Direct intramyocardial transthoracic transplantation of bone marrow
               mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL, a prospective
               randomized controlled trial

Sant'Anna, Roberto T.; Fracasso, James; Valle, Felipe H.; Castro, Iran; Nardi, Nance B.; Sant'Anna, João Ricardo M.; Nesralla, Ivo Abrahão; Kalil, Renato A. K.

doi:10.5935/1678-9741.20140091

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Brazilian Journal of Cardiovascular Surgery

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SPECIAL ARTICLES • Rev Bras Cir Cardiovasc 29 (3) • Jul-Sep 2014 • https://doi.org/10.5935/1678-9741.20140091 copy

Direct intramyocardial transthoracic transplantation of bone marrow mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL, a prospective randomized controlled trial

Ensaio clínico prospectivo randomizado sobre terapia com células mononucleares da medula óssea para cardiomiopatia dilatada idiopática: INTRACELL

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective:

We tested the hypothesis that direct intramyocardial injection of bone marrow mononuclear cells in patients with non-ischemic dilated cardiomyopathy can improve left ventricular function and physical capacity.

Methods:

Thirty non-ischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% were randomized at a 1:2 ratio into two groups, control and treated. The bone marrow mononuclear cells group received 1.06±108 bone marrow mononuclear cells through mini-thoracotomy. There was no intervention in the control group. Assessment was carried out through clinical evaluations as well as a 6-min walk test, nuclear magnectic resonance imaging and echocardiogram.

Results:

The bone marrow mononuclear cells group showed a trend toward left ventricular ejection fraction improvement, with magnectic resonance imaging - at 3 months, showing an increase from 27.80±6.86% to 30.13±9.06% (P=0.08) and returning to baseline at 9 months (28.78%, P=0.77). Magnectic resonance imaging showed no changes in left ventricular ejection fraction during follow-up of the control group (28.00±4.32%, 27.42±7.41%, and 29.57±4.50%). Echocardiogram showed left ventricular ejection fraction improved in the bone marrow mononuclear cells group at 3 months, 25.09±3.98 to 30.94±9.16 (P=0.01), and one year, 30.07±7.25% (P=0.001). The control group showed no change (26.1±4.4 vs 26.5±4.7 and 30.2±7.39%, P=0.25 and 0.10, respectively). Bone marrow mononuclear cells group showed improvement in New York Heart Association functional class, from 3.40±0.50 to 2.41±0.79 (P=0.002); patients in the control group showed no change (3.37±0.51 to 2.71±0.95; P=0.17). Six-minute walk test improved in the bone marrow mononuclear cells group (348.00±93.51m at baseline to 370.41±91.56m at 12 months, P=0.66) and there was a non-significant decline in the control group (361.25±90.78m to 330.00±123.42m after 12 months, P=0.66). Group comparisons were non-significant.

Conclusion:

The trend of intragroup functional and subjective improvement was not confirmed when compared to the control group. Direct intramyocardial application of bone marrow mononuclear cells in non-ischemic dilated cardiomyopathy was not associated with significant changes in left ventricular function. Differences observed within the bone marrow mononuclear cells group could be due to placebo effect or low statistical power.

Cardiomyopathy, Dilated; Heart Failure; Cells; Myocardial Contraction; Transplantation

Abbreviations, acronyms & symbols
BMMC	Bone marrow mononuclear cells
DCM	Dilated cardiomyopathy
LVEF	Left ventricular ejection fraction
MLHF	Minnesota Living with Heart Failure
MRI	Magnetic resonance cardiac imaging
NIDCM	Non-ischemic dilated cardiomyopathy
NYHA	New York Heart Association
PO	Post-operatively

	BMMC group	Control group
	(n=20)	(n=10)
Male	13 (65%)	5 (50%)
Age	48.3 (8.71)	51.6 (7.79)
NYHA class	3.5 (0.52)	3.35 (0.48)
Minnesota QOL score (Minnesota)	66.2 (22.46)	50.6 (14.84)
Minnesota QOL score (Minnesota)
Six minute walk test (min)	358.5 (88.69)	353 (86.67)
LVEF by ECHO (%)	21.75 (41.19)	24.76 (4.64)
Final diastolic diameter, ECHO (mm)	73.4 (8.18)	70.3 (7.4)
LVEF by MRI (%)	27.80±6.86	28.00±4.32
N° of injected cells	1.06 x 10⁸	none

Surgery	Mean ±DP	Max value
Thoracotomy procedure (min)	84.7±29	120
Post-operative, %
Length of ICU Stay (days)	1.86±1.3	6
Length of hospital stay (days)	4.50±2.0	9

Parameter	BMMC group	Control group	P
	(n = 15)	(n=9)
Ejection Fraction, %
Baseline	27.80±6.86	28.00±4.32	NS
3 months	30.13±9.06	27.42±7.41	NS
Change from baseline	2.33	-0.58
P value comparing to baseline	0.08	0.79
9 months	28.78±9.97	29.57±4.50	NS
Change from baseline	0.98	+1.57
P value comparing to baseline	0.77	0.46
End-diastolic volume, mL
Baseline	272.73±63.41	250.85±67.00	NS
3 months	264.86±72.24	222.42±96.19	NS
Change from baseline	-7.87	-28.43
P value comparing to baseline	0.41	0.32
9 months	258.64±82.97	258.85±75.55	NS
Change from baseline	-14.09	+8.00
P value comparing to baseline	0.54	0.71
End-svstolic volume, mL
Baseline	200.40±61.59	182.00±55.70	NS
3 months	195.93±78.49	161.67±67.83	NS
Change from baseline	-4.47	- 20.43
P value comparing to baseline	0.66	0.18
9 months	190.00±82.18	184.14±58.55	NS
Change from baseline	-10.40	2.14
P value comparing to baseline	0.73	0.91

