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 AorticStenosis, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.04.026.

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Left Ventricular Remodeling in Aortic Stenosis

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

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

Massachusetts, USA

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

Short Title: LV remodeling in AS

Word count: 5,765

Address for correspondence:

Sammy Elmariah, MD, MPH

Massachusetts General Hospital

55 Fruit Street, GRB 800

Boston, MA 02114-2696

Phone: (617) 726-6120

Fax: (617) 726-6800

Email: selmariah@mgh.harvard.edu

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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,

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

thereby preserving normal LV chamber size and inotrope.8

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

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

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

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

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

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

(RAAS) activation, catecholamine excess, altered myocardial energetics and calcium

metabolism, and dysregulation of small G proteins and nuclear factor-κB.18-20

Maladaptive remodeling

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

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

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

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

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

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 <30). An inverse correlation was seen between EF and myocyte

degeneration and fibrosis, suggesting that cell loss and fibrosis of the extracellular matrix

contribute significantly to the progression to LV systolic dysfunction,25 and further that the LV

response to AS typically occurs via a continuum that begins with hypertrophy with resultant

reduction in diastolic function and progressive fibrosis and ultimately over time progresses to

reduced systolic function (Figure 3). These findings support the maladaptive nature of excessive

LV remodeling and specifically that myocardial fibrosis leads to decrements in systolic and

diastolic function and worse outcomes.

Various phenotypes of LV remodeling exist that are manifested not only by differing LV

geometry, but also involve varying degrees of concomitant systolic and diastolic dysfunction,

impaired longitudinal shortening, and myocardial fibrosis. Although the mechanisms responsible

for the hypertrophic response to physiologic stressors are incompletely understood, possible

modulators include gender; comorbid conditions such as coronary artery disease, diabetes,

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obesity, and renal dysfunction; medications; genetic factors; and other valve lesions (Table 1).

For example, concomitant coronary artery disease and regurgitant valve lesions are associated

with eccentric LVH; whereas, female gender is associated with an increased prevalence of

concentric LVH with preservation of LV systolic function. The impact of gender on LV

remodeling is largely attributable to sex-based differences in collagen synthesis and architecture,

cytokine expression, and interactions with estrogen.16, 34 The aforementioned modulators of LV

response thereby alter signaling pathways and neurohormonal responses to AS and in part

explain the mosaic of possible LV phenotypes that exist in patients with severe AS.

Paradoxical low-flow, low-gradient severe AS in the setting of preserved LV ejection

fraction is increasingly being recognized.35 The entity is characterized by higher LV afterload,

restrictive physiology, and reduced stroke volume and by definition, requires the presence of

concentric hypertrophy.35-40 While LVEF is preserved in these patients, significant aberrations in

contractile function, systolic strain rate, and longitudinal deformation have been observed,39, 41

and LV fibrosis has been implicated as the underlying pathologic process.39 An elegant study by

Herrmann and colleagues stratified patients with moderate or severe AS into four groups based

on AV area, mean valve gradient, and EF.39 The authors found more extensive myocardial

fibrosis and diminished longitudinal systolic function in patients with low gradients. Moreover, a

strong correlation between mitral ring displacement, a measure of longitudinal shortening, and

the extent of myocardial fibrosis was identified, perhaps offering a simple noninvasive means by

which myocardial fibrosis can be assessed. This selective alteration of the longitudinal function

is related to the fact that in AS, fibrosis is predominantly located in the subendocardial layer

where the myocardial fibers are oriented longitudinally. The presence of extensive fibrosis in

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paradoxical low-flow, low-gradient AS patients indicates a late stage of myocardial injury that

perhaps could have been circumvented with earlier valve replacement.

Clinical Consequences of LV remodeling

Symptoms

With the realization that initial adaptive remodeling leads to maladaptive remodeling with LV

hypertrophy and subsequent myocyte death, fibrosis, and diastolic dysfunction, investigators

increasingly evaluated the possible relationship between LV fibrosis and the presence of

symptoms in severe AS. A study evaluating patients with asymptomatic severe AS found that

those with inappropriate LV hypertrophy (>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.

