Safety and utility of dobutamine and pressure wire ...

Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Cardiovascular Revascularization Medicine

Safety and utility of dobutamine and pressure wire use in the hemodynamic assessment of low flow, low gradient aortic stenosis with reduced left ventricular ejection fraction☆ Zaher Fanari a,⁎, Prasad C. Gunasekaran b, Arslan Shaukat b, Sumaya Hammami c, Buddhadeb Dawn b, Mark Wiley b, Peter Tadros b a b c

Heartland Cardiology/Wesley Medical Center, University of Kansas, Wichita, KS, United States Division of Cardiovascular Diseases, University of Kansas, Kansas City, KS, United States Department of Medicine, University of Kansas, Wichita, KS, United States

a r t i c l e

i n f o

Article history: Received 3 September 2017 Received in revised form 2 October 2017 Accepted 2 October 2017 Available online xxxx Keywords: Low flow low gradient aortic stenosis Dobutamine Pressure wire

a b s t r a c t Background: The ACC/AHA guidelines recommend low-dose dobutamine challenge for hemodynamic assessment of the severity of AS in patients with low flow, low gradient aortic stenosis with reduced ejection fraction (EF) (LFLG-AS; stage D2). Inherent pitfalls of echocardiography could result in inaccurate aortic valve areas (AVA), which have downstream prognostic implications. Data on the safety and efficacy of coronary pressure wire and fluid-filled catheter use for low dose dobutamine infusion is sparse. Methods: We retrospectively analyzed 39 consecutive patients with EF b 50%, AVA b 1 cm2 and SVI b 35 ml/m2 on echocardiography who underwent simultaneous right and left heart catheterization. Hemodynamic assessments were performed at baseline and at every increment in the dobutamine infusion rate (The infusion was continued until maximal dose of dobutamine or a mean AV gradient N 40 mm Hg was attained. The occurrence of sustained ventricular arrhythmias, symptomatic hypotension or intolerable symptoms leading to cessation of infusion was recorded. Transient ischemic attacks (TIAs) or clinically apparent strokes periprocedurally or up to 30 days after the procedure were recorded. Results: Dobutamine challenge confirmed true AS in 26 patients (67%) and pseudosevere AS in 34%. No sustained arrhythmias, hypotension or cessation of infusion from intolerable symptoms were observed. No clinical strokes or TIAs were observed up to 30 days after procedure in any of these patients. Conclusions: Hemodynamic assessment of AS using a pressure wire with dobutamine challenge is a safe and effective tool in identifying truly severe AS in patients with LFLG-AS with reduced EF. © 2017 Elsevier Inc. All rights reserved.

1. Introduction Low flow, low gradient severe aortic stenosis (LFLG - AS) with reduced ejection fraction (EF) is defined as symptomatic severe AS with an aortic valve area (AVA) b1 cm2, stroke volume index (SVI) b35 ml/ m 2 coupled with a resting peak systolic velocity (Vmax) b4 m/s or a mean pressure gradient b 40 mm Hg across velocity across the aortic valve (AV) in patients with low ejection fraction (EF). This group constitutes a distinctive group of patients with unique diagnostic and prognostic features that earned a distinct entity (as a stage D2) in the

☆ Conflict of interest: The authors report no relationships that can be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: University Of Kansas, Heartland Cardiology/Wesley Medical Center, 551 N Hillside St #410, Wichita, KS 67214, United States. E-mail address: [email protected] (Z. Fanari).

