Phenylephrine provocation to evaluate the etiology of mitral regurgitation in patients with obstructive hypertrophic cardiomyopathy

Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy (oHCM) is common and often requires septal reduction therapy to alleviate symptoms when maximal medical therapy fails. The obstruction is related to systolic anterior motion (SAM) of the mitral valve (MV), which can cause significant mitral regurgitation (MR).^{1, 2} While relief of outflow tract obstruction may be sufficient to ameliorate SAM-associated MR, up to 20% of patients with oHCM have concomitant intrinsic MV disease; furthermore, intrinsic MR increases with age.³ Elucidating the etiology of MR is critical, as it affects management. Here we present a method for determining the etiology MR in oHCM using a dynamic drug suppression test (phenylephrine provocation procedure, or PPP) during pre-operative transesophageal echocardiography (TEE) to help guide septal reduction planning.

Fifty-eight patients with oHCM referred to our HCM Center of Excellence for septal reduction therapy with at least moderate or poorly visualized MR on pre-operative echocardiography, underwent a pre-operative HCM-focused TEE with PPP. MV morphology and MR were assessed in multiple views, specifically recording MR jet direction, timing of MR, valve coaptation, and presence/absence of systolic flow reversal in pulmonary veins, while also recording simultaneous systolic blood pressure (SBP). After this assessment, bolus doses of 100 – 300 μg of phenylephrine were administered intravenously in an attempt to raise the SBP at least 25 mmHg and MR was reassessed. Patients were assigned both a baseline and post-provocation MR severity score (0 – none/trivial, 1 – mild, 2 – mild/moderate, 3 – moderate, 4 – moderate/severe, and 5 – severe). The results of PPP were categorized as follows: “positive” PPP, where the operator reported an appreciable decrease of MR severity by at least 1 point associated with an increase in SBP after phenylephrine administration (i.e. MR improved with higher afterload, as would be expected with SAM-related MR); “negative” PPP, where the operator reported no appreciable change in MR severity despite an increase in SBP of at least 25 mmHg after phenylephrine administration; and “non-diagnostic” PPP, where the operator reported no appreciable change in MR severity after phenylephrine administration but noted that this was in the setting of failing to increase the SBP by at least 25 mmHg. Patients then underwent a septal reduction procedure. For all patients undergoing surgical myectomy, the surgeon re-assessed MR severity following septal muscle resection by intra-operative TEE, and performed valvular intervention as indicated for residual severe MR. The majority of patients had a 3-month post-procedure echocardiogram, where MR severity was reassessed and reported. For those patients without a 3-month post-procedure study (N = 15), MR severity as determined by intra-operative TEE following the procedure was used. We performed a sensitivity analysis without these subjects included and found similar results. Data including all patients are reported hereafter.

58 patients met inclusion criteria and were included in the analysis. The cohort was 40% male, with a mean age of 60 ± 11 (SD) years. All patients had persistent symptoms and evidence of hemodynamically significant outflow tract obstruction despite maximal medical therapy. Of the 58 patients, 41 underwent septal myectomy, and 17 underwent alcohol septal ablation (ASA).

47 patients had a positive PPP (Figure). Pre-PPP MR jet direction was posterior in 31 patients (66%) and central or anterior in 16 patients (34%). Phenylephrine administration resulted in a change from average baseline MR severity grade of 4.60 ± 0.12 (moderate/severe) to 2.06 ± 0.17 (mild/moderate) with a concomitant increase in SBP of 43 ± 3 mmHg. A correlation between change in SBP and ability to confidently determine a change in MR severity was noted. None of the patients in the positive PPP cohort required MV repair or replacement at the time of the septal reduction procedure, indicating that a positive PPP showed a positive predictive value (PPV) of 100%. After septal reduction, the average post-procedure MR decreased even further to 0.91 ± 0.10 (mild).

Figure. (A-D) Example of positive PPP with decrease in MR with increase in SBP.

There is marked variation in severity of MR as well as leaflet coaptation over a range of nearly 1100mmHg SBP in response to phenylephrine. (A) Severe “wide-open” central MR with impaired leaflet coaptation at a SBP of 92mmHg. Upon raising the SBP to 134 mmHg (panel B), the MR diminishes, as does the turbulence of the LVOT. (C) At SBP of 144 mmHg the MR decreases to trivial. (D) At SBP of 187mmHg, there is marked improvement in leaflet coaptation, trivial SAM, and absence of MR. Note that all of these images were obtained at the same TEE probe angle, and at the same time in systole. (E) Boxplot analysis of MR score in the positive PPP cohort. As noted in the text, the baseline MR was 4.60, which improved to 2.06 after phenylephrine provocation. After septal reduction, the average MR was 0.91. On each box, the central mark indicates the median, and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. The whiskers extend to the most extreme data points not considered outliers. N = 47 patients in the positive PPP cohort. MR score of 5 – severe, 4 – moderate/severe, 3 – moderate, 2 – mild/moderate, 1 – mild, 0 – trace / none. (F) Correlation between SBP change after phenylephrine administration and change in MR severity for the positive PPP group. For those with ≤ 25mmHg change in SBP, the change in MR grade was modest (−2.25), as compared to 25–40mmHg (−2.33) and >40mmHg (−2.81). While there is a trend, no group attained statistical significance.

In those with a negative PPP (N = 6), MR grade was 4 ± 0.68 (moderate/severe), which persisted, despite an increase in SBP of 44 ± 6 mmHg with phenylephrine. In this group, 2 patients were felt to need MV repair at the time of surgery. In the non-diagnostic PPP cohort (N = 5), baseline MR was 4.6 ± 0.24 (severe), which remained similar in the absence of a change in SBP with phenylephrine provocation (change of 5 ± 4 mmHg). Taken together, a positive PPP at the time of pre-procedure assessment with TEE was 92.2% sensitive and 100% specific for predicting whether the MV would require surgical intervention at the time of septal reduction. In our cohort, PPP appeared to be a better discriminator than MR direction.

MR is highly prevalent among patients with oHCM, and may be a consequence of SAM of the mitral valve or intrinsic mitral valve disease. The prevalence of intrinsic MR, which carries significant morbidity and mortality, increases with age,³ and no current method has been described for its differentiation from SAM-related MR. Management of SAM-related vs. intrinsic MR is distinct, making the correct diagnosis imperative. We propose that PPP should be performed in patients who have at least moderate MR or in whom MR is poorly visualized to inform preoperative planning and decision-making prior to septal reduction therapy. We further propose that the PPP should be performed pre-operatively (rather than intra-operatively), as changing loading conditions under general anesthesia may complicate the assessment of MR severity and etiology.^{4, 5} Furthermore, there are additional concerns related to risks associated with replacement of a competent MV during myectomy, and the inability to intervene upon the MV during a noninvasive ASA procedure.

In summary, we present a novel provocative test that has 100% PPV and 100% specificity for predicting whether MV surgery will be required at the time of septal reduction therapy in oHCM. We believe that this test has important clinical utility.