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,

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

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,

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

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

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

longitudinal contractility.41

AVR Periprocedural Outcomes

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

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-

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 in-

hospital 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

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,

Clavel and colleagues demonstrated similar perioperative mortality after TAVR and SAVR in

patients with LV dysfunction. Similarly, within the randomized PARTNER (Placement of Aortic

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

and SAVR.62

Post-AVR Outcomes

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

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

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%; P<0.001). Similarly, another study by Le

Ven and colleagues found that among patients undergoing TAVR, low flow but not low EF or

low gradients was an independent predictor of early and late mortality.66 Importantly, despite

worse postoperative outcomes, valve replacement prolongs survival in patients with paradoxical

low-flow, low-gradient severe AS.36, 38, 65, 67

LV reverse remodeling after valve replacement

Several studies have characterized the regression of maladaptive LV remodeling after AVR.

Within 18-months of SAVR, marked reductions in LV mass (~30-40%) occur.68-70 This initial

change was demonstrated using endomyocardial biopsies and thought to be largely due to

regression of myocyte hypertrophy. Because fibrous content remains relatively unchanged over

this period, the proportion of LV mass made up by interstitial fibrosis increases.68, 69 While left

heart filling pressures improve soon after AVR, the relative increase in fibrosis results in greater

passive myocardial stiffness.68-70 Over the subsequent 5 to 6 years, interstitial fibrosis slowly

regresses, although it can remain long after AVR.68-71

The clinical ramifications of LV reverse remodeling after AVR are significant.

Reductions in LV mass and normalization of geometry consistently result in significant

improvements in LV diastolic filling within 6 to 12 months of SAVR.72, 73 Given the persistence

of LV fibrosis shortly after AVR, early improvements are likely due to afterload reduction and

improved active myocardial relaxation. Acute improvement in diastolic function are not seen

after SAVR,72 although they have been documented after TAVR.74 This discrepancy most likely

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relates to the impact of cardiopulmonary bypass and cardioplegia on diastolic parameters. Rost

and colleagues used speckle-tracking echocardiography to demonstrate improvements in LV

contractile performance at 6-months after SAVR. Interestingly, longitudinal deformation

improved to a lesser degree than circumferential and radial strain.72 Given the predominant

impact of LV fibrosis on longitudinal contractility, this finding may reflect the slow regression of

LV fibrosis. Beyond LV systolic and diastolic performance, recent evidence suggests that reverse

remodeling also influences survival. In an analysis of 147 patients, Ali et al. found that a

reduction in LV mass >150 g within the first post-operative year is associated with improved

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

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

of CABG with SAVR in approximately 60% of patients in the Clavel study.78 Alternatively,

because patients with severe LV dysfunction (LVEF<20%) are the most responsive to LV

afterload, their exclusion from the PARTNER trial may have failed to capture those most likely

to reap an advantage from the superior hemodynamic profile of transcatheter heart valves.64, 79

Several clinical factors impact the extent and rate of LV reverse remodeling. Patient-

prosthesis mismatch and hypertension following AVR are each associated with attenuated LV

reverse remodeling due to the persistence of elevated afterload.80, 81 Within the PARTNER trial,

the presence of a permanent pacemaker and low aortic valve gradients were associated with

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reduced likelihood of LV functional improvement after valve replacement.62 Interestingly, the

administration of angiotensin receptor blocking agents after SAVR has also been associated with

augmented LV reverse remodeling, similar to findings for patients with LV hypertrophy in the

absence of AS.82

Future Directions

LV remodeling in the setting of AS begins as a compensatory process to maintain wall stress, but

often transitions to a maladaptive response characterized by myocyte hypertrophy, interstitial

fibrosis, and apoptosis. These progressive myocardial changes frequently lead to the

development of symptoms and clinical decompensation and have implications on post-AVR

outcomes. Although LV reverse remodeling occurs after AVR, it is clear that AVR is often

performed late after irreversible maladaptive LV remodeling and fibrosis have occurred. Further

evaluation of noninvasive measures capable of assessing the extent of maladaptive LV

remodeling and of predicting its reversal are needed in order to enhance the personalized

delivery of AVR for severe AS. We support aggressive assessment of symptomatic status with

more frequent clinical follow-up and exercise testing in asymptomatic individuals with severe