current American College of Cardiology/American Heart Association (ACC/AHA) valvular heart disease guidelines [1]. The low flow variant represents up to 55% of patients diagnosed with AS and portends a significantly worse prognosis in comparison to normal flow, high gradient (NFHG-AS) when subjected to surgical (SAVR) or transcatheter aortic valve replacement (TAVR) by virtue of the underlying low flow state (defined as a SVI b35 ml/m 2) in terms of all-cause mortality [2]. Data from the Placement of Aortic Transcatheter Valves (PARTNER) trial elicits low flow state as an independent predictor of all-cause mortality in patients with severe AS who underwent TAVR or SAVR while left ventricular ejection fraction (LVEF) and mean transvalvular gradient across the AV were not predictive [2]. The ACC/AHA Valvular heart disease guidelines recommend lowdose dobutamine echocardiographic or catheter-based direct invasive hemodynamic assessment of the severity of AS in patients with stage D2 (Class IIa, level of evidence B) [1]. However, multiple inherent pitfalls of echocardiographic assessment such as load dependence of

https://doi.org/10.1016/j.carrev.2017.10.001 1553-8389/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: Fanari Z, et al, Safety and utility of dobutamine and pressure wire use in the hemodynamic assessment of low flow, low gradient aortic stenosis wit..., Cardiovasc Revasc Med (2017), https://doi.org/10.1016/j.carrev.2017.10.001

2

Z. Fanari et al. / Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx

measurements, inaccuracies from outflow tract measurements in severely calcified valves, suboptimal sampling of peak systolic velocity due to limited acoustic windows, angulation errors, inaccurate sampling of the Doppler signals further away from the AV, assumption of the circular geometry of the LV outflow tract as opposed to an actual elliptical shape and the discrepancies between calculated AVA by continuity equation and the actual anatomical orifice arising from aberrations in the structure of the AV are to be noted [3]. A resultant effect of these limitations is either underestimation or overestimation of AVA, which have downstream prognostic implications on outcomes in this high-risk group [4,5]. Therefore, there exists an adjunctive role for direct, invasive catheter-based measurements of AVA with the use of a pressure wire in cases of discrepant echocardiographic findings or as a primary modality for hemodynamic assessment in this subgroup of patients with severe AS [6]. Although safety of using pressure wires in hemodynamic assessment of patients with severe AS was shown in small cohort of patients, [6] there is no reports assessing the safety and utility of combining the use of dobutamine with pressure wire in the hemodynamic assessment patients with stage D2 AS. 2. Methods We performed a retrospective analysis of the electronic health records of the University of Kansas Health System from 2012 to 2016 to identify patients with an echocardiographic diagnosis of LFLG-AS stage D2 AS (AVA b 1 cm 2 and Vmax b 4 m/s or mean transvalvular gradient b 40 mm Hg) based on the ACC/AHA guidelines who underwent invasive hemodynamic assessment for ascertaining the true severity of AS and measurement of underlying LV contractive reserve. Patients with concomitant valvular disease such mitral and tricuspid regurgitation more than mild in severity or other concomitant valvular stenosis of any degree in addition to AS and right ventricular dysfunction of any magnitude were excluded from the current study to eliminate other causes of underlying low flow state. A total of 39 consecutive patients meeting echocardiographic criteria for Stage D2 AS were identified after these exclusions were made. These patients had been subjected to left, right heart catheterizations and coronary angiography within the same setting for the aforementioned purpose as part of the routine workup for SAVR or TAVR. 2.1. Procedural details of the left and right heart catheterization After obtaining written informed consent, these patients underwent right and left heart catheterization under moderate conscious sedation. The femoral approach was adopted for both catheterizations using either a 5 or 6-French (F) sheath for arterial access and 8F sheath for venous access. Right heart catheterization was performed using insertion of a standard balloon-tipped 7.5 French Swan-Ganz catheter via the common femoral vein and subsequently the inferior vena cava. Cardiac output was measured using the thermodilution technique as an average of 3 different values with b 10% variation amongst each other. Cardiac output assessment based on estimated Fick was used only if severe tricuspid regurgitation was present (1 case). Oxygen saturations were measured using a nomogram for oxygen consumption. Baseline cardiac output was measured while the Swan-Ganz catheter was left in place in the pulmonary arterial position while the left heart catheterization was performed. Stroke volume (SV) was calculated in all patients as the CO divided by the heart rate (HR) and was indexed to body surface area for calculation of the SVI. 2.2. Passage of the pressure wire across the stenotic aortic valve and simultaneous recording of left ventricular and aortic pressures Left heart catheterization was performed retrogradely using an Amplatz-1 (AL-1) or Judkins right (JR) 5-F catheter from the femoral approach with the tip of the catheter positioned 5 cm above the annulus of

