Arquivos Brasileiros de Cardiologia

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Original Article • Arq. Bras. Cardiol. 123 (2) • Feb 2026 • https://doi.org/10.36660/abc.20240616i linkcopy

PRKAG2 Cardiomyopathy: A Case-Control Study on the Diagnostic Yield Of Histopathology and Ultrastructural Analysis from Endomyocardial Biopsy

Authorship SCIMAGO INSTITUTIONS RANKINGS

Background The histopathological features of PRKAG2 cardiomyopathy have been reported in a fragmentary manner.

Objective We aimed to systematically evaluate the cardiac pathological features of PRKAG2 cardiomyopathy in a large patient cohort and assess their diagnostic potential compared to genetic sequencing.

Methods We conducted an observational, cross-sectional, case-control study including 18 patients with PRKAG2 cardiomyopathy and 11 heart transplant recipients as controls. All patients underwent percutaneous right ventricular endomyocardial biopsy. Tissue samples were analyzed using H&E staining, Periodic Acid-Schiff staining for glycogen, Masson’s trichrome for fibrosis, and ultrastructural assessment by transmission electron microscopy. Statistical significance was set at p < 0.05 for all analyses.

Results PRKAG2 cardiomyopathy hearts exhibited significant cardiomyocyte enlargement, normal-appearing mitochondria, extensive vacuolization of most myofibers, minimal interstitial fibrosis (only two patients had mild fibrosis), and no inflammatory cell infiltration. Transmission electron microscopy revealed abundant cytosolic glycogen, primarily in the perinuclear region, with additional deposits in intermyofibrillar and subsarcolemmal areas. This pronounced glycogen accumulation, consistently observed in all PRKAG2 patients, was absent in controls.

Conclusion Histological and ultrastructural examination of right ventricular endomyocardial biopsy samples reveals a distinct set of features that strongly suggest PRKAG2 cardiomyopathy.

Keywords
AMP-Activated Protein Kinases; Cardiomegaly; Microscopy, Electron, Transmission

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Central Illustration:
PRKAG2 Cardiomyopathy: A Case-Control Study on the Diagnostic Yield Of Histopathology and Ultrastructural Analysis from Endomyocardial Biopsy

