Aortic Stenosis * Identification of high-risk valve pathology using STRESS physiology (AoS-STRESS)

1.1 Aortic valve stenosis (AoS)

The natural history of medically treated severe aortic stenosis follows a
typical progression from asymptomatic to a classic triad of angina, syncope,
and heart failure [4894151].

However, uncertainty exists regarding the most appropriate metric to judge the
physiologic severity of AoS. Guidelines from the United States and Europe
discuss resting measurements of maximum velocity (Vmax), transvalvular gradient
(*P), aortic valve area (AVA) as well as secondary parameters of AVA indexed to
body surface area and the velocity ratio (also called the dimensionless
velocity index).

Additionally, some patients with severe AoS have no symptoms, while other
patients with moderate stenosis have typical exertional symptoms. Currently
neither type of patient has been well studied in outcomes-based randomized
controlled trials (RCT).


1.2 Transcatheter aortic valve implantation (TAVI)

Historically only surgical aortic valve replacement (AVR) treated severe aortic
stenosis. However, recent advances have demonstrated transcatheter aortic valve
implantation (TAVI) to be a valid, alternative therapy.

For patients deemed too high risk for surgical AVR, all-cause death can be
reduced through TAVI compared to medical therapy [20961243]. For high-risk
patients who are candidates for either surgical AVR or TAVI, all-cause survival
remains equivalent but with differences in peri-procedural risk [21639811].

Potentially TAVI may offer benefit to less extreme patients, although at the
moment high-quality RCT have not yet been performed.


1.3 Rationale for stress assessment of aortic stenosis

The current study links three major points from the preceding two sections:
-Physiologic quantification of aortic stenosis needs refinement outside of
severe and symptomatic patients.
-TAVI may offer clinical benefits to lower risk patients who have been excluded
from existing clinical trials.
-Before a new, outcomes-based RCT, we must identify a high-risk subset with
aortic stenosis whose pathology offers appropriate physiologic substrate for
TAVI.

Most non-extreme patients with aortic stenosis have exertional complaints, not
resting symptoms. Additionally, by analogy with coronary stenosis, resting
measurements cannot predict hyperemic conditions due to a number of
unmeasurable and patient-specific factors. Therefore, to identify a high-risk
subset, it makes physiologic sense to characterize the response of the stenotic
aortic valve and its accompanying left ventricle under both rest and stress
conditions.

If a stress characterization of aortic stenosis indeed has clinical potential
to guide treatment, we must first answer two basic questions. First, what
physiologic characteristics emerge only under stress conditions that cannot be
observed at rest? Second, can these characteristics be observed non-invasively
or is their invasive assessment mandatory.


1.4 Summary

Therefore, the current project will enroll a cohort of patients undergoing TAVI
and/or balloon aortic valvuloplasty (BAV). Both invasive and non-invasive
assessment of transvalvular pressure gradient and flow will be assessed during
a graded, dobutamine infusion. Repeat measurements will be performed after
value implantation or valvuloplasty.

The primary objective is to classify high-risk physiologic patterns, likely a
diminished contractile reserve yet a large increase in gradient. Secondary
objectives include clarifying the stress response to typical resting
measurements, comparing invasive to non-invasive techniques, and correlating
with standard clinical variables and outcomes.

2.1 Primary objective

To determine patterns of response in the transvalvular pressure gradient while
altering transvalvular flow.

2.2 Secondary objectives
-To quantify any added value or differentiation from stress assessment of
aortic stenosis compared to classic resting parameters.
-To explore if stress assessment of the aortic valve can be imaged
non-invasively or if it requires invasive hemodynamic measurement.
-To describe the relationship between stress response patterns and typical
clinical variables and outcomes.
-To compare stress response patterns before and after TAVI or balloon
valvuloplasty.

2.3 Endpoints
Due to the exploratory and pilot nature of this study, it will collect standard
clinical endpoints after TAVI and/or BAV as already being assessed in an
ongoing quality database.

Single center, non-randomized, non-blinded, observational cohort undergoing
advanced diagnostic evaluation before and after treatment with TAVI/BAV or
during a coronary angiogram

Unlike a drug or device trial, this study only makes diagnostic measurements
without altering planned treatment. However, dobutamine infusion is not without
risk, although used routinely for stress testing [18579481] and with a solid
experience in patients with moderate to severe aortic stenosis [9842014]
[10377300] [12176952] [16461844] [11419894]. Thus any adverse events related to
dobutamine will be prospectively recorded and reviewed by the investigators and
medical ethics board.

9842014. Lin SS, Roger VL, Pascoe R, Seward JB, Pellikka PA. Dobutamine stress
Doppler hemodynamics in patients with aortic stenosis: feasibility, safety, and
surgical correlations. Am Heart J. 1998 Dec;136(6):1010-6.

10377300. Takeda S, Rimington H, Chambers J. The relation between transaortic
pressure difference and flow during dobutamine stress echocardiography in
patients with aortic stenosis. Heart. 1999 Jul;82(1):11-4.

12176952. Nishimura RA, Grantham JA, Connolly HM, Schaff HV, Higano ST, Holmes
DR Jr. 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 Aug 13;106(7):809-13.

16461844. Blais C, Burwash IG, Mundigler G, Dumesnil JG, Loho N, Rader F,
Baumgartner H, Beanlands RS, Chayer B, Kadem L, Garcia D, Durand LG, Pibarot P.
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 Feb 7;113(5):711-21.

11419894. Monin JL, Monchi M, Gest V, Duval-Moulin AM, Dubois-Rande JL, Gueret
P. Aortic stenosis with severe left ventricular dysfunction and low
transvalvular pressure gradients: risk stratification by low-dose dobutamine
echocardiography. J Am Coll Cardiol. 2001 Jun 15;37(8):2101-7.

18579481. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti
P, Poldermans D, Voigt JU, Zamorano JL; European Association of
Echocardiography. Stress echocardiography expert consensus statement: European
Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J
Echocardiogr. 2008 Jul;9(4):415-37.