This study directly compared several SIs obtained from VM in patients with graded SF. I3, which measures the difference between the baseline BP and the BP at the end of phase 2, had clear advantages over the other indexes, being the only index that separated all SF groups from each other. At the same time, I3 had the highest correlation with OH, a proxy for SF. Perhaps the main reasons why this index performed the best are that it represents the sympathetic vasoconstrictor responses due to the preceding drop in BP and at the same time has the highest dynamic range. I2, which theoretically reflects the “pure” vasoconstrictor response, could not differentiate between studied groups. The suboptimal performance of I2 is due to its low dynamic range. Although I1 segregated both moderate and severe SF, it was not sensitive enough to distinguish between the control and mild SF group or between the mild and moderate SF groups. With I1, the stimulus (BP fall) and the responses (BP recovery) are blended, and hence this method most likely reflects more complex mechanisms. For example, the initial drop in BP at the beginning of phase 2 depends on conditions other than sympathetic activity, such as volume status–venous capacitance, that could contribute to the limited performance of I1.
Methods focusing on the duration of BP changes evoked by VM were less sensitive than I3 in differentiating between studied groups. PRT (I5) separated the moderate from the severe SF group, but was unable to separate the other groups from each other. BRSa was even less sensitive, failing to differentiate between any groups. Without normalization, i.e., division by PRT, the BRSa is essentially a combined I1 with I2 method. The addition of normalization to the BRSa lessened its ability to differentiate between the study groups, thus suggesting that loss of BRSa sensitivity is due to PRT. PRT reflects changes of BP during phase 4 and phase 4 is under more complex influences. In addition to sympathetic vasoconstrictor activation, phase 4 also reflects cardiovagal and cardiac sympathetic functions.3
Surprisingly, simple latency of minimal BP during phase 2 either outperformed or matched all indexes except I3.
The I3 method correlated with the BP fall during the tilt test. The highest correlation was within the first minute of the tilt whereas the correlation later during the tilt was reduced. This observation is consistent with the time profile of sympathetic activation. In general, sympathetic-mediated responses occur within 5–15 seconds after the stimulus. The initial response to tilt (within the first 30 seconds) is biphasic and results in an initial fall in BP and then recovery due to generalized sympathetic-mediated peripheral vasoconstriction.16
Then increased correlation between VM and initial tilt responses indicates that both responses reflect sympathetic-mediated vasoconstriction. At the same time, VM does not provide the same information as the whole tilt test since the correlation between VM and tilt is reduced toward the end of the tilt. Therefore VM cannot replace the tilt test in detection of sympathetic impairment but both tests complement each other.
The I3 method segregated all SF groups using median and diastolic BP but not when using systolic BP. This finding may be related to the fact that diastolic BP (and median BP since it is more weighted by diastolic than by systolic BP) reflects primary the peripheral resistance as indicated by its association with the muscle sympathetic activity17
while systolic BP is under more complex influences that include sympathetic drive and cardiac output.
This study has several limitations. First, this is a retrospective study where the SIs were applied to selected patients and might not be applicable for other patients. However, all indexes were calculated using the same data covering a wide spectrum of SF. Second, sympathetic functions were not measured directly. Instead, the degree of SF was primarily graded according to the degree of OH. Neurogenic OH is a commonly accepted proxy of sympathetic dysfunction providing that there are no non-neurogenic causes of OH such as hypovolemia/dehydration, systemic infection, or cardiac dysfunction.18
None of the non-neurogenic causes of OH were observed in this study, suggesting that the VM-induced BP changes indeed reflected sympathetic functions. Furthermore, it would be impractical to measure invasively the sympathetic activity directly in such a large sample, especially in patients with severe autonomic failure.
An inherent limitation of VM is that a substantial number of patients had to be excluded from analysis. Common reasons for exclusion are inability to perform VM or use of medications that interfere with the BP response to VM. Frequently, it is unsafe to discontinue such medication before the testing. However, the most common reason for exclusion was frequent occurrence of a square wave response (SWR) or partial SWR that precludes calculations of SI. The SWR variant of VM can be indicative of congestive heart failure19
or be a normal variant.13
There are no established criteria for differentiation between partial SWR and abnormal VM due to SF. The partial SWR can mimic normal VM responses, and can result in normal-like VM-derived responses in patients with sympathetic failure. In this study, the SWR determination was made on a case-by-case basis.
The I3 is the optimal method for calculation of SI since it tracks the full spectrum of SF from mild to severe and it easily differentiates between healthy controls and those with SF.