Cases	Diagnosis	Variant	Age - donor	Age - cases	Gender	ECG Delta wave	Fasciculo ventricular pathway	Atrial tachycardia	Atrial flutter	Atrial fibrillation	Echocardiogram LV Hypertrophy	vacuoles (HE/Masson)	vacuoles qualitative	Interstitial fibrosis	Myocyte disarray	Inflammation	Myocyte diameter (um²)	Vv Myofibrils (%)	Vv Mitochondria (%)	Vv Glycogen (%)
1	PRKAG2	R302Q		47	F	yes/ PM	yes*				no	yes	pronounced	no	no	no	19.20	48.18	27.58	14.85
2	PRKAG2	R302Q		32	F	yes	yes				no	yes	pronounced	no	no	no	20.16	29.09	33.03	31.82
3	PRKAG2	R302Q		48	F	no	no				no	yes	pronounced	no	no	no	18.85	x	x	x
4	PRKAG2	R302Q		38	F	yes	yes	paroxysmal			no	yes	pronounced	no	no	no	20.18	39.40	38.18	13.64
5	PRKAG2	R302Q		50	M	yes/ PM	yes*			paroxysmal	no	yes	pronounced	no	no	no	17.20	45.10	29.21	16.89
6	PRKAG2	R302Q		39	F	no	no				no	yes	pronounced	no	no	no	19.32	41.52	27.88	21.21
7	PRKAG2	R302Q		57	M	yes/ PM	yes*				yes	yes	pronounced	no	no	no	25.84	33.64	28.49	31.21
8	PRKAG2	R302Q		55	M	yes/ PM	yes*		yes (RF)	persistent	yes	yes	pronounced	yes mild	no	no	28.38	29.70	25.15	40.31
9	PRKAG2	R302Q		52	M	yes/ PM	yes*				yes	yes	pronounced	no	no	no	17.71	42.42	29.70	24.85
10	PRKAG2	R302Q		32	M	yes	yes				yes	yes	pronounced	no	no	no	25.08	32.43	30.00	33.34
11	PRKAG2	R302Q		34	M	yes/ PM	yes		yes (RF)		yes	yes	pronounced	no	no	no	26.09	24.85	22.12	38.49
12	PRKAG2	R302Q		36	M	yes/ PM	yes*	paroxysmal			yes	yes	pronounced	no	no	no	21.33	39.09	29.40	20.30
13	PRKAG2	R302Q		46	F	yes	yes	paroxysmal	yes (RF)		yes	yes	pronounced	no	no	no	18.24	29.70	24.85	34.85
14	PRKAG2	R302Q		39	M	yes	yes	paroxysmal			yes	yes	pronounced	yes mild	no	no	x	51.22	31.52	10.00
15	PRKAG2	R302Q		30	M	yes/ PM	yes			persistent	yes	yes	pronounced	no	no	no	23.00	32.43	21.52	39.09
16	PRKAG2	H401Q		19	F	yes	yes			paroxysmal	yes	yes	pronounced	no	no	no	21.68	45.76	30.91	15.46
17	PRKAG2	H401Q		18	F	yes	yes				yes	yes	pronounced	no	no	no	21.35	42.12	36.37	10.31
18	PRKAG2	R302Q		22	M	yes	yes				yes	yes	pronounced	no	no	no	21.97	34.25	20.61	33.03
19	transplant		24	64	M	no	no				no	no		no	no	yes mild	13.95	54.58	28.05	13.11
20	transplant		31	53	M	no	no				no	yes	mild	no	no	no	16.28	55.46	25.76	9.70
21	transplant		29	55	M	no	no				no	no		yes mild	no	no	13.03	55.28	32.83	2.78
22	transplant		18	52	M	no	no				no	no		no	no	no	16.51	59.88	28.65	5.95
23	transplant		26	61	F	no	no				no	no		no	no	no	16.42	61.79	29.45	4.24
24	transplant		24	56	M	no	no				no	no		no	no	no	17.49	58.79	31.05	3.99
25	transplant		33	33	F	no	no				no	yes	mild	yes mild	no	no	12.77	x	x	x
26	transplant		30	62	M	no	no				yes	no		no	no	no	18.24	x	x	x
27	transplant		15	45	M	no	no				yes	no		yes mild	no	yes mild	21.15	x	x	x
28	transplant		20	68	F	no	no				yes	no		no	no	no	18.18	58.71	30.73	3.97
29	transplant		47	55	M	no	no				yes	no		no	no	no	21.21	49.70	40.30	2.73

	Heart Transplant (n= 11)	PRKAG2 cardiomyopathy (n= 17)	p-value
Fibrosis	2/11 (18%)	2/17 (12%)	0.3697^a
Inflammation	2/11 (18%)	0/17 (0%)	0.1967^a
Vacuolization	2/11 (18%)	17/17 (100%)	<0.0001^a
Glycogen (TEM)	0/8 (0%)	17/17 (100%)	<0.0001^a
Cardiomyocyte diameter m)^#	16.84 ± 2.86	21.50 ± 3.23	0.0018^b

	Cardiomyocyte diameter (µm)		Vv myofibrils (%)		Vv mitochondria (%)		Vv glycogen (%)
	Person r	p-value	Person r	p-value	Person r	p-value	Person r	p-value
Cardiomyocyte diameter (µm)			-0,757	< 0.0001	-0,217	0,309	0,706	< 0.001
Vv myofibrils (%)					0,338	0,099	-0,924	< 0.0001
Vv mitochondria (%)							-0,616	< 0.001
Vv glycogen (%)

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