LVH or impaired longitudinal function. However, whether early valve replacement is

advantageous in patients with evidence of maladaptive LV remodeling in the absence of

symptoms remains unknown, but is certainly worthy of further investigation.

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References

1. Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: Disease prevalence and

number of candidates for transcatheter aortic valve replacement: A meta-analysis and modeling

study. J Am Coll Cardiol. 2013;62:1002-1012

2. Elmariah S, Mohler ER, 3rd. The pathogenesis and treatment of the valvulopathy of aortic

stenosis: Beyond the seas. Curr Cardiol Rep. 2010;12:125-132

3. Ross J, Jr., Braunwald E. Aortic stenosis. Circulation. 1968;38:61-67

4. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in

patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607

5. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the acc/aha

2006 guidelines for the management of patients with valvular heart disease: A report of the

american college of cardiology/american heart association task force on practice guidelines

(writing committee to revise the 1998 guidelines for the management of patients with valvular

heart disease): Endorsed by the society of cardiovascular anesthesiologists, society for

cardiovascular angiography and interventions, and society of thoracic surgeons. Circulation.

2008;118:e523-661

6. Pellikka PA, Sarano ME, Nishimura RA, et al. Outcome of 622 adults with asymptomatic,

hemodynamically significant aortic stenosis during prolonged follow-up. Circulation.

2005;111:3290-3295

7. Goldbarg SH, Elmariah S, Miller MA, Fuster V. Insights into degenerative aortic valve disease. J

Am Coll Cardiol. 2007;50:1205-1213

8. Sasayama S, Ross J, Jr., Franklin D, Bloor CM, Bishop S, Dilley RB. Adaptations of the left ventricle

to chronic pressure overload. Circ Res. 1976;38:172-178

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

16

9. Huber D, Grimm J, Koch R, Krayenbuehl HP. Determinants of ejection performance in aortic

stenosis. Circulation. 1981;64:126-134

10. Dweck MR, Joshi S, Murigu T, et al. Left ventricular remodeling and hypertrophy in patients with

aortic stenosis: Insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson.

2012;14:50

11. Capoulade R, Clavel MA, Dumesnil JG, et al. Insulin resistance and lvh progression in patients

with calcific aortic stenosis: A substudy of the astronomer trial. JACC. Cardiovasc Imag.

2013;6:165-174

12. Dumesnil JG, Pibarot P. The obesity paradox in aortic stenosis: To be or not to be. J Am Coll

Cardiol. 2013;62:1691-1693

13. Kostkiewicz M, Tracz W, Olszowska M, Podolec P, Drop D. Left ventricular geometry and

function in patients with aortic stenosis: Gender differences. Int J Cardiol. 1999;71:57-61

14. Legget ME, Kuusisto J, Healy NL, Fujioka M, Schwaegler RG, Otto CM. Gender differences in left

ventricular function at rest and with exercise in asymptomatic aortic stenosis. Am Heart J.

1996;131:94-100

15. Page A, Dumesnil JG, Clavel MA, et al. Metabolic syndrome is associated with more pronounced

impairment of left ventricle geometry and function in patients with calcific aortic stenosis: A

substudy of the astronomer (aortic stenosis progression observation measuring effects of

rosuvastatin). J Am Coll Cardiol. 2010;55:1867-1874

16. Petrov G, Regitz-Zagrosek V, Lehmkuhl E, et al. Regression of myocardial hypertrophy after

aortic valve replacement: Faster in women? Circulation. 2010;122:S23-28

17. Lund BP, Gohlke-Barwolf C, Cramariuc D, Rossebo AB, Rieck AE, Gerdts E. Effect of obesity on

left ventricular mass and systolic function in patients with asymptomatic aortic stenosis (a

simvastatin ezetimibe in aortic stenosis [seas] substudy). Am J Cardiol. 2010;105:1456-1460