the AV visualized fluoroscopically. A 0.014 in. pressure wire (PressureWire Certus, Radi or PressureWire Aeris, St. Jude Medical) which is commonly used for fractional flow reserve assessment during coronary angiography then was passed via the catheter and passed through the AV into the LV with the tip of the JR-4 or AL-1 catheter at 5 cm above the aortic annulus and the tip of the pressure wire within the LV for simultaneous real time recording of the LV and aortic pressures. Equalization of pressures was performed in the ascending aorta before crossing of the AV with a pressure wire. If initial attempts at passage of the pressure wire were unsuccessful, minor rotational movements of the catheter were coupled with repeated attempts at advancing the pressure wire across the AV. If multiple attempts were unsuccessful in crossing the AV with the pressure wire, a hydrophilic straight wire was used instead to cross the AV and the rotational maneuvers were repeated with the AL-1 or JR-4 catheters. Once this manoeuver was successful in guiding the hydrophilic wire into the LV across the AV, the catheter was moved over the wire into the LV. The straight wire was then removed keeping the catheter inside the LV. Subsequently; the pressure wire was reintroduced via the catheter into the LV. Then we will advance the tip the wire outside the catheter and equalize the pressure in the LV. Once pressure equalization is performed we will pullback catheter to 5 cm above the aortic valve annulus keeping the pressure wire inside the LV. Activated clotting time was maintained between 250 and 300 s during the procedure. We were able to measure simultaneous LV-aortic pressure gradients using this technique in all 39 study patients. The baseline means transvalvular pressure gradient (Δ MPG) between the LV and ascending aorta was measured using the electronic pressure tracings. The AVA was calculated using the Gorlin formula:

AVA ¼ ðSV=ETÞ=44:3

pffiffiffiffiffiffiffiffiffiffiffiffiffiffi ΔMPG

where SV = stroke volume, ET = ejection time and Δ MPG = mean transvalvular gradient. 2.3. Dobutamine infusion protocol Keeping the tip of the Swan-Ganz catheter one of the main pulmonary arteries for calculation of cardiac output, we ensured simultaneous pressure tracings of the LV and aorta were obtained from the pressure wire in the LV and the AL-1/JR-4 catheter in the aorta, respectively. We then proceeded to the infusion of Dobutamine. Blood pressure, oxygen saturation, heart rate, clinical neurological and continuous EKG monitoring were performed beginning of the procedure through recovery. Peripheral intravenous infusion of dobutamine was initiated at 5 μg/kg/min and increased in increments of 5 μg/kg/min every 3– 5 min up to a maximum of 20 μg/kg/min. At every increment of dobutamine dosage, the CO, the mean gradient and AVA were reassessed. 2.4. Clinical and safety endpoints Endpoints for the dobutamine infusion were defined as achievement of maximal dose of dobutamine, attainment of a ΔMPG N 40 mm Hg, occurrence of sustained ventricular tachycardia (VT), symptomatic hypotension or other intolerable symptoms as outlined by Nishimura et al. [7]. Moderate conscious sedation was administered with fentanyl and midazolam. Augmentation in SVI N 20% from baseline values of b 35 ml/m 2 was considered intact contractile reserve. The Δ MPG was monitored at each level of augmentation of dobutamine dose from the LV-aorta pressure tracings along with the CO from the Swan-Ganz catheter. If there was incident atrial fibrillation during the infusion, ΔMPG was measured as an average value of 5 successive beats with minimal R-R variation. With incident ventricular ectopy, the Δ MPG was measured as an average between 5 consecutive sinus beats. The occurrence of TIA or strokes (based on clinical assessment and imaging confirmation if clinically indicated) periprocedurally or in the



ensuing 30 days after the procedure was recorded as the primary safety endpoint. The occurrence of sustained VT, symptomatic hypotension or intolerable symptoms leading to cessation of dobutamine infusion was also recorded. 2.5. Statistical analysis Continuous variables were expressed as mean ± standard deviation and categorical variables as percentages. Comparison of categorical variables was performed using Chi-Square test and continuous variables before and after dobutamine infusion with the Student's t-test. A p-value of b 0.05 was considered statistically significant. All analyses were performed using STATA 8 SE, StataCorp, College Station, TX. 3. Results

