In patients undergoing elective percutaneous coronary intervention (PCI), vitamin C infusion both improves microperfusion and reduces markers of oxidative stress after revascularization, according to a study published in the February 2010 issue of JACC: Cardiovascular Interventions. The findings suggest that oxidative stress plays a role in causing periprocedural myocardial injury and that vitamin C may help counteract it, the authors say.

To explore the possibility that an antioxidant strategy might reduce impaired microperfusion, investigators led by Francesco Violi, MD, of the University of Rome “La Sapienza” (Rome, Italy), randomized 56 patients at their institution who were scheduled for elective PCI to receive either an infusion of 1 g of ascorbic acid (16.6 mg/min) or a placebo given over the course of an hour prior to the procedure.

Blood samples were collected at baseline and 60 minutes following PCI to measure levels of 2 markers of oxidative stress. In addition, serum cardiac troponin-I was measured at baseline and every 6 hours over the next 2 days, while serum creatinine was measured the morning of the day before angiography and the day of the procedure.

The median absolute increase in troponin was similar for both the treatment and placebo groups (0.027 ng/mL vs. 0.008 ng/mL; P = 0.0832) and remained within the upper limits of normal in both groups. On the other hand, serum creatinine levels increased within 24 hours of contrast administration in the placebo group while decreasing in the vitamin C group, resulting in a significant difference in changes from baseline in the 2 groups (P < 0.001).

TIMI Flow Improved in Microcirculation

Before treatment, the majority of patients in both the vitamin C group (86%) and the placebo group (71%) had TIMI flow grades suggestive of impaired microcirculation (corrected TIMI frame counts [cTFC] ranging from 20 to 40 frames/sec). PCI reduced the levels significantly in both groups, but the reduction in cTFC was greater among patients who received vitamin C compared with those who received a placebo (median change -41% vs. -23%; P < 0.0001). In fact, only 1 patient (4%) in the placebo group compared with 16 patients (57%) in the vitamin C group achieved lower-risk status (≤ 20 frames/sec).

In another angiographic index of microcirculation, 89% of placebo patients and 86% of vitamin C patients had a TIMI myocardial perfusion grade < 2 at baseline. After PCI, those percentages declined to 32% in the placebo group (P < 0.001) and 4% in the vitamin C group (P < 0.001). Although both reductions were significant, the difference was greater in the vitamin C group.

Vitamin C Appears to Neutralize Oxidative Stress 

Changes in levels of oxidative stress largely paralleled improvements in perfusion. Before intervention, levels of 2 markers of oxidative stress, 8-iso-prostaglandin F_2alpha (8-iso-PGF_2alpha) and 8-hydroxy-2-deoxyguanosine (8-OHdG), were similar in both groups and correlated with each other in the overall cohort. One hour after balloon inflation, however, levels of the biomarkers increased in the placebo group while decreasing in the vitamin C group, yielding a significant difference between the groups in the levels of both biomarkers (P < 0.001 for 8-OHdG and P < 0.0001 for 8-iso-PGF_2alpha).

Although cTFC changes did not correlate with the oxidative stress biomarkers, TIMI myocardial perfusion grade changes did: P < 0.006 for 8-OHdG and P < 0.01 for 8-iso-PGF_2alpha.

In addition, LVEF levels, which were comparable between the 2 groups at baseline, increased in both groups after PCI (from 52.3 ± 4.3% to 58.3 ± 2.9% among vitamin C patients and from 53.7 ± 3.9% to 54.1 ± 4.7% among placebo patients), but more so in the vitamin C group (P < 0.01).

There were no in-hospital complications, and no thrombosis-related events occurred in either group over a mean follow-up of 15 ± 4.5 months. Three patients (5.3%) in the placebo group and 1 patient (3.5%) in the vitamin C group underwent TVR. 

“Our data extend [earlier] findings as we show that oxidative stress is implicated in impairing microcirculatory flow,” the authors write. “Thus, infusion of vitamin C, which is known to quench oxygen radicals, was associated with improvement of microcirculatory perfusion coincidentally with inhibition of oxidative stress.”

Vasodilation Boosted?

Vitamin C may act by a number of mechanisms, Dr. Violi and colleagues suggest, including restoring endothelial synthesis of the vasodilator nitric oxide and in general scavenging free radicals.

The authors readily acknowledge that the clinical implications of the observed improvement in LVEF are unknown and the very limited number of cardiovascular events precludes drawing any conclusions about benefit. Moreover, the coincidental increase in microvascular perfusion paired with the reduction in oxidative stress does not prove a cause-effect relationship. But the finding is suggestive and provides a rationale for testing the clinical efficacy of vitamin C infusion, they conclude.

In an editorial accompanying the study, Patrice Delafontaine, MD, and Asif Anwar, MD, of Tulane University Heart and Vascular Institute (New Orleans, LA), agree. They observe that 15% to 35% of patients who receive PCI suffer periprocedural myocardial damage, which confers a long-term risk of mortality.

In addition, the editorialists note that despite the improvement in microperfusion among vitamin C-treated patients, troponin levels rose to a similar extent in both groups. Nonetheless, they speculate, given the short half-life of parenteral vitamin C, it is possible that continued infusion of the antioxidant during PCI might have resulted in a reduction of the biomarker.

Clinical Impact in Doubt 

In a telephone interview with TCTMD, Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), called the paper a very well-designed hypothesis-generating study that validates the importance of the oxidative pathway in myocardial injury. Whether it will eventually have any clinical impact, however, is “the $64,000 question,” he said.

“One issue is the [elective PCI] patient population [in this study],” he noted. “A lot of these myocardial preservation strategies are done in STEMI patients [who have] large infarcts and a very clear time of insult.” On the other hand, it does not make sense to delay opening STEMI patients’ blocked arteries for an hour while they are infused with vitamin C, Dr. Rao noted.

Moreover, most myocardium preservation studies, like the APEX MI trial, have been negative, he added. “Despite all the phase II data that suggested you would see an effect, when you actually translated it into a phase III clinical outcome study, there was absolutely no effect,” he said. “That’s probably because the mechanisms [of impaired microperfusion] are incredibly complex. We tend to be a little naïve to think that there is one pathway that we can intervene on and change all this . . . . Despite our gut-level reaction to think that antioxidants are good, they don’t seem to work.”

The reason for some positive results from ischemic conditioning may be that it mimics a physiological process that affects the myocardium on all fronts, not just the oxidative pathway, Dr. Rao observed.

It might be helpful to be able to identify which patients are more likely to benefit from vitamin C therapy, Dr. Rao said—for example, to determine if elevated CRP or troponin levels correlate with oxidative stress and use those as markers. However, one problem is that those patients already tend to get different medical therapy from elective PCI patients as a whole, he noted.

In general, myocardial preservation strategies are very challenging because they must take into account numerous variables, from the patient population to the type of agent, the dose, and the timing relative to the insult, Dr. Rao observed. Nonetheless, he said, from a mechanistic standpoint this study is positive, and the antioxidant approach deserves further investigation. “I’m always in favor of pursuing different hypotheses because outcomes from higher-risk PCI can always be improved,” he concluded.

2. Delafontaine P, Anwar A. Vitamin C and percutaneous coronary intervention. J Am Coll Cardiol Intv. 2010;3:230-232.

Disclosures:

• The paper and editorial contain no statements regarding conflicts of interest.
• Dr. Rao reports no relevant conflicts of interest.
  

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