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

17

18. Cacciapuoti F. Molecular mechanisms of left ventricular hypertrophy (lvh) in systemic

hypertension (sh)-possible therapeutic perspectives. J Am Soc Hypertens. 2011;5:449-455

19. Esposito G, Rapacciuolo A, Naga Prasad SV, et al. Genetic alterations that inhibit in vivo

pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress.

Circulation. 2002;105:85-92

20. Mandavia CH, Pulakat L, DeMarco V, Sowers JR. Over-nutrition and metabolic cardiomyopathy.

Metabolism. 2012;61:1205-1210

21. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of

echocardiographically determined left ventricular mass in the framingham heart study. N Engl J

Med. 1990;322:1561-1566

22. Bluemke DA, Kronmal RA, Lima JA, et al. The relationship of left ventricular mass and geometry

to incident cardiovascular events: The mesa (multi-ethnic study of atherosclerosis) study. J Am

Coll Cardiol. 2008;52:2148-2155

23. Duncan AI, Lowe BS, Garcia MJ, et al. Influence of concentric left ventricular remodeling on early

mortality after aortic valve replacement. Ann Thorac Surg. 2008;85:2030-2039

24. Dweck MR, Joshi S, Murigu T, et al. Midwall fibrosis is an independent predictor of mortality in

patients with aortic stenosis. J Am Coll Cardiol. 2011;58:1271-1279

25. Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the

pressure-overloaded human heart: Structural deterioration and compensatory mechanisms.

Circulation. 2003;107:984-991

26. Cioffi G, Faggiano P, Vizzardi E, et al. Prognostic effect of inappropriately high left ventricular

mass in asymptomatic severe aortic stenosis. Heart. 2011;97:301-307

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

18

27. Neubauer S, Horn M, Pabst T, et al. Cardiac high-energy phosphate metabolism in patients with

aortic valve disease assessed by 31p-magnetic resonance spectroscopy. J Investig Med.

1997;45:453-462

28. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830-840

29. Rajappan K, Rimoldi OE, Camici PG, Bellenger NG, Pennell DJ, Sheridan DJ. Functional changes in

coronary microcirculation after valve replacement in patients with aortic stenosis. Circulation.

2003;107:3170-3175

30. Cecchi F, Sgalambro A, Baldi M, et al. Microvascular dysfunction, myocardial ischemia, and

progression to heart failure in patients with hypertrophic cardiomyopathy. J Cardiovasc Transl

Res. 2009;2:452-461

31. Yarbrough WM, Mukherjee R, Ikonomidis JS, Zile MR, Spinale FG. Myocardial remodeling with

aortic stenosis and after aortic valve replacement: Mechanisms and future prognostic

implications. J Thorac Cardiovasc Surg. 2012;143:656-664

32. Leone BJ, Norris RM, Safwat A, Foex P, Ryder WA. Effects of progressive myocardial ischaemia

on systolic function, diastolic dysfunction, and load dependent relaxation. Cardiovasc Res.

1992;26:422-429

33. Kupari M, Turto H, Lommi J. Left ventricular hypertrophy in aortic valve stenosis: Preventive or

promotive of systolic dysfunction and heart failure? Eur Heart J. 2005;26:1790-1796

34. Villari B, Campbell SE, Schneider J, Vassalli G, Chiariello M, Hess OM. Sex-dependent differences

in left ventricular function and structure in chronic pressure overload. Eur Heart J.