3

Table 2 Baseline echocardiographic parameters, loading conditions during image acquisition and global hemodynamic burden in patients with low flow, low gradient, severe aortic stenosis with reduced left ventricular ejection fraction (N = 39). Left ventricular ejection fraction (%)

30 ± 10

Aortic valve area (cm2) Mean gradient (mm Hg) Peak velocity (m/s) Peak gradient (mm Hg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (bpm) Atrial fibrillation at the time of image acquisition Severe tricuspid regurgitation Severe mitral regurgitation Stroke volume index (ml/min/m2) Zva (valvuloarterial impedance) (mm Hg/ml/m2)

0.9 ± 0.1 25 ± 8 3.4 ± 0.4 44 ± 13 122 ± 17 70 ± 10 78 ± 11 23% 2.5% 2.5% 26 ± 6 5.8 ± 1.3

Zva = (systolic blood pressure + mean aortic valve gradient)/stroke volume index.

A total of 39 patients with LFLG-AS were identified from the electronic medical records that were subjected to concurrent left and right heart catheterization with dobutamine challenge along with coronary arteriography as part of the workup for TAVR. Baseline characteristics and echocardiographic parameters of these patients with LFLG severe AS with reduced LVEF are listed in Tables 1 and 2. Cardiac catheterization and coronary pressure wire-derived hemodynamic parameters before and after dobutamine infusion are listed in Table 3. Out of the 39 patients with LFLG-AS, 26 (67%) patients were confirmed to have truly severe AS based on dobutamine challenge and invasive catheterization resulting in a rise in Δ MPG above 36 mm Hg with an AVA b 1 cm 2 while the remaining 33% demonstrated an intact contractile reserve with increase in ΔMPG due to augmented flow from dobutamine use coupled with an improvement in AVA N 1 cm 2, thereby indicating pseudosevere AS. A high prevalence of underlying significant obstructive coronary artery disease (CAD) defined as a luminal stenosis N 70% in a non-left main artery or bypass conduit and N 50% stenosis in an unprotected left main artery or prior percutaneous coronary intervention or coronary artery bypass grafting was noted (87%) in this cohort. In patients who were confirmed to have severe AS following dobutamine challenge, there was no significant change in AVA before and at the time of cessation of dobutamine infusion (0.8 ± 0.2 vs. 0.8 ± 0.2 cm2, p = 0.99). However, with dobutamine challenge, there was a significant rise in the Δ MPG compared to baseline (29 ± 8 vs. 43 ± 3 mm Hg, p b 0.01). Changes in AVA and MPG across the AV based on coronary pressure wire based dobutamine infusion in patients classified as true vs. pseudo severe AS following cessation of infusion are shown in Figs. 1 and 2. The incidence of periprocedural and 30-day postprocedural safety endpoints are listed in Table 4. No significant sustained atrial or ventricular arrhythmias, symptomatic hypotension or intolerable symptoms requiring cessation of infusion were noted periprocedurally. No TIAs or strokes were noted periprocedurally and

Table 1 Baseline demographic and clinical characteristics of patients with low flow, low gradient, severe aortic stenosis with reduced left ventricular ejection fraction (b50%) [N = 39]. Age (years)

80 ± 10

Male gender Ethnicity Caucasian African American Hispanic Hypertension Hyperlipidemia Diabetes mellitus Obstructive coronary artery disease Smoking (prior or current) Peripheral arterial disease (prior carotid, renal or lower extremity revascularization, ankle-brachial index b 0.8 or abdominal aortic aneurysm)

