Accepted Manuscript Left Ventricular Remodeling in Aortic Stenosis Andrew N. Rassi, MD Philippe Pibarot, DVM, PhD Sammy Elmariah, MD, MPH PII:

S0828-282X(14)00292-X

DOI:

10.1016/j.cjca.2014.04.026

Reference:

CJCA 1202

To appear in:

Canadian Journal of Cardiology

Received Date: 1 February 2014 Revised Date:

21 April 2014

Accepted Date: 27 April 2014

Please cite this article as: Rassi AN, Pibarot P, Elmariah S, Left Ventricular Remodeling in Aortic Stenosis, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.04.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Left Ventricular Remodeling in Aortic Stenosis

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Andrew N. Rassi, MD*, Philippe Pibarot, DVM, PhD†, Sammy Elmariah, MD, MPH*

*Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Short Title: LV remodeling in AS

Address for correspondence:

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Sammy Elmariah, MD, MPH

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Word count: 5,765

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†Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada

Massachusetts General Hospital

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55 Fruit Street, GRB 800 Boston, MA 02114-2696 Phone: (617) 726-6120 Fax: (617) 726-6800

Email: [email protected]

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Brief Summary Aortic valve stenosis is characterized by indolent progression followed by the late development of symptoms once left ventricular compensatory mechanisms fail. Left ventricular remodeling,

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initially compensatory, becomes maladaptive as cardiomyocyte apoptosis and fibrosis ensue with progressive impairment of diastolic relaxation and systolic contractile function. Here we review left ventricular response to aortic stenosis, discuss the impact it has on symptoms and clinical

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outcomes, and highlight its reversibility after valve replacement.

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Unstructured abstract Aortic stenosis is a progressive condition associated with high mortality if not treated. The hemodynamic effects of aortic stenosis have serious implications on the left ventricle. In this

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review, we describe the responses of the left ventricle to aortic stenosis by highlighting the process of adaptive remodeling, which begins as a beneficial compensatory mechanism but ultimately transitions to a maladaptive process with potentially irreversible consequences. We

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discuss the impact of left ventricular remodeling on diastolic and systolic function and on the development of symptoms. In addition, we review the adverse consequences of maladaptive left

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ventricular remodeling on clinical outcomes before and after aortic valve replacement. The relative irreversibility of maladaptive remodeling and the clear relationship between its progression and clinical outcomes suggests a need to incorporate measures of left ventricular

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performance beyond simply systolic function when deciding on the timing of valve replacement.

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Introduction Calcific aortic valve disease, which frequently culminates in severe aortic stenosis (AS), is the most common cause of valvular heart disease in the Western world, present in over 20% of older

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adults.1, 2 As the severity of AS worsens, symptoms including angina, syncope, and heart failure develop, after which 1-year survival is dismal, 50% without aortic valve replacement (AVR).3, 4 American College of Cardiology/American Heart Association guidelines recommend AVR for

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patients with severe AS who are symptomatic or have developed left ventricular (LV) systolic dysfunction in the absence of symptoms.5 Decisions for timing AVR are largely dependent on

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balancing the surgical risks with those of AS if left untreated. Because the risk of sudden cardiac death is approximately 1%/year, lower than anticipated with surgery, for patients with asymptomatic severe AS with normal LV ejection fraction (EF),6 AVR is not recommended. The aforementioned calculus for timing AVR depends largely on the notion that AVR

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completely reverses the pathologic disease process; however, recent advances in our understanding of the LV response to AS suggests the presence of longstanding maladaptive changes that often do not reverse after valve replacement and importantly, that these changes

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may adversely impact clinical outcomes despite AVR. There is consequently a growing appreciation of the need to consider LV performance in clinical decisions for patients with AS.

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We review LV response to AS, discuss the impact it has on symptoms and clinical outcomes, and highlight its reversibility after AVR.

Compensatory LV Response to AS Calcific AS develops via an insidious process spanning years, with lipid deposition and inflammation leading to calcification of the aortic valve.2, 7 The valve leaflets become thick and

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less mobile resulting in a narrowed valve orifice. Early animal studies provided initial understanding of the body’s response to increased afterload. Sasayama et al assessed the ventricular response to ascending aortic banding in conscious dogs by using intraventricular

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micromanometers and pairs of ultrasonic crystals for measurement of LV wall thickness and internal chamber diameter. They found that the LV responds to chronically elevated pressure (2.5 weeks) with initial dilatation due to increased wall stress.8 This acute response is followed

thereby preserving normal LV chamber size and inotrope.8

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by gradual wall thickening and consequent reductions in wall stress to near normal levels,

