Chronotropic Incompetence Rather than Stroke Volume Is the Main Driver of Impaired Cardiac Output Response in Patients on Hemodialysis

Background: Impaired cardiovascular functional capacity (CFC) is a major complication in hemodialysis (HD) patients and contributes to diminished survival rates and compromised quality of life. Reduced CFC (as assessed by VO2Peak) is known to arise from both reduced cardiac output (CO) response and impaired oxygen extraction at the level of the contracting skeletal muscle (Fick Principle). However, at the CO level, it is unclear which determinant, heart rate (HR), or stroke volume (SV) primarily drives impaired response at peak exercise (PE) in patients on dialysis. Herein, we sought to determine the major cardiac determinants of impaired CO response during PE in HD patients. Methods: We recruited seven HD patients and five healthy controls (CON). All participants underwent comprehensive breath-by-breath cardiopulmonary exercise testing (CPET) with simultaneous 12-lead EKG, pulse oximetry and CO monitoring via impedance cardiography. A t-test and a repeated measures two-way ANOVA were performed for analysis between groups, and a multiple linear regression to test for associations. Results: Both groups were well-matched by age (HD:47±15,CON:51±8yr) and BMI (HD:28.2±5.0, CON:26.7±2.9kg/m2). VO2Peak was impaired in HD patients compared to CON (HD:12.9±4.5; CON:27.1±6.3mL/min-1kg-1, p<0.001). Both HD and CON patients demonstrated progressive increase in HR, SV, and CO during warm-up to the PE compared to resting measures (p<0.05). However, HD patients exhibited significant chronotropic incompetence at PE (HRR:+36±20%) compared to CON (HRR: +82±5.2%, p<0.05). The delta changes observed at rest to PE were significantly lower in the HD group compared to the CON group for HR (+34.±18;CON: +86±22 bpm;p=0.001), SV (+20±6;CON:+38±14mL;p=0.008), and CO (+4.7±1.5;CON:+14.8±4.6L.min-1;p=0.0002). Multiple linear regression modeling showed that delta changes in HR, but not in SV were associated with CO at peak exercise (β(standard error)= 0.08(0.02), p=0.008) in HD patients. Conclusion: HD patients exhibited a smaller increase in HR and SV at peak exercise. However, our findings suggest that chronotropic incompetence is the major cardiac determinant of impaired CO response at PE in patients on dialysis.