26 (67%) 27 (69%) 2 (5%) 10 (26%) 35 (90%) 36 (92%) 14 (36%) 34 (87%) 22 (56%) 12 (31%)

in the following 30 days based on clinical assessment and imaging confirmation when clinical suspicion was noted. 17 out of the 26 patients (65%) who were confirmed to have severe AS based on the above protocol underwent TAVR while one underwent SAVR (Table 4). Over a mean follow-up period of 3.3 ± 1.2 years, the allcause mortality rate in the 17 patients who underwent TAVR was 29% which is slightly better than the mortality of LFLG-severe AS patients with reduced LVEF from the PARTNER trial (47%) [2]. 4. Discussion The most important findings of this study are two-fold: firstly, a combination of peripheral intravenous low-dose dobutamine infusion combined with coronary pressure wire derived AV mean transvalvular gradient assessment is safe for assessing the severity of AS in LFLG-AS. There was no incidence of TIA or strokes in the periprocedural setting and in the ensuing 30 days following the procedure. Additionally, there were no significant occurrences of periprocedural hemodynamic changes necessitating cessation of dobutamine infusion. Secondly, our results demonstrate that this technique can discriminate up to 33% of patients with LFLG-AS as having pseudosevere AS. 4.1. Prognostic implications and the need for accurate diagnosis of symptomatic LFLG-AS with reduced EF (stage D2) Robust and recent data from the Society of Thoracic Surgeons/ACC Transcatheter Valve Therapies Registry encompassing 11, 292 realworld TAVR recipients showed that pre-TAVR low AV gradient was the only independent predictor of 1-year mortality and recurrence in heart failure whereas EF was not [8]. If patient with LFLG-AS with reduced EF are identified appropriately they do better with TAVR in comparison to medical therapy (47% vs 80%, p b 0.01) in inoperable patients and they do equally fair if they underwent either SAVR or

Table 3 Baseline hemodynamic parameters and loading conditions in patients with true vs. pseudosevere aortic stenosis based on subsequent dobutamine challenge coupled with pressure assessments based on coronary pressure wire and a fluid-filled catheter.

Cardiac output by thermodilution (L/min) Stroke volume index (L/min/m2) Systolic arterial blood pressure (mm Hg) Diastolic arterial blood pressure (mm Hg) Heart rate (bpm) LV systolic blood pressure (mm Hg) LV end-diastolic pressure (mm Hg) Mean maximum dose of dobutamine

Truly Severe AS (n = 26)

Pseudosevere AS (n = 13)

4.2 ± 1.4 29 ± 8 113 ± 18 58 ± 9 76 ± 15 141 ± 17 18 ± 9 10 ± 5

4.4 ± 1.4 31 ± 16 126 ± 24 61 ± 14 73 ± 11 150 ± 17 20 ± 7 15 ± 5


4


Fig. 1. Changes in aortic valve area after dobutamine infusion in patients with true vs. pseudo-severe aortic stenosis.

TAVR in high-risk patients (43% vs. 37%, p = 0.5) [2]. Although it seems this group may be a higher risk group than HG AS, patients who are appropriately determined to be severe AS seems to do better with either SAVR or TAVR. It is therefore imperative to accurately identify patients with symptomatic, truly severe AS in the population with LFLG along with AVA b 1 cm2 based on echocardiographic assessment. 4.2. Risk of clinically silent and apparent neurological adverse outcomes following retrograde cardiac catheterization with a pigtail catheter While invasive assessment of severe AS offers an important diagnostic tool when there are discrepant findings on echo, crossing the valve with catheter is associated with safety concerns considering the potential to cause dislodgement of calcific debris and resultant strokes. Prior studies have validated the efficacy of this technique in differentiating true from pseudo severe AS. However, there is lack of neurological safety data following this maneuver [3,7,9,10]. Majority of the available safety data for retrograde crossing of the AV is limited to a prospective randomized of 101 patients with severe AS wherein retrograde crossing of the AV was performed with a pigtail catheter (6F or 7F arterial access) and a 150 cm Terumo wire with a more robust profile compared to a coronary pressure wire used in our study. In this study by Omran et al., demonstrated a staggering 22% incidence of clinically silent,

