of SCD, massive left ventricle (LV) hypertrophy, unexplained syncope, LV systolic dysfunction, LV apical aneurysm, and extensive late gadolinium enhancement (LGE) (≥15% of LV mass) on cardiac magnetic imaging (MRI) non-sustained ventricular tachycardia (NSVT) on ambulatory monitor.⁴ ESC-SCD score includes age, LV outflow gradient, and left atrium diameter also.⁵

Endomyocardial fibrosis (EMF) is rare; its pathologic hallmark is endocardium and myocardium scarring, evolving to dystrophic calcification. In literature, only few cases are described.

On MRI, a hypointense component at early gadolinium enhancement (EGE) sequences, compatible with calcium, and a deep layer, with hyperintensity at LGE sequences, referable to fibrosis, suggests an EMF diagnosis.

Case Reports

We report five clinical cases of apex intramyocardial dystrophic calcification in patients diagnosed with ApHCM and admitted to our ‘cardiomyopathies outpatient clinic’ for a clinical check-up. Patients' features are reported in Table 1.

Table 1 Patients characteristics

	Ethnicity	Age	Co-morbidities	EF	LV dilation	RV involvement	Diastolic pattern	E/e′ ratio	LV GLS	LV gradient	Apical aneurism	MRI LGE	ESC SCD score
Pt 1	Caucasian	48	Severe obesity, depression	45%	1	0	Type II	12	−11%	0	0	1	1.8%
Pt 2	Non-Caucasian	41	Previous malaria, CKD	69%	0	0	Normal	6	−18%	0	0	1	1.7%
Pt 3	Caucasian	50	Thalassemia, ICD	64%	1	0	Normal	6	−19%	0	1	1	4.4%
Pt 4	Caucasian	71	CKD, BAV, microangiopathy	55%	1	0	Type II	13	−11%	0	0	1	1.2%
Pt 5	Non-Caucasian	65	Hypertension, DM II, CKD	52%	1	1	Type II	12	−8%	0	0	1	1%

The first patient was a 48 years old, Caucasian female with previous history of non-cardiogenic syncope and non-sustained ventricular tachycardia at Holter electrocardiogram (ECG). She suffered severe obesity, had undergone sleeve gastrectomy surgery, and was in therapy with metoprolol and torasemide. Genetic test was negative for main HCM genes mutations.

The second patient was a 41-year-old non-Caucasian male. He suffered from moderate chronic kidney disease (CKD) and had a previous malaria infection with cerebral microangiopathy. He was in therapy with atenolol, amlodipine, and thiazide diuretic. Genetic test is still ongoing.

The third patient was a 50-year-old Caucasian female, with intermediate thalassemia and a positive genetic test for heterozygous MYH7 and COX 15 genes mutation of uncertain significance. Her therapy was metoprolol and thiazide diuretic.

The fourth patient, a 71-year-old Caucasian man, had a history of melanoma and peripheral microangiopathy with Raynaud phenomenon. At blood test, a hyper-eosinophilia was evident, unconfirmed at a subsequent lab check. He assumed bisoprolol and furosemide. At genetic test, a heterozygous MYLK2 gene mutation was detected.

The last patient, a 65-year-old non-Caucasian man, suffered from diabetes and severe CKD. He does not report taking any drugs. On genetic test, mutations of MYBPC3, MYO6, and TTN genes of uncertain significance were detected.

All of them, at clinical follow up, were asymptomatic for chest pain and dyspnoea in New York Heart Association (NYHA) class I, except one patient in NYHA class II, complaining of mild dyspnoea. Haemodynamic parameters and physical examination were stable. Typically, on ECG, giant negative T-waves and high QRS voltage were detected.

An echocardiogram was performed in all patients. They presented a preserved ejection fraction (EF), except one patient with mild reduced EF (45%). However, global longitudinal strain (GLS) values were reduced in three patients. Severe LV thickening and hypertrophy lead to apical cavity obliteration and typical appearance of the LV cavity as ‘ace of spades’. Of note, fibrocalcific material on the endomyocardial side was also evident in these patients. Left ventricular thrombus was not observed in each case.

LV was dilated in medio-basal segments in all patients, while diastolic dysfunction with an E/e′ ratio >10 was evidenced in three patients. Right ventricle involvement was detected in only one patient, in which a thickness of 7 mm was found. Typically, none of these patients had a left ventricular outflow tract obstruction, but in one patient, the presence of an apical aneurysm has been described. Indeed, this patient had the higher ESC-SCD risk score and implanted an ICD.

To better define cardiac function and morphology, an MRI was performed (Figures 1–5).

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In the first patient, MRI confirmed LV hypertrophy (apex and interventricular septum of 18 mm) and apical LV cavity obliteration with stratified material characterized by a superficial hypointense component at EGE sequences, compatible with calcific material and by a deep layer with sub-endocardial LGE related to fibrotic tissue. LV mid-ventricular cavity was dilated, with reduced LV EF (45%). The right ventricle showed preserved thicknesses and dimensions. These findings described were compatible with EMF associated with ApHCM.