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Early controversy arose regarding the cause of depressed LV contractility in the setting of severe AS: Is abnormal contractility due to an imbalance of wall stress and LV hypertrophy or is there inherent impairment of LV contractile function? Huber and colleagues attempted to address this uncertainty using LV micromanometry and quantitative cineangiography. They divided 76

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patients with AS into four groups based on isovolumic contractility and peak systolic wall stress. They found that contractile state can be either normal or impaired in the setting of normal or increased systolic wall stress, suggesting that depressed contractility can be demonstrated even in

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the presence of compensatory hypertrophy. Because they also found that LV mass was greatest in those with depressed contractile function, the authors concluded that LV hypertrophy leads to

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intrinsic reduction in LV contractility.9 Although it is well accepted that the LV response to AS typically involves wall hypertrophy in order to maintain normal wall stress, it is increasingly being acknowledged that the hypertrophic process is heterogeneous. Dweck et al utilized cardiac magnetic resonance (CMR) imaging to assess patterns of LV hypertrophy in 91 patients with moderate or severe AS. They confirmed the presence of multiple phenotypes of LV remodeling in AS patients, including

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normal geometry, concentric remodeling, asymmetric remodeling, concentric hypertrophy, asymmetric hypertrophy, and eccentric hypertrophy (Figure 1). In addition, they found that the severity of AS is unrelated to the pattern of hypertrophy suggesting that other factors mediate or

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impact LV hypertrophy.10 Associations of LV hypertrophy with gender and systemic processes including diabetes, obesity, insulin resistance, and kidney disease further support the

multifactorial nature of LV remodeling (Table 1).11-17 Associations of insulin resistance and

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obesity with increased LV mass in the absence of increased afterload, for example, indicate the involvement of non-hemodynamic factors including renin-angiotensin-aldosterone system

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(RAAS) activation, catecholamine excess, altered myocardial energetics and calcium metabolism, and dysregulation of small G proteins and nuclear factor-κB.18-20

Maladaptive remodeling

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Although LV remodeling is considered a compensatory mechanism aimed at normalization of wall stress and maintenance of systolic function in AS, it is increasingly being associated with diminished LV performance and with adverse clinical outcomes.21-26 The factors responsible for

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the unfavorable consequences of LV remodeling remain unclear; however, subendocardial ischemia, altered myocardial energetics, and especially fibrosis appear to play a role.27 As the

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LV hypertrophies, myocardial oxygen demand increases and outpaces the oxygen supplied by the coronary arteries.26 Coronary flow reserve is also reduced with concentric LV hypertrophy and AS due to microvascular dysfunction, low coronary perfusion pressure, increased extravascular compressive forces, and reduced diastolic perfusion time.28, 29 Together, these factors cause ischemia and necrosis that lead to interstitial fibrosis (Figure 2).28, 30

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Recent studies suggest that LV fibrosis serves as the primary cause of diastolic dysfunction and is responsible for the clinical progression from compensated LV hypertrophy to heart failure.25, 31 With worsening diastolic dysfunction, LV end-diastolic pressure rises, reducing

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coronary perfusion pressure and increasing ischemia, further perpetuating fibrosis (Figure 2). This self-perpetuating cycle often continues to progress even after AVR in those with more extensive fibrosis, leading to adverse clinical outcomes.25, 32 Higher LV mass on

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echocardiography is associated with an increased risk of systolic dysfunction and of heart failure, irrespective of severity of AS.33 In an elegant study evaluating the cellular changes that occur in

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the transition from compensatory to decompensated heart failure, Hein et al studied myocardial biopsy specimens from patients with isolated AS with varying levels of systolic function (EF >50%, EF 30-50%, and EF 10% expected) had a 4.5-fold higher risk of death, AVR, and hospital admission.26 This suggests that those with excessive LV hypertrophy, perhaps a marker of increased LV fibrosis,42 are more likely to become symptomatic.