diffusion-weighted magnetic resonance imaging (MRI) confirmed (48 h following catheterization) acute embolic lesions and a 3% incidence of clinically evident strokes with most of these lesions being confined to the middle cerebral artery distribution [11]. Another smaller study from Hamon et al. demonstrated a modest 5.9% incidence of clinically silent, MRI confirmed microemboli when catheterization was performed with a 0.035″ wire and either a pigtail, AL-1 or Judkins right catheter (5F) [12]. In theory, a 0.014 in. coronary pressure wire has intuitively lower potential to cause dislodgement of calcific debris from the AV than the 4–5 F pigtail catheter with a much larger outer diameter and an accompanying 0.035″ guiding wire when used for retrograde crossing of the AV, the latter having a higher potential for a prolonged procedure with multiple attempts, greater chance of AV and ascending aortic trauma. Moreover, safety data specifically pertaining to pressure wire use for this purpose is a relatively novel technique with minimal safety data for periprocedural neurological events. Our study differs from the aforementioned results in terms of methodology. We used a 0.014″ coronary pressure wire as opposed to a 0.035″ guide wire and there was no passage of the AL-1 catheter into the LV, thereby reducing the likelihood of catheter or wire induced dislodgement of calcific debris from the severely stenosed AV. Our results demonstrate no TIA or clinically evident strokes amongst the 39 patients analyzed either periprocedurally or in the 30 days following the

Fig. 2. Changes in mean gradient after dobutamin infusion in patients with true vs. pseudo-severe aortic stenosis.


Z. Fanari et al. / Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx Table 4 Distribution of treatment modalities, periprocedural and long-term (mean follow-up period of 3.3 ± 1.2 years) outcomes of patients who underwent aortic valve replacement based on a combination of dobutamine challenge and coronary pressure wire based assessment of aortic stenosis severity.

Subsequent TAVR Subsequent SAVR All-cause mortality following TAVR All-cause mortality following SAVR Cessation of dobutamine infusion due to symptomatic hypotension or sustained ventricular arrhythmias TIA/clinically apparent strokes in the intraprocedural period or up to 30 days following pressure wire/dobutamine infusion

Truly severe AS (n = 26)

Pseudosevere AS (n = 13)

17 (65%) 1 (4%) 5/17 (29%) 1/1 (100%) None

1 (8%) 2 (15%) 1/1 (100%) 2/2 (100%) None

None

None

Abbreviations: SAVR: surgical aortic valve replacement; TAVR: transcatheter aortic valve replacement; TIA: transient ischemic attack.

procedure, thereby eliciting the neurological safety profile of this method of transvalvular gradient assessment. The lack of imaging data prior to and after the catheterization procedure precludes definitive comments on the incidence of cerebral microemboli in our study. However, the lack of clinically apparent strokes in our study is to be noted. In a similar Study reported by Yang et al. of 40 AS patient, Pressure wire use was shown to be associated with no signs of stroke or TIA [6]. However, contrary to our study, dobutamine challenge was not used in that study. It is worth noting that a combination of dobutamine challenge with doses of up to 20 μg/kg/min coupled with left heart catheterization with a pressure wire did not produce any sustained atrial or ventricular arrhythmias, hypotension or intractable symptoms necessitating cessation of dobutamine infusion in any of the patients. Neither did this cause incidence of clinically apparent TIA or strokes following augmentation in contractility. These findings further attest to the safety of this technique. Additionally, 24% of patients with AVA b 1 cm2 and discrepant mean gradients b 40 mm Hg across the AV based on echo were confirmed to be actual cases of pseudosevere AS due to an increase in AVA N 1 cm 2 and rise in MPG with increase in contractility stemming from dobutamine infusion. Results from studies which evaluated severity of AS using the conventional LV catheterization with a pigtail catheter have shown a yield of 21% for identifying pseudosevere AS which is similar to the yield on our study (24%) [7]. Data from the Truly or Pseudo Severe AS (TOPAS) study shows a high incidence (up to 75%) of underlying coronary artery disease (CAD) in the truly severe LFLG-AS group [13]. In our study the extent of underlying CAD was 87%, which is similar to the extent described in the TOPAS study. Despite a significantly higher prevalence of underlying CAD, these patients tolerated the dobutamine infusion well, further substantiating the safety profile of this technique.