1995;16:1410-1419

35. Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low-gradient severe aortic

stenosis despite preserved ejection fraction is associated with higher afterload and reduced

survival. Circulation. 2007;115:2856-2864

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

19

36. Eleid MF, Sorajja P, Michelena HI, Malouf JF, Scott CG, Pellikka PA. Flow-gradient patterns in

severe aortic stenosis with preserved ejection fraction: Clinical characteristics and predictors of

survival. Circulation. 2013;128:1781-1789

37. Hachicha Z, Dumesnil JG, Pibarot P. Usefulness of the valvuloarterial impedance to predict

adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol. 2009;54:1003-1011

38. Herrmann HC, Pibarot P, Hueter I, 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;127:2316-2326

39. Herrmann S, Stork S, Niemann M, et al. Low-gradient aortic valve stenosis myocardial fibrosis

and its influence on function and outcome. J Am Coll Cardiol. 2011;58:402-412

40. Pibarot P, Dumesnil JG. Low-flow, low-gradient aortic stenosis with normal and depressed left

ventricular ejection fraction. J Am Coll Cardiol. 2012;60:1845-1853

41. Mehrotra P, Jansen K, Flynn AW, et al. Differential left ventricular remodelling and longitudinal

function distinguishes low flow from normal-flow preserved ejection fraction low-gradient

severe aortic stenosis. Eur Heart J. 2013;34:1906-1914

42. Lee SP, Park SJ, Kim YJ, et al. Early detection of subclinical ventricular deterioration in aortic

stenosis with cardiovascular magnetic resonance and echocardiography. J Cardiovasc Magn

Reson. 2013;15:72

43. Weidemann F, Herrmann S, Stork S, et al. Impact of myocardial fibrosis in patients with

symptomatic severe aortic stenosis. Circulation. 2009;120:577-584

44. Dahl JS, Christensen NL, Videbaek L, et al. Left ventricular diastolic function is associated with

symptom status in severe aortic valve stenosis. Circ Cardiovasc Imag. 2013;Oct 30 (epub ahead

of print)

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45. Rassi AN, Aljaroudi W, Naderi S, et al. Exercise stress echocardiography in patients with aortic

stenosis: Impact of baseline diastolic dysfunction and functional capacity on mortality and aortic

valve replacement. Cardiovasc Diagn Ther. 2013;3:205-215

46. Spann JF, Bove AA, Natarajan G, Kreulen T. Ventricular performance, pump function and

compensatory mechanisms in patients with aortic stenosis. Circulation. 1980;62:576-582

47. Gerdts E, Cramariuc D, de Simone G, Wachtell K, Dahlof B, Devereux RB. Impact of left

ventricular geometry on prognosis in hypertensive patients with left ventricular hypertrophy

(the life study). Eur J Echocardiogr. 2008;9:809-815

48. Clavel MA, Fuchs C, Burwash IG, et al. Predictors of outcomes in low-flow, low-gradient aortic

stenosis: Results of the multicenter topas study. Circulation. 2008;118:S234-242

49. Jander N, Minners J, Holme I, et al. Outcome of patients with low-gradient "severe" aortic

stenosis and preserved ejection fraction. Circulation. 2011;123:887-895

50. Barasch E, Fan D, Chukwu EO, et al. Severe isolated aortic stenosis with normal left ventricular

systolic function and low transvalvular gradients: Pathophysiologic and prognostic insights. J

Heart Valve Dis. 2008;17:81-88

51. Mehta RH, Bruckman D, Das S, et al. Implications of increased left ventricular mass index on in-

hospital outcomes in patients undergoing aortic valve surgery. J Thorac Cardiovasc Surg.

2001;122:919-928

52. Fuster RG, Argudo JA, Albarova OG, et al. Left ventricular mass index in aortic valve surgery: A

new index for early valve replacement? Eur J Cardiothorac Surg. 2003;23:696-702

53. Orsinelli DA, Aurigemma GP, Battista S, Krendel S, Gaasch WH. Left ventricular hypertrophy and

mortality after aortic valve replacement for aortic stenosis. A high risk subgroup identified by

preoperative relative wall thickness. J Am Coll Cardiol. 1993;22:1679-1683

MANUSCRIP

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54. Powell DE, Tunick PA, Rosenzweig BP, et al. Aortic valve replacement in patients with aortic

stenosis and severe left ventricular dysfunction. Arch Intern Med. 2000;160:1337-1341