In the second patient, there was evidence of apical cavity obliteration due to hypertrophic myocardial wall and stratified material, appearing hypointense in the cine MRI EGE sequences and hyperintense in LGE sequences referable to EMF. A dilation of medium LV and atria was detected, while right ventricle sections were preserved.

In the third patients, MRI highlighted an apical hypertrophy and hypertrabeculation determining cavity obliteration, with normal EF, but increased LV diameters. After gadolinium administration, sub-endocardial apical linear LGE distribution was detected. Moreover, a corresponding hypointense area was evidenced in all sequences.

In the fourth patient, MRI also confirmed the presence of layered apical material appearing hypointense in EGE sequences and hyperintense in LGE ones, a pattern compatible with myocardial fibrosis.

The latter patient underwent cardiac MRI without contrast medium, because of severe chronic kidney disease (serum creatinine 2.9 mg/dL), but cine MRI sequences showed the presence of sub-endocardial chemical shift artefact at the apical level, likely due to the calcification presence.

According to the ESC-SCD risk score, only the third patient implanted an ICD, because of a score of 4.49%, while the other patients continues the ongoing therapy with beta-blockers or calcium channel blockers and diuretics and are followed up every 6 months.

Discussion

EMF was first described in 1947 by Davies et al. in Uganda; its pathologic hallmark is endocardium and myocardium scarring, evolving to dystrophic calcification. Five EMF types have been described: type 1 affecting the apex only; type 2 affecting the apex and the valve area; type 3 affecting the valve area only; type 4 with isolated lesions in the apex and valve area; type 5 with patchy lesions located in areas other than apex and valve.⁶

Two different EMF variants are described: primary, related to malnutrition, allergy, infective agents and abnormal eosinophils and secondary, occurring in patients with underlying ischaemic heart disease, primary myocardial disease and related to myocardium thickness, leading to small arteries compression during filling. Although concomitant inflammatory triggers are not essential in secondary EMF, our cases may represent a new additional pathophysiological hypothesis of the secondary EMF. Our cases are all secondary EMF examples.

Severe LV thickening and hypertrophy are related to apical cavity obliteration, which together with persistent diastolic apical contraction leads to dynamic small vessel obstruction causing recurrent microvascular ischaemia.³ These pathophysiological mechanisms are responsible for myofibrosis and myocardial stiffness, substrates of another typical feature of ApHCM: the impaired filling with different diastolic dysfunction degree, up to the restrictive pattern.³

However, in clinical practice, it is evident as only a minority of ApHCM patients develops EMF and calcifications. Actually, in literature only, seven cases of EMF in ApHCM patients are described in six different papers,^7–12 so our clinical series is the largest one.

All patients reported in the published clinical cases, complained exercise chest pain, dyspnoea and fatigue, except one admitted in hospital for ECG anomalies. At ECGs, high QRS voltages and negative deep T waves in anterior precordial leads were detected. Some of them had conduction disorders like atrioventricular first-degree block. Echocardiographic and cardiac MRI findings were comparable with those reported in our case series. However, these case reports lack of data concerning the course of treatment.

Analysing our patients' history, a concomitant inflammatory trigger was evident in all of them. Their co-morbidities can represent a further cause of small vessel disease, in the context of microvascular stress due to hypertrophy.

The first patient suffered with severe obesity and was treated with sleeve gastrectomy surgery. The second patient had a previous malaria infection with cerebral microangiopathy evidenced at MRI. The third patient had an intermediate form of thalassemia. The fourth patient had a history of melanoma and peripheral microangiopathy with Raynaud phenomenon. The last patient suffered from severe chronic kidney disease and diabetes.

All these co-morbidities can represent a further cause of small vessel disease, in the context of microvascular stress due to the myocardial walls' thickness increase.

Indeed, diabetes is widely demonstrated to be associated with cardiac fibrosis and heart failure pathogenesis.¹³ Pre-clinical and clinical studies demonstrated an association between cardiac fibrosis and obesity, increasing the pro-inflammatory and pro-fibrotic cytokines expression.¹⁴ Chronic kidney disease should also be involved in the remodelling process leading to increased myocardial fibrosis.¹⁵

Over the last years, progresses in inflammatory trigger identification in EMF have been made. Some evidences highlighted how patients with recent onset EMF have increased levels of IL-6, endothelial cells activation, and increased fibrinolysis, strongly suggesting that inflammation, endothelial injury, and pro-coagulant changes play an important role in the early stages of this condition.¹⁶

These results suggest that biomarkers could potentially be used for early detection and follow up of patients. It is not yet clear whether drugs against IL-6, like tocilizumab improves the EMF outcome.

(although this strategy may be limited in low-income EMF endemic areas¹⁷).

Conclusions

This case series could probably demonstrate the pathophysiological relation between dystrophic calcification, hypertrophy and inflammatory triggers (Figure 6).

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A broader case series would be desirable in order to evaluate any correlation with their long-term outcome and management strategies.

Conflict of interest

None declared.

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