4.3. Invasive versus noninvasive assessment of severe AS with reduced ejection fraction Direct catheterization and dobutamine challenge-based assessment of the severity of AS is often not considered first line in the assessment of LGLG-AS considering the invasive nature of the procedure, especially considering the similar yield of diagnosis with noninvasive low-dose dobutamine challenge echocardiography. However, considering the advanced age, high prevalence of underlying CAD as well as atherosclerotic risk factors, these patients are often subjected to coronary angiography to assess for underlying obstructive CAD as the etiology of the symptoms. Moreover, coronary angiography is considered a class I indication in patients with valve disease prior to valve interventions, specifically in the presence of angina, LV dysfunction, history of CAD, objective

5

evidence of CAD or high prevalence of atherosclerotic risk factors, all of which are hallmarks of LFLG-AS patients [1,13]. A single arterial puncture with a 5F sheath could effectively accomplish both coronary arteriography and pressure wire assessment of the severity of AS. In addition, performance of coronary angiography prior to pressure wire assessment in the same setting not only avoids an additional arterial puncture and its associated bleeding complications but also provides us with the knowledge of high-risk coronary anatomy such as unprotected left main, proximal disease or high grade lesions in bypass grafts supplying a significant myocardial territory. In the latter case, clinicians could help risk stratify these patients and avoid dobutamine challenge in an ischemic milieu that could compromise the safety of the procedure or perform dobutamine challenge in the same setting after revascularization. Nevertheless, disadvantages to the invasive approach such as radiation use, inability to ascertain AV morphology and higher procedural expenses cannot be disregarded. A high prevalence of systemic hypertension in this cohort could further augment the afterload several-fold resulting in reduced flow and subsequently reduced gradient across the AV in addition to that caused high afterload from severe AS [14]. The cardiac catheterization laboratory is a more controlled environment where patients are often sedated and hence, afterload due to decreased systemic arterial compliance from uncontrolled hypertension could be negated to unmask the magnitude of flow resulting from AS per se. The latter could be challenging when echocardiography is the sole mode of assessment in LFLG-AS. Though multiple modalities such echocardiographic low-dose dobutamine challenge, CT AV calcium score and pressure wire/dobutamine challenge are available to assess LFLG-AS, these are not mutually exclusive. There is paucity of data directly comparing the safety and efficacy profile of these tools. An integrated assessment using these techniques could serve as the best tool in the armamentarium of the clinician to improve patient selection, which ultimately is the most important step in producing optimal outcomes following TAVR or SAVR. 5. Limitations of our study Several inherent limitations to our study are to be noted. First, the retrospective nature of our cohort is prone to selection bias that we unable to correct for. Second, although we reported the absence of clinical TIA and stroke, we unable to rule out silent microembolization due to the lack of pre and post-procedural neuroimaging. Third, we used thermodilution technique to assess CO, which has known pitfall and it not the gold standard technique of invasive CO assessment [15,16]. Similarly we unable to compare our invasive findings with concomitant dobutamine stress echocardiography, it is quite possible that combing dobutamine imaging with -dimensional echocardiographic assessment of LV outflow diameter may offer better discrimination [17]. 6. Conclusion The use of a coronary pressure wire and fluid-filled catheter for mean transvalvular gradient assessment coupled with low dose (up to 20 μg/kg/min) dobutamine is a safe, feasible and effective method for differentiating true from pseudosevere AS in patients with LFLG-AS based on initial echocardiographic assessment. The absence of clinically significant TIA, strokes or hemodynamic or arrhythmic perturbations substantiates the safety profile of this technique. References [1] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin III JP, Guyton RA, et al. AHA/ ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2014;63(22):2438–88. [2] Herrmann HC, Pibarot P, Hueter I, Gertz ZM, Stewart WJ, Kapadia S, et al. Predictors of mortality and outcomes of therapy in low-flow severe aortic stenosis: a placement of aortic transcatheter valves (PARTNER) trial analysis. Circulation 2013; 127(23):2316–26.