55. Morris JJ, Schaff HV, Mullany CJ, et al. Determinants of survival and recovery of left ventricular

function after aortic valve replacement. Ann Thorac Surg. 1993;56:22-29; discussion 29-30

56. Halkos ME, Chen EP, Sarin EL, et al. Aortic valve replacement for aortic stenosis in patients with

left ventricular dysfunction. Ann Thorac Surg. 2009;88:746-751

57. Roques F, Nashef SA, Michel P, et al. Risk factors and outcome in european cardiac surgery:

Analysis of the euroscore multinational database of 19030 patients. Eur J Cardiothorac Surg.

1999;15(6):816-822; discussion 822-813

58. Shroyer AL, Plomondon ME, Grover FL, Edwards FH. The 1996 coronary artery bypass risk

model: The society of thoracic surgeons adult cardiac national database. Ann Thorac Surg.

1999;67:1205-1208

59. Pereira JJ, Lauer MS, Bashir M, et al. Survival after aortic valve replacement for severe aortic

stenosis with low transvalvular gradients and severe left ventricular dysfunction. J Am Coll

Cardiol. 2002;39:1356-1363

60. Tarantini G, Buja P, Scognamiglio R, et al. Aortic valve replacement in severe aortic stenosis with

left ventricular dysfunction: Determinants of cardiac mortality and ventricular function recovery.

Eur J Cardiothorac Surg. 2003;24:879-885

61. Pai RG, Varadarajan P, Razzouk A. Survival benefit of aortic valve replacement in patients with

severe aortic stenosis with low ejection fraction and low gradient with normal ejection fraction.

Ann Thorac Surg. 2008;86:1781-1789

62. Elmariah S, Palacios IF, McAndrew T, et al. Outcomes of transcatheter and surgical aortic valve

replacement in high-risk patients with aortic stenosis and left ventricular dysfunction: Results

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from the placement of aortic transcatheter valves (partner) trial (cohort a). Circ Cardiovasc

Interv. 2013;6:604-614

63. Azevedo CF, Nigri M, Higuchi ML, et al. Prognostic significance of myocardial fibrosis

quantification by histopathology and magnetic resonance imaging in patients with severe aortic

valve disease. J Am Coll Cardiol. 2010;56:278-287

64. Kulik A, Burwash IG, Kapila V, Mesana TG, Ruel M. Long-term outcomes after valve replacement

for low-gradient aortic stenosis: Impact of prosthesis-patient mismatch. Circulation.

2006;114:I553-558

65. Mohty D, Magne J, Deltreuil M, et al. Outcome and impact of surgery in paradoxical low-flow,

low-gradient severe aortic stenosis and preserved left ventricular ejection fraction: A cardiac

catheterization study. Circulation. 2013;128:S235-242

66. Le Ven F, Freeman M, Webb J, et al. Impact of low flow on the outcome of high-risk patients

undergoing transcatheter aortic valve replacement. J Am Coll Cardiol. 2013;62:782-788

67. Clavel MA, Messika-Zeitoun D, Pibarot P, et al. The complex nature of discordant severe calcified

aortic valve disease grading: New insights from combined doppler echocardiographic and

computed tomographic study. J Am Coll Cardiol. 2013;62:2329-2338

68. Hess OM, Ritter M, Schneider J, Grimm J, Turina M, Krayenbuehl HP. Diastolic stiffness and

myocardial structure in aortic valve disease before and after valve replacement. Circulation.

1984;69:855-865

69. Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G, Turina M. Left ventricular myocardial

structure in aortic valve disease before, intermediate, and late after aortic valve replacement.

Circulation. 1989;79:744-755

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70. Monrad ES, Hess OM, Murakami T, Nonogi H, Corin WJ, Krayenbuehl HP. Time course of

regression of left ventricular hypertrophy after aortic valve replacement. Circulation.