Parameter	BMMC group	Control group	P
	(n = 15)	(n=9)
Ejection Fraction, %
Baseline	25.09±3.98	26.10 ± 4.49	NS
3 months	28.11±7.22	26.525 ± 4.71	NS
Change from baseline	3.02	0.425
P value comparing to baseline	0.06	0.628
6 months	30.94±9.16	28.51 ± 6.98	NS
Change from baseline	5.85	2.41
P value comparing to baseline	0.01	0.250
12 months	30.07±7.25	30.23±7.39	NS
Change from baseline	4.98	4.13
P value comparing to baseline	0.01	0.100
End-diastolic diameter, mm
Baseline	69.80±4.41	69.375±7.81	NS
3 months	68.33±6.38	68.62±8.39	NS
Change from baseline	-1.47	0.75
P value comparing to baseline	0.18	0.170
6 months	68.28±6.48	69.85±9.66	NS
Change from baseline	-1.52	0.479
P value comparing to baseline	0.27	0.98
12 months	68.66±7.35	68.28±8.47	NS
Change from baseline	-1.14	-1.09
P value comparing to baseline	0.49	0.612
End-svstolic diameter, mm
Baseline	61.46±4.65	60.75±7.86	NS
3 months	60.33±7.64	60.00±8.28	NS
Change from baseline	-1.13	-0.75
P value comparing to baseline	0.47	0.28
6 months	58.14±8.12	60.42±9.98	NS
Change from baseline	-3.32	-0.33
P value comparing to baseline	0.08	0.63
12 months	58.83±8.50	58.42±9.10	NS
Change from baseline	-2.63	-2.33
P value comparing to baseline	0.17	0.42

Parameter	BMMC group	Control group	P
	(n = 15)	(n=9)
Minnesota LHFQ
Baseline	69.00±20.71	48.87±16.32	NS
3 months	43.13±27.92	54.37±23.71	NS
Change from baseline	-25.87	+5.50
P value comparing to baseline	0.005	0.57
6 months	48.92±24.26	40.28±23.59	NS
Change from baseline	-20.08	-8.58
P value comparing to baseline	0.018	0.31
12 months	37.08±21.15	41.71±27.46	NS
Change from baseline	-31.92	-7.16
P value comparing to baseline	0.001	0.48
6-minutes-walk test
Baseline	348.00±93.51	361.25±90.78	NS
3 months	338.66±116.48	336.25±114.38	NS
Change from baseline	-9.34	- 25
P value comparing to baseline	0.73	0.44
6 months	355.35±67.77	365.00±126.45	NS
Change from baseline	7.35	3.75
P value comparing to baseline	0.81	0.98
12 months	370.41±91.56	330.00±123.42	NS
Change from baseline	22.41	-31.25
P value comparing to baseline	0.66	0.39
NYHA
Baseline	3.40±0.50	3.37±0.51	NS
3 months	2.60±0.82	3.00±0.75	NS
Change from baseline	-0.8	- 0.37
P value comparing to baseline	0.005	0.19
6 months	2.50±0.75	2.57±0.78	NS
Change from baseline	-0.9	-0.8
P value comparing to baseline	0.005	0.04
12 months	2.41±0.79	2.71±0.95	NS
Change from baseline	-0.99	- 0.66
P value comparing to baseline	0.002	0.17

Authors' roles & responsibilities
RTSA	Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript, conception and design of the study, realization of operations and/or experiments, drafting of the manuscript and critical review of the content
JF	Analysis and/or interpretation of data, realization of operations and/or experiments
FHV	Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript conception and design of the study, realization of operations and/or experiments,
	Drafting of the manuscript and critical review of the content
IC	Analysis and/or interpretation of data, realization of operations and/or experiments
NBN	Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript, realization of operations and/or experiments
JRMSA	Analysis and/or interpretation of data, realization of operations and/or experiments
IAN	Analysis and/or interpretation of data, final approval of the manuscript conception and design of the study, realization of operations and/or experiments
RAKK	Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript conception and design of the study, realization of operations and/or experiments, drafting of the manuscript and critical review of the content

Sociedade Brasileira de Cirurgia Cardiovascular Rua Afonso Celso, 1178 Vila Mariana, CEP: 04119-061 - São Paulo/SP Brazil, Tel +55 (11) 3849-0341, Tel +55 (11) 5096-0079 - São Paulo - SP - Brazil
E-mail: bjcvs@sbccv.org.br

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[1] Correspondence address: Renato Abdala Karam Kalil, Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC), Avenida Princesa Isabel, 395 - Santana, Porto Alegre, RS Brazil - Zip Code: 90620-000. E-mail: kalil.pesquisa@gmail.com