Role of CCBs in Pulmonary Arterial Hypertension

Table 1.

Clinical Characteristics, Baseline Hemodynamics, and Exercise Capacity of the Studied Patient Sample

Used with permission from: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

Table 2.

	Acute NO/Epoprostenol Responders Group (n = 70)	Long-term CCB Responders Group (n = 38)	CCB Failure Group (n = 32)	P*
Drug tested (NO:epoprostenol) (n)	57:13	33:5	24:8	.2
Mean PAP reached during acute vasodilator testing (mm Hg)	38 ± 11 (18-65)	33 ± 8 (18-50)	46 ± 10 (18-65)	< .001
Fall in mean PAP during acute vasodilator testing (mm Hg)	19 ± 7 (10-36)	21 ± 7 (10 - 36)	16 ± 6 (10 - 33)	.006
Percent fall in mean PAP	33 ± 11 (20-59)	39 ± 11 (20 - 59)	26 ± 7 (20 - 49)	< .001
PVR reached during acute vasodilator testing (WU)	6.6 ± 3.4 (1.1 - 17.4)	5.2 ± 2.7 (1.1 - 13.1)	8.6 ± 3.3 (1.1 - 17.4)	< .001
Fall in PVR during acute vasodilator testing (WU)	5.6 ± 3.3 (1.6 - 16.7)	5.1 ± 3.1 (1.7 - 15.4)	6.2 ± 3.4 (1.6 -16.7)	.16
Percent fall in PVR	45 ± 15 (24-77)	50 ± 15 (24 - 77)	40 ± 13 (26 - 75)	.007

Hemodynamic Values Reached During Vasodilator Testing in Acute Responders

Values are mean ± SD (range).
*Comparison between long-term CCB responders and CCB failure groups (unpaired Student t or x ² test, as appropriate.
CCB = calcium channel blockers; CO = cardiac output; NO = nitric oxide; PAP = pulmonary arterial pressure; PVR = pulmonary vascular resistance; WU = Wood units
Used with permission from: Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

Table 2.

	Acute NO/Epoprostenol Responders Group (n = 70)	Long-term CCB Responders Group (n = 38)	CCB Failure Group (n = 32)	P*
Drug tested (NO:epoprostenol) (n)	57:13	33:5	24:8	.2
Mean PAP reached during acute vasodilator testing (mm Hg)	38 ± 11 (18-65)	33 ± 8 (18-50)	46 ± 10 (18-65)	< .001
Fall in mean PAP during acute vasodilator testing (mm Hg)	19 ± 7 (10-36)	21 ± 7 (10 - 36)	16 ± 6 (10 - 33)	.006
Percent fall in mean PAP	33 ± 11 (20-59)	39 ± 11 (20 - 59)	26 ± 7 (20 - 49)	< .001
PVR reached during acute vasodilator testing (WU)	6.6 ± 3.4 (1.1 - 17.4)	5.2 ± 2.7 (1.1 - 13.1)	8.6 ± 3.3 (1.1 - 17.4)	< .001
Fall in PVR during acute vasodilator testing (WU)	5.6 ± 3.3 (1.6 - 16.7)	5.1 ± 3.1 (1.7 - 15.4)	6.2 ± 3.4 (1.6 -16.7)	.16
Percent fall in PVR	45 ± 15 (24-77)	50 ± 15 (24 - 77)	40 ± 13 (26 - 75)	.007

Hemodynamic Values Reached During Vasodilator Testing in Acute Responders

Table 3.

Used with permission from: Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208.

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Rationale for Use of CCBs in the Treatment of PAH

Three findings led to the evaluation of CCBs for the treatment of PAH in the late 1970s: (1) smooth muscle hypertrophy was noted on histologic specimens from the lungs of patients with PAH, (2) CCBs were shown to be beneficial in the treatment of systemic hypertension, and (3) CCBs demonstrated potential ability to inhibit hypoxic vasoconstriction in animal models.^[1,2] Although not identified until later, there are additional reasons why CCBs might be efficacious in the treatment of PAH. Investigators have shown that voltage-gated potassium (Kv) channels are downregulated in patients with IPAH.^[3] This, in turn, causes membrane depolarization and release of intracellular calcium, leading to pulmonary artery smooth muscle cell contraction and proliferation. In addition, endothelin, a potent endogenous vasoconstrictor whose production is increased in PAH, exerts its effects through downstream second messengers, which increase free intracellular calcium, whereas nitric oxide, whose production is decreased in PAH, works through the second messenger cyclic GMP, which decreases free intracellular calcium, leading to vasodilation.^[4,5]