Background-The muscle hypothesis implicates abnormalities in peripheral muscle as a source for the stimulus to the symptoms and reflex abnormalities seen in chronic heart failure (CHF). We investigated the relationship between skeletal muscle mass (with dual-energy x-ray absorptiometry) and activation of the ergoreflex (a peripheral reflex originating in skeletal muscle sensitive to products of muscle work) in CHF patients and whether this rapport is affected by the progression of the syndrome. Methods and Results-We assessed 107 consecutive CHF patients (mean age, 61.9Ϯ10.9 years; 95% male; 25 cachectics) and 24 age-matched normal subjects (mean age, 59.0Ϯ11.1 years; 91% male). Compared with normal subjects, patients had a higher ergoreflex (in ventilation, 6.2Ϯ.6.1 versus 0.6Ϯ0.6 L/min; PϽ0.0001) and a reduction in muscle mass (51.9Ϯ10.0 versus 60.3Ϯ8.8 kg; PϽ0.001). The ergoreflex was particularly overactive in cachectics (PϽ0.05), accompanied by marked muscle mass depletion (PϽ0.0005). In CHF, ergoreceptor hyperresponsiveness in both the arm and leg correlated with reduced muscle mass, abnormal indexes of exercise tolerance (peak V O 2 , V E/V CO 2 slope), ejection fraction, and NYHA functional class (PϽ0.0001). In the cachectic population, the ventilatory response from ergoreflex to arm exercise was strongly inversely correlated with arm (rϭϪ0.65), leg (rϭϪ0.64), and total (rϭϪ0.61) lean tissues (PϽ0.001 for all). Multivariate analysis showed that these relationships were independent of NYHA class, peak V O 2 , and V E/V CO 2 slope. Conclusions-Depleted

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His Bundle Pacing LBBB Reversal Biventricular Pacing LV LV LV RV RV RV Mean LV Activation Time Reduction SBP change compared to intrinsic activation Above: Epicardial maps of LV and RV activation in one patient during intrinsic rhythm (LBBB), His pacing (LBBB has resolved) and biventricular pacing. The colour scale (left) shows that the late (blue) activation of the LV in intrinsic activation is not seen with His pacing: LBBB is overcome, shortening LV Activation Time (LVAT). BVP shows earliest (red) activation apically, as expected, in both the RV and LV. Right: Left Ventricular Activation Time is reduced by His Bundle Pacing (HBP) overcoming LBBB. Biventricular Pacing (BVP) also reduces activation time but to a lesser extent. BP is improved by BVP, but not as much as with HBP with resolution of LBBB. The white BVP HBPLVAT reduction from intrinsic (ms)