Flatheads have built-in disadvantages of limited breathing, poor chamber shape, and low max compression ratio that even nice modern EFI and other controls can't fully compensate for.
Other than that, the main disadvantage the old stuff had was in fuel delivery. Put a sophisticated modern EFI on just about any old non-flathead and I bet it would have vastly improved fe, perhaps in some cases almost as good as modern day engines.
That said, there are other disadvantages old engines are burdened with. Air-cooleds like VW and Corvair experience wider temp operating ranges (less controllable heat mgmt) so the pistons and rings are set up a bit looser causing more blow-by, and the carbs are set to run a bit rich to aid in cooling, neither of which help fe. In spite of that, VWs and Vairs can get good fe because of the efficiency of the rest of the vehicle.
Even the older liquid-cooleds don't have the nice tight tolerance control today's engines have. Combined with today's improved pistons and rings, there is less blow-by now.
Today's better chamber and piston crown shapes further enhance complete combustion. We can run higher compression ratios on lower grades of fuel. Yes some older engines had very high CRs but they required premium.
Today's materials are better too. For example, small block Chevys were usually made from a really soft grade of cast iron because GM was more concerned about the longevity of their factory boring tools than the longevity of the cylinders in the hands of the customer. Achieving 100,000 miles back then was a rarity; now we would be angry if an engine didn't go 200,000 miles (well, some of us anyway).
There have also been improvements in internal friction reduction via lighter rotating assemblies, smaller bearing surfaces, lower distortions in cylinders, better piston skirt and ring designs, and better balancing.
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