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Interestingly, in biopsy specimens taken at surgical AVR (SAVR), the degree of fibrosis had a direct relationship with pre-operative New York Heart Association (NYHA) functional class. Fibrosis also correlated well with markers of longitudinal systolic function (longitudinal strain,

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strain rate, and mitral ring displacement), but not EF or valve area.43 Other studies demonstrate that in severe AS, symptom status and reduced functional capacity is associated with impaired

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diastolic function, LV hypertrophy, concentric remodeling, and LA dilatation.42, 44-46

Survival

Several studies have highlighted the negative impact of maladaptive LV remodeling on survival. An increased risk of cardiovascular events is observed in patients with LV hypertrophy, regardless of the cause.26, 47 Moreover, excessive LV hypertrophy in patients with severe AS is

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associated with an increased risk of the combined endpoint of death, AVR, or hospital admission at 5 years (Figure 4).26 In patients with moderate to severe AS, Dweck and colleagues found that those with midwall fibrosis identified by either histopathology or delayed enhancement on CMR,

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had a 5-fold increase in all-cause mortality.24 Importantly, the risk associated with midwall fibrosis persisted even after AVR.

While conflicting data exist, the preponderance of evidence suggests that paradoxical

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low-flow, low-gradient severe AS is a high-risk patient population.35, 38, 40, 41, 48-50 Hachicha et al. found that low flow, defined by stroke volume index ≤ 35 ml/m2, conferred a 70% increase in

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death, although only age, valvulo-vascular impedance, and medical treatment independently predicted mortality.35 Mehrotra and colleagues similarly identified flow to be an important predictor of event-free survival, as was increased relative wall thickness and reduced

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longitudinal contractility.41

AVR Periprocedural Outcomes

The efficacy and safety of AVR is well established, although recent data suggest that patients

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with LV hypertrophy have worse perioperative outcomes. In retrospective studies, the presence of elevated LV mass index on preoperative echocardiogram is associated with increased post-

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procedural complications, intensive care unit length of stay, and in-hospital mortality.51, 52 In a propensity matched analysis, concentric LV geometry conferred a two-fold increased risk of inhospital all-cause and cardiac mortality.23, 53 Interestingly, increased relative wall thickness was associated with adverse outcomes, and not LV mass, highlighting the negative impact of concentric geometry.

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Left ventricular systolic dysfunction is a well-established risk factor for adverse perioperative mortality with SAVR.54-58 Although patients with LV dysfunction face increased early risk, SAVR for severe AS is associated with a large survival advantage and improvements

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in LVEF and clinical symptoms when compared to conservative management, regardless of baseline LV function.55, 59-61 Limited data are available regarding the impact of systolic

dysfunction on outcomes in transcatheter AVR (TAVR). In a propensity-score matched analysis,

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Clavel and colleagues demonstrated similar perioperative mortality after TAVR and SAVR in patients with LV dysfunction. Similarly, within the randomized PARTNER (Placement of Aortic

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Transcatheter Valves) trial, we demonstrated equivalent 30-day and 2-year survival after TAVR and SAVR.62

Post-AVR Outcomes

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Mid- and long-term clinical outcomes following SAVR vary depending on the degree of myocardial remodeling. As previously mentioned, midwall fibrosis on CMR or by histopathology is associated with markedly reduced survival after SAVR,24, 63 in addition to

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persistence of symptoms.63 LV longitudinal shortening, an emerging surrogate for LV fibrosis, has also been shown to predict improvements in NYHA functional class after SAVR.39 If based

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on what has recently been learned, low-flow, low-gradient AS is a consequence of severe myocardial fibrosis, it is not surprising that low-flow, low-gradient AS is associated with greater odds of death and heart failure 10 years after AVR.64, 65 In a recent analysis from the PARTNER trial, low flow was more closely associated with mortality than LVEF and gradient, independent of whether valve replacement was performed.38 In addition, low flow portended significantly reduced 2-year survival, regardless of whether

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SAVR or TAVR had been performed; however, outcomes were comparable between TAVR and SAVR. Within the inoperable cohort, TAVR was associated with marked reductions in 2-year mortality in patients with low flow (76.2% vs 45.9%; P150 g within the first post-operative year is associated with improved

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long-term survival.75, 76

Because patients with LV systolic dysfunction are exquisitely sensitive to afterload,77 improvements in LVEF are noted soon after AVR. Rapid recovery of LV systolic function is seen within 30 days of TAVR or SAVR.62, 78 Clavel and colleagues observed greater

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improvements in LVEF after TAVR than with SAVR;78 however, within the randomized PARTNER trial, we demonstrated comparable improvement in LVEF after both techniques.62 The discrepancy between the two studies may be a consequence of the concomitant performance

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of CABG with SAVR in approximately 60% of patients in the Clavel study.78 Alternatively, because patients with severe LV dysfunction (LVEF

Left ventricular remodelling in aortic stenosis.

Aortic stenosis (AS) is a progressive condition associated with high mortality if not treated. The hemodynamic effects of AS have serious implications...
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