Improved Patient Outcomes by Normalizing Sympathovagal Balance: Differentiating Syncope-Precise Subtype Differentiation Leads to Improved Outcomes

Abstract

Syncope is difficult to definitively diagnose, even with tilt-table testing and beat-to-beat blood pressure measurements, the gold-standard. Both are qualitative, subjective assessments. There are subtypes of syncope associated with autonomic conditions for which tilt-table testing is not useful. Heart rate variability analyses also include too much ambiguity. Three subtypes of syncope are differentiated: vasovagal syncope (VVS) due to parasympathetic excess (VVS-PE), VVS with abnormal heart rate response (VVS-HR), and VVS without PE (VVS-PN). P&S monitoring (ANSAR, Inc., Philadelphia, PA) differentiates subtypes in 2727 cardiology patients (50.5% female; average age: 57 years; age range: 12-100 years), serially tested over four years (3.3 tests per patient, average). P&S monitoring noninvasively, independently, and simultaneously measures parasympathetic and sympathetic (P&S) activity, including the normal P-decrease followed by an S-increase with head-up postural change (standing). Syncope, as an S-excess (SE) with stand, is differentiated from orthostatic dysfunction (e.g., POTS) as S-withdrawal with stand. Upon standing, VVS-PE is further differentiated as SE with PE, VVS-HR as SE with abnormal HR, and VVS-PN as SE with normal P- and HR-responses. Improved understanding of the underlying pathophysiology by more accurate subtyping leads to more precise therapy and improved outcomes.

Figure 1

A spectral domain comparison of the LFa and RFa method [8] and the LF and HF method [12, 13] (see Methods for abbreviations). The vertical broken line represents the respiratory frequency over the four-second measurement period. The respiratory frequency is independently computed in the respiratory activity spectrum (not shown) and then transferred here to the HRV spectrum to locate the RFa (parasympathetic) spectrum. In this way, the RFa spectrum is based on the breathing rate of the subject. In this example, the respiratory frequency is 0.125 Hz (equivalent to 7.5 breathes per minute). The LF spectrum is represented in dark grey from 0.04 Hz to 0.15 Hz [12, 13]. The HF spectrum is represented in light grey from 0.15 Hz to 0.40 Hz [12, 13]. The RFa spectrum, in this example, is from 0.065 Hz to 0.185 Hz [8]. The RFa is computed from a frequency range centered on the respiratory frequency (0.125 Hz, see above) and moves as the respiratory frequency moves [8]. The LFa spectrum, in this example, is from 0.04 Hz to 0.065 Hz. The LFa is computed as the (fixed) LF frequency range (0.04 Hz to 0.15 Hz) minus the portion of the RFa frequency range that overlaps the LF frequency range (in this example, 0.065 Hz to 0.15 Hz) [8]. LFa, in (beats per minute)² or bpm², represents sympathetic activity, and RFa, in bpm², represents parasympathetic activity [, –17].

Figure 2

Instantaneous HR, instantaneous breathing, and instantaneous P&S responses (trends) to the standard clinical study from a syncopal, 23-year-old male. Note the instantaneous S-excess (SE, red trace) during the stand challenge (section “F”) of the trends plot (right plot). The SE correlates with the abnormal HR response to stand (left plot). HR remains high during stand, and there is no return to baseline. See text for details and Methods for abbreviations.

Figure 3

Instantaneous HR, breathing, and P&S responses (from left to right) to the standard clinical study from a healthy, 44-year-old female. Her average resting responses are a HR of 65 bpm, BP of 102/59 mmHg, S-activity (LFa) of 1.65 bpm², P-activity (RFa) of 1.66 bpm², and an SB (LFa/RFa) of 1.00 (unitless). See text for details and Methods for abbreviations.

Figure 4

Average challenge responses from instantaneous responses in Figure 1. Patient's average resting responses included a HR of 84 bpm, BP of 109/73 mmHg, S-activity (LFa) of 2.38 bpm², P-activity (RFa) of 0.68 bpm², and a sympathovagal balance (LFa/RFa) of 2.49 (unitless). All average responses are within published normal limits (as represented by the grey areas) [5], except the stand response which indicates SE. See text for details and Methods for abbreviations.

Figure 5

Results from a 34-year-old male, non diabetic patient, with a BMI of 25.7/in², treated for labile hypertension with complaints of lightheadedness. At rest, his HR was 85 bpm, BP was 132/89, LFa was 0.58 bpm², RFa was 0.41 bpm², and SB was 1.41. At rest, he demonstrates advanced autonomic dysfunction (from the first plot on the second row, his response (point “A”) is below the grey, or normal, area due to his RFa being less than 0.5 bpm²) and PE with Valsalva (left panel of the last plot on the second row). From his trends plot (the last plot on the first row), his peak (red) S-response to stand (section “F”) is greater than one-third of that of Valsalva (section “D”), indicating an instantaneous SE, associated with (preclinial)syncope. Taken together, the SE with PE, VVS-PE is diagnosed. Treating the Vagal component and history of hypertension with Carvedilol [23] relieved both the syncopal events and the labile hypertension.

Figure 6

Clinical autonomic study results from a 36 year-old-male diagnosed with posttraumatic stress disorder and hypertension, with a BMI of 54.2/in², and tilt-positive for vasovagal syncope. At rest, his HR was 75 bpm, BP was 147/94 mmHg, LFa was 2.34 bpm², RFa = 0.26 bpm², and SB was 9.16. At rest, he demonstrates advanced autonomic dysfunction (the first plot on the second row, his response (point “A”) is below the grey, or normal, area due to his RFa being less than 0.5 bpm²) and PE with Valsalva and stand (left panel of the last plot on the second row). From his trends plot (the last plot on the first row), his peak (red) S-response to stand (section “F”) is greater than one-third of that of Valsalva (section “D”), indicating an instantaneous SE, associated with (preclinical) syncope. Taken together, the SE with PE, VVS-PE is diagnosed. Treating the vagal component with the hypertension with carvedilol [23] prevented syncope and reduced his resting BP.