The Cardinals (50-12) move one game from advancing to the College World Series with the victory, while the Commodores (54-11) must win the final two contests in the best-of-three series, which resumes Sunday at 3 p.m. CT.
Louisville plated three runs in the seventh inning to take the lead for good, including a two-out RBI single to left by Wasserman that tied the contest at two. Three batters later Helms poked a 1-2 pitch through the hole on the left side, plating two runs for a 4-2 Louisville advantage.
"I guess our demise was that seventh inning, we just couldn't get out of it," said Vanderbilt Head Coach Tim Corbin. "Helms did a good job of staying on the ball off a tough pitcher, and he drove it and clocked it into the infield and we really couldn't defend. It was in between the third baseman and shortstop, but we were kind of out of balance because of the base runners that they had on base."
The Cardinals added an insurance run in the eighth on a sacrifice fly from Shane Crain, a run they would need, as Vanderbilt scored once in the bottom of the eighth while stranding a pair, before leaving the bases loaded in the ninth.
Louisville starter Chad Green worked five innings, allowing two runs on six hits with two walks, but the right-hander did not figure in the decision. Dace Kime (6-1) struck out two in 1.1 hitless frames for the win, while closer Nick Burdi picked up his 16th save, working in-and-out of trouble for the final five outs.
Vanderbilt starter Kevin Ziomek (11-3, photo at right) suffered the loss, giving up four runs on five hits in 6.1 innings. The lefthander walked two and struck out four before departing with the bases loaded in a tie game. Helms' single to left came against reliever Brian Miller.
Louisville managed just six hits against Vanderbilt pitching, but took advantage of four hit batters and scored a pair of runners with sacrifice flies as well as driving in the other three runs with two-out hits.
Xavier Turner accounted for two hits and two runs scored for the Commodores, but Vanderbilt managed just seven hits in the game as well.
The Commodores got on the board with a run in the first after a one-out single from Turner, who stole second. He moved to third on a groundout by Mike Yastrzemski and after a two-out walk to Harrell, scored on Conrad Gregor's single through the right side for an early lead.
The Cardinals tied the contest in the second when Jeff Gardner was hit with one out and Cole Sturgeon walked. Crain followed with a single to right, loading the bases, before a sac fly from Wassermann plated the run.
Vanderbilt added a run in the third when Turner led off with a single to center before stealing second again. He went to third on a fly ball down the right field line by Yastrzemski and scored on Harrell's sharp single to left.
Gregor followed with a walk and with two outs, Vince Conde singled to left, but Coco Johnson made a great throw to the plate, nailing Harrell and keeping it a one-run game.
The Cards took the lead in the seventh, starting with a leadoff single from Gardner. He went to second on a groundout by Sturgeon and scored on a two-out single through the left side by Wasserman. Sutton Whiting followed with a single and Adam Engel walked, ending the day for Ziomek. Helms reached out and poked a single through the hole on the left side, plating the go-ahead runs for Louisville.
Louisville pushed across an insurance run in the eighth when Johnson was hit to leadoff, stole second and went to third on a groundout by Gardner. He scored on Crain's sac fly to right for a 5-2 advantage.
Vanderbilt cut into the deficit in the bottom of the inning after back-to-back walks to Yastrzemski and Harrell to start the frame, but Gregor struck out looking against lefty Cody Ege. Pinch-hitter Zander Wiel fouled out on a 3-1 pitch against Burdi, but after both runners moved up on a stolen base, UL third baseman Ty Young booted a routine grounder from Conde, allowing a run to score.
In the ninth Tony Kemp singled with one out and Yastrzemski drew another free pass. Harrell worked a two-out walk, but Gregor grounded out to second on the first pitch to end the game. The Commodores stranded 11 base runners in the contest, including five in the final two frames.
Corbin knows his team will still be fighting come tomorrow's game two.
"To me, it's a three round fight, and they won the first round, but they didn't knock us out," the coach said. "That's not going to happen. I like my bunch. We're in the same situation before we started today. We have 18 innings to win. We just have to concentrate on winning pockets of the game."
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Vince Condi (3) tags out Louisville Cardinals outfielder Adam Engel (10) during the second inning of the Nashville super regional of the 2013 NCAA baseball tournament at Hawkins Field. (Jim Brown-USA TODAY Sports)