6


[3] Lauten J, Rost C, Breithardt OA, Seligmann C, Klinghammer L, Daniel WG, et al. Invasive hemodynamic characteristics of low gradient severe aortic stenosis despite preserved ejection fraction. J Am Coll Cardiol 2013;61(17):1799–808. [4] Garcia D, Dumesnil JG, Durand LG, Kadem L, Pibarot P. Discrepancies between catheter and Doppler estimates of valve effective orifice area can be predicted from the pressure recovery phenomenon: practical implications with regard to quantification of aortic stenosis severity. J Am Coll Cardiol 2003;41(3):435–42. [5] Burwash IG, Thomas DD, Sadahiro M, Pearlman AS, Verrier ED, Thomas R, et al. Dependence of Gorlin formula and continuity equation valve areas on transvalvular volume flow rate in valvular aortic stenosis. Circulation 1994; 89(2):827–35. [6] Yang CS, Marshall ES, Fanari Z, Kostal MJ, West JT, Kolm P, et al. Discrepancies between direct catheter and echocardiography-based values in aortic stenosis. Catheter Cardiovasc Interv 2016;87(3):488–97. [7] Nishimura RA, Grantham JA, Connolly HM, Schaff HV, Higano ST, Holmes DR, et al. Low-output, low-gradient aortic stenosis in patients with depressed left ventricular systolic function: the clinical utility of the dobutamine challenge in the catheterization laboratory. Circulation 2002;106(7):809–13. [8] Baron SJ, Arnold SV, Herrmann HC, Holmes Jr DR, Szeto WY, Allen KB, et al. Impact of ejection fraction and aortic valve gradient on outcomes of transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67(20):2349–58. [9] Jayne JE, Catherwood E, Niles NW, Friedman BJ. Double-lumen catheter assessment of aortic stenosis: comparison with separate catheter technique. Cathet Cardiovasc Diagn 1993;29(2):157–60. [10] Hays J, Lujan M, Chilton R. Aortic stenosis catheterization revisited: a long sheath single-puncture technique. J Invasive Cardiol 2006;18(6):262–7.

[11] Omran H, Schmidt H, Hackenbroch M, Illien S, Bernhardt P, von der Recke G, et al. Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003;361(9365): 1241–6. [12] Hamon M, Gomes S, Oppenheim C, Morello R, Sabatier R, Lognoné T, et al. Cerebral microembolism during cardiac catheterization and risk of acute brain injury: a prospective diffusion-weighted magnetic resonance imaging study. Stroke 2006;37(8): 2035–8. [13] Blais C, Burwash IG, Mundigler G, Dumesnil JG, Loho N, Rader F, et al. Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-gradient aortic stenosis: the multicenter TOPAS (truly or pseudo-severe aortic stenosis) study. Circulation 2006;113(5):711–21. [14] Briand M, Dumesnil JG, Kadem L, Tongue AG, Rieu R, Garcia D, et al. Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment. J Am Coll Cardiol 2005; 46(2):291–8. [15] Fanari Z, Grove M, Rajamanickam A, Hammami S, Walls C, Kolm P, et al. The impact of direct cardiac output determination on using a widely available direct continuous oxygen consumption measuring device on the hemodynamic assessment of aortic valve. Del Med J 2016;88(9):270–5. [16] Fanari Z, Grove M, Rajamanickam A, Hammami S, Walls C, Kolm P, et al. Cardiac output determination using a widely available direct continuous oxygen consumption measuring device: a practical way to get back to the gold standard. Cardiovasc Revasc Med 2016;17(4):256–61. [17] Nadeau S, Noble WH. Limitations of cardiac output measurements by thermodilution. Can Anaesth Soc J 1986;33(6):780–4.
