In a group of 7dos healthy, relatively young subjects, we found the CardOut vs. V? o _{2} relationship to be significantly nonlinear in 27 (38%), most (25 subjects) of whom had a negative curvature. After separating the subjects into those with significant negative curvature compared with those with nonsignificant or positive curvature, the negative curvature group was found to have higher fitness level as measured by higher V? o _{2 max}/kg, maximal O_{2} extraction, and resting SV with lower resting HR. If negative curvature of the CardOut vs. V? o _{2} relationship indicates an approaching mechanical limitation to cardiac fatflirt dating pumping capacity, these results suggest that higher levels of fitness may, in some individuals, be associated with a true mechanical cardiac limitation to exercise.

## Sourced elements of mistake.

Our noninvasive method for measuring CardOut has been validated using the direct Fick method in healthy subjects (9). Nevertheless, it is worth considering whether the method was underestimating CardOut at higher levels of V? o _{2}, causing the negative curvature. Because the open-circuit method relies on efficiency of gas exchange, it may underestimate CardOut in the presence of alveolar ventilation/perfusion mismatch. However, this group of healthy subjects was free of lung disease and were lifetime nonsmokers, and we did not observe O_{2} desaturation >4% in any subject at maximal exercise. 3). Thus we feel this is likely a common finding, especially in athletic individuals, and not an artifact of the method.

## Comparison having literature.

Figure 3 compares mean regressions from our data with our laboratory’s previous validation study (9) as well as five other studies that provided data for all stages of exercise using more invasive techniques. Two of these (2, 5) show somewhat higher CardOut at any given V? o _{2} compared with both our data and the other studies. Both of these studies involved elite athletes (skiers and cyclists, respectively); other groups included athletes in their studies, although not exclusively. Astrand et al. (1) found the rate of increase in CardOut per unit change in V? o _{2} to be less above 70% of V? o _{2 max} compared with lower V? o _{2}, consistent with a significant negative curvature in CardOut vs. V? o _{2} in many of their subjects. Similarly, Sullivan et al. (19) found the CardOut vs. V? o _{2} relationship was best fit by a negatively curved power law relationship in 9 of 12 subjects. Neither study correlated this curvature in CardOut vs. V? o _{2} in relation to subject fitness as we have in our study. Astrand et al. (1) also documented a plateau in SV above 40% maximal capacity, indicating the curvature in CardOut vs. V? o _{2} was likely due to curvature of HR vs. V? o _{2}, although they did not present an analysis of this.

## Make of CardOut controls.

We believe that these data are consistent with the following model of CardOut regulation. _{2} is nearly linear. As V? o _{2} increases proportionate with external power output, the rate of increase in CardOut will depend on the rates of increase in HR and SV with increasing V? o _{2}. The derivative of the simple equation CardOut = SV ? HR gives the two components to the rate of change in CardOut:

These three illustrative examples suggest a conceptual framework for defining when CardOut is likely contributing to limitation of V? o _{2 maximum}. Assume for illustrative purposes that maximal O_{2} extraction is constant at 18 ml O_{2}/100 ml blood. When the CardOut vs. V? o _{2} relationship is purely linear, V? o _{dos maximum} is defined by the V? o _{2} at which maximal O_{2} extraction is reached, determined by the slope, with no limitation in CardOut. With increasing curvature of the CardOut vs. V? o _{2} relationship, as CardOut falls off with increasing V? o _{2}, the maximal O_{2} extraction is reached at a lower V? o _{2}, and one could argue that V? o _{2 max} is in part determined by O_{2} extraction and in part by a relative reduction in CardOut. The V? o _{dos maximum} value attained will be determined by the initial slope and the degree of curvature in the CardOut vs. V? o _{2} relationship. The extreme case is illustrated by the lower curve, where the final slope at V? o _{2 max} is zero and CardOut reaches an upper limit that is not exceeded, even if V? o _{2} could increase.

## CardOut.

Values are means ± SD (with range in parentheses). BMI, body mass index [wt(kg)/ht(m) 2 ]; HR, heart rate; SV, stroke volume; BSA, body surface area; CardOut, cardiac output; RER, respiratory exchange ratio (V? co _{2}/V? o _{2}, where V? co _{2} is CO_{2} production); Hgb, hemoglobin concentration in blood (mg/100 ml); V? e , minute ventilation; group 1, subjects with a statistically significant negative CardOut vs. V? o _{2} curvature; group 2, subjects whose CardOut vs. V? o _{2} curvature was not statistically significantly negative. Max, maximal; Rest, resting; Min, lowest V? e /V? co _{2} during exercise test, or minimal V? e /V? co _{2}. All P values for comparison of group 1 and group 2 are from Wilcoxon rank sum tests or ? 2 tests.

To investigate whether the difference in exercise responses between groups was not simply associated with differing performance effort or possible hyperventilation that might affect the CardOut measurement in the exercise test, the average ventilatory equivalent for CO_{2} at its minimum (minute ventilation; an index of degree of hyperventilation near the ventilatory threshold) and at maximal exercise were not found to be different between the groups. Protocol duration, maximal HR, and maximal RER were also found to be not significantly different (Table 1). Furthermore, the slope of the work intensity vs. V? o _{2} relationship averaged 10.5 ml·min ?1 ·W ?1 (R 2 = 0.96) for the negative curvature group and 10.3 ml·min ?1 ·W ?1 (R 2 = 0.97) for the non-negative curvature group.

The ratio of maximal to resting values for V? o _{2}, CardOut, O_{2} extraction, and HR were correlated in the entire group in an effort to quantify the capacity of the subjects to expand V? o _{2} and the components of that capacity. There was a high correlation between the V? o _{2} ratio and O_{2} extraction ratio (r = 0.58, P < 0.01). There was a reasonable correlation between V? o _{2} ratio and CardOut ratio (r = 0.46, P < 0.01), indicating V? o _{2} capacity is related to a subjects’ capacity for expanding CardOut. The correlation of V? o _{2} ratio with HR ratio was not as good (r = 0.22, P = 0.06). There was poor correlation between V? o _{2} ratio and our measure of curvature, the final/initial slope ratio of the CardOut vs. V? o _{2} relationship (r = ?0.11, P = 0.36).

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