Clinical characteristics and cardiac function
Clinical characteristics of the study population are shown in . The HFpEF participants were predominantly female, and ranged in age from 42–88 (median = 63). The HFpEF patients had a higher prevalence of smoking than the control group. Both groups were overweight, with similar resting heart rates and blood pressures. No control participants were being treated with antihypertensive medications. The majority of HFpEF patients were on treatment for hypertension with multidrug regimens. While exercise tolerance was not evaluated, all HFpEF patients reported decreased exercise tolerance, as determined by medical history and study questionnaire, while no control participants reported this symptom. No HFpEF subject had a significant secondary explanation for their dyspnea, as participants were excluded if they had any evidence of significant non-cardiac disease causing dyspnea. Most patients completed the dobutamine protocol, however one HFpEF participant developed severe hypertension at dobutamine doses ≥8 mcg/kg/min. Data from this participant obtained at lower dobutamine doses were included in the analysis.
Standard echocardiographic data obtained from 2D and Doppler measurements at baseline are shown in . The ventricles of the participants with HFpEF were of normal size, although left ventricular end diastolic dimension was increased compared to controls, as was the left ventricular mass index. Relative wall thickness was normal, despite the presence of hypertension in this population. LA volume, however, was 80% larger in HFpEF than in control participants, consistent with the presence of HF. Despite the presence of clinical heart failure in all subjects, echocardiographic evidence of diastolic dysfunction was not present in most subjects. (),
In both control and HFpEF participants, dobutamine had a similar dose-dependent effect to increase HR with no significant HR differences between groups at any dose (). However, the effect of dobutamine on systolic blood pressure (SBP) differed in the two groups at the maximal level of dobutamine infusion (16mcg/kg/min). At lower doses of dobutamine infusion, there was no difference in SBP between groups. In control participants, SBP rose and fell at the higher doses of dobutamine infusion, whereas HFpEF participants hadconsistently increased SBP with increasing doses of dobutamine, such that the SBP was significantly higher at 16 mcg/kg/min in HFpEF than control participants (). End systolic volume was similar for both groups at baseline (HFpEF = 26.9 ± 3.6ml vs. control = 26.3 ± 2.2ml) but differed significantly at 16 mcg/kg/min (HFpEF = 25.0 ± 3.8ml vs. control = 14.7 ± 2.5ml; p=0.04), whereas no significant differences were detected for end diastolic volume at either baseline (HFpEF = 75.7 ± 7.8ml vs. control = 70.2 ± 6.3ml) or at the maximal dobutamine dosage (HFpEF = 64.0 ± 8.5ml vs. control = 72.0 ± 7.7ml).
A dose-dependent effect of dobutamine on heart rate and systolic blood pressure in control and HFpEF participants
Inter-reader variability for all measurements was low, e.g., measurements of tissue Doppler E/E′ in the control group was 6.64 ± 0.8mm vs. 6.78 ± 0.6mm (p = 0.96).
At baseline, EF in HFpEF (63.2±3.2%) and control (68.4±1.6%) participants was not significantly different. While EF increased with dobutamine in a dose-dependent manner in control participants, no increase in EF was evident in HFpEF participants (). Thus, contractile reserve, defined as change in EF, was reduced in HFpEF participants compared to controls at low dose (4mcg/kg/min; ΔEF HFpEF = 0.4 ± 2.1 vs. control = 7.9 ± 1.7, p<0.02) and the maximal 16 mcg/kg/min dose (Δ EF HFpEF = 0.4±1.9% vs. control = 19.0±1.4%, p<0.001).
A dose-dependent effect of dobutamine on contractile reserve in control and HFpEF participants
Longitudinal displacement and velocity
Myocardial displacement () and velocity tangential to the long axis of the ventricle () were analyzed using the basal LV segments. At baseline, there was no significant difference in mean peak longitudinal displacement between HFpEF (6.5±1.4 mm) and control (7.5±1.1 mm) participants. The dobutamine response in HFpEF participants was blunted relative to control participants ( and ). For example, 4 mcg/kg/min infusion of dobutamine increased the displacement of lateral segment from 7.5 ± 1.1 mm to 9.4 ± 1.4 mm in control participants with no significant change seen in HFpEF patients (6.5±1.4 mm to 5.0 ± 0.8 mm). A similar response was seen in the basal septal segment. Peak systolic velocity measured in the basal lateral segment was significantly different between the two groups at baseline, and failed to increase significantly in HFpEF, but increased significantly in control participants, such that velocity was significantly greater in controls than in HFpEF under all conditions (). Significant differences were also detected for the septal basal segment between groups at higher dobutamine doses, although not at baseline, likely due to the lower velocities in the septal region. VVI-determined early diastolic velocities were only significantly different at maximum dobutamine doses, and only in the lateral segment ().
Longitudinal displacement before and after infusion of dobutamine
A dose-dependent effect of dobutamine on systolic and diastolic longitudinal velocities in control and HFpEF participants
A dose-dependent effect of dobutamine on systolic and early diastolic strain rate in control and HFpEF participants
Radial velocities and displacement increased modestly with dobutamine in both groups, typically reaching maximal values at 4mcg/kg/min for velocity measurements and 8mcg/kg/min for displacement measurements, with no further increases at higher doses of dobutamine. No significant differences were found between groups in the radial dimension for either velocity or displacement.
Systolic strain rate and early diastolic strain rate yielded robust statistical differences following dobutamine infusion both between groups and when compared to baseline values for the control group. The systolic component of strain rate rose significantly in the control group, while an increase in strain rate in the HFpEF participants was not evident at lower dobutamine doses. When comparing the increases in strain rate, differences between groups were found at the lower dobutamine doses (2 and 4mcg/kg/min, ).
Similarly early diastolic values of strain rate increased reproducibly in the control group, with a far less impressive increase in HFpEF participants. The magnitude of the difference between the groups in early diastolic strain rate was maximal at 4mcg/kg/min (Control 2.5 ± 0.4 s−1 vs. HFpEF 1.2 ± 0.2 s−1). Differences did not reach statistical significance between groups for the remaining dosages, most likely due to variability and small sample size.
When examining change in strain rate vs. baseline, significant changes were found between the control and HFpEF groups at 2mcg/kg/min, 4mcg/kg/min and 8mcg/kg/min for the early diastolic component (E′) of strain rate (), and at 2mcg/kg/min and 4mcg/kg/min for the systolic (S′) component of strain rate () measured in the basal lateral free wall.