Review of Hemoglobin-Induced Myocardial Lesions

Figures & data

Figure 1. Dose response characteristics of heart lesion development in primates 48 h after a single infusion of DCLHb.

Figure 2. Incidence and dose response of myocardial degeneration and necrosis in various species.

Figure 3. Photomicrographs of H&E stained sections of myocardium from the left ventricle of different swine following infusion of 2000 mg/kg of DCLHb, illustrating typical heart lesions of different severity. (nec = necrosis).

Figure 4. Percent of heart tissue with degeneration and/or necrosis 7 days following infusion of 2000 mg/kg of DCLHb into rhesus monkeys.

Table 1. Incidence and severity of heart lesions in primates

Dose (mg/kg)	Incidence	Average severity score
50	0/5	0
100	0/5	0
200	1/5	0.6
350	3/5	1.2
700	5/5	2.0
2000	14/15	2.3

Table 2. Incidence of myocardial degeneration vs. Dose in rhesus monkeys during a 28 day repeat dose study

	Dose level (mg/kg)
	1000 mg/kg (10 mL/kg)	2000 mg/kg (20 mL/kg)	4000 mg/kg (40 mL/kg)
Early death–sacrificea
bof animals with lesions	0	2 (2)b
		(2-mild)	8 (2)b
			(2-minimal, 3-mild, 3-moderate)
bTotal of animals examined	2	3	8
	Cumulative dose (mg/kg)
Day 29–sacrifice	28,000 mg/kg (280 mL/kg)	56,000 mg/kg (560 mL/kg)	1,12,000 mg/kg (1120 mL/kg)
bof animals with lesions	2 (1.5)b	3 (1.3)b	2 (2)b
	(1-minimal, 1-mild)	(2-minimal, 1 mild)	(mild)
bTotal of animals examined	7	7	3
Day 64–sacrifice
bof animals with lesions	0	0	0
bTotal of animals examined	3	2c	1

Note: The DCLHb was formulated at a concentration of 100 mg/mL.

^a = Unfortunately, some animals died during this study of other causes (additional studies strongly suggested fluid overload as the cause of death), but yet, their hearts and other tissues were examined.

^bAverage numerical score — 1 = minimal, 2 = mild, 3 = moderate, 4 = severe.

^cEvidence of minimal focal myocardial fibrosis which may have been related to myocardial degeneration.

Table 3. Heart lesions following infusion of DCLHb (reference range in swine)

Treatment variation	DCLHb dose (mg/kg)	Incidence	%	Mean severity
Cumulative DCLHb	2000	101/105	96	2.1
HSA (8 g/dL)	1600	3/27	11	0.1
Sham	0	0/17	0	0

Table 4. Incidence and severity of heart lesions in pigs infused with DCLHb and co-medicaments

Treatment variation Hb variations	DCLHb dose (mg/kg)	Incidence	%	Mean severity
Chromatographically purified	2000	4/4	100	2.5
Human SFHb	2000	4/4	100	1.3
Porcine SFHb	2000	5/6	83	2.3
Cyanomet–DCLHb	2000	3/4	75	1.3

Table 5. Incidence and severity of heart lesions in pigs infused with DCLHb and various co-medicaments

Treatment variation {Co-med}	DCLHb dose (mg/kg)	Incidence	%	Mean severity
L-NAME alone^*	100 mg/kg	1/1	100	2.0
L-NAME alone^*	40 mg/kg	5/5	100	1.5

Table 6. Incidence and severity of heart lesions in pigs infused with various hemoglobin solutions

Treatment agent	K’NO (µM^−1S^−1)	MW (kD)	Incidence (%)	Overall severity
HSA	—	64	3/27 (11)	0.1
DCLHb	∼60	64	35/37 (95)	1.9
rHb1.1	60	64	4/4 (100)	2.0
NO Mutant Hb	2	64	0/4 (0)	0