1988;77:1345-1355

71. Ikonomidis I, Tsoukas A, Parthenakis F, et al. Four year follow up of aortic valve replacement for

isolated aortic stenosis: A link between reduction in pressure overload, regression of left

ventricular hypertrophy, and diastolic function. Heart. 2001;86:309-316

72. Rost C, Korder S, Wasmeier G, et al. Sequential changes in myocardial function after valve

replacement for aortic stenosis by speckle tracking echocardiography. Eur J Echocardiogr.

2010;11:584-589

73. Lamb HJ, Beyerbacht HP, de Roos A, et al. Left ventricular remodeling early after aortic valve

replacement: Differential effects on diastolic function in aortic valve stenosis and aortic

regurgitation. J Am Coll Cardiol. 2002;40:2182-2188

74. Guarracino F, Talini E, Landoni G, Petronio S, Giannini C, Di Bello V. Effect of aortic valve surgery

on left ventricular diastole assessed by echocardiography and neuroendocrine response:

Percutaneous versus surgical approach. J Cardiothorac Vasc Anesth. 2010;24:25-29

75. Ali A, Patel A, Ali Z, et al. Enhanced left ventricular mass regression after aortic valve

replacement in patients with aortic stenosis is associated with improved long-term survival. J

Thorac Cardiovasc Surg. 2011;142:285-291

76. Mihaljevic T, Nowicki ER, Rajeswaran J, et al. Survival after valve replacement for aortic stenosis:

Implications for decision making. J Thorac Cardiovasc Surg. 2008;135:1270-1278; discussion

1278-1279

77. Blais C, Dumesnil JG, Baillot R, Simard S, Doyle D, Pibarot P. Impact of valve prosthesis-patient

mismatch on short-term mortality after aortic valve replacement. Circulation. 2003;108:983-988

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78. Clavel MA, Webb JG, Rodes-Cabau J, et al. Comparison between transcatheter and surgical

prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular

ejection fraction. Circulation. 2010;122:1928-1936

79. Clavel MA, Webb JG, Pibarot P, et al. Comparison of the hemodynamic performance of

percutaneous and surgical bioprostheses for the treatment of severe aortic stenosis. J Am Coll

Cardiol. 2009;53:1883-1891

80. Lund O, Emmertsen K, Dorup I, Jensen FT, Flo C. Regression of left ventricular hypertrophy

during 10 years after valve replacement for aortic stenosis is related to the preoperative risk

profile. Eur Heart J. 2003;24:1437-1446

81. Tasca G, Brunelli F, Cirillo M, et al. Impact of valve prosthesis-patient mismatch on left

ventricular mass regression following aortic valve replacement. Ann Thorac Surg. 2005;79:505-

510

82. Dahl JS, Videbaek L, Poulsen MK, et al. Effect of candesartan treatment on left ventricular

remodeling after aortic valve replacement for aortic stenosis. Am J Cardiol. 2010;106:713-719

83. Ganau A, Devereux RB, Roman MJ, et al. Patterns of left ventricular hypertrophy and geometric

remodeling in essential hypertension. J Am Coll Cardiol. 1992;19:1550-1558

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Table 1. Factors Associated with LV Remodeling in Aortic Stenosis

Variable Effect on LV

Female gender ↑ relative wall thickness

↑ ejection fraction

↓ LV mass

↓ chamber size

Coronary artery disease ↓ relative wall thickness

↑ systolic dysfunction

Left-sided regurgitant valve lesions ↓ relative wall thickness

↑ LV mass

↑ systolic dysfunction

Hypertension ↑ LV mass

Insulin resistance ↑ LV mass

Metabolic syndrome ↑ relative wall thickness

↑ concentric LVH

Obesity ↑ LV mass

Renal dysfunction ↑ LV mass

↑ diastolic dysfunction

↑ systolic dysfunction

LV=left ventricle, LVH=left ventricular hypertrophy

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FIGURE LEGENDS

Figure 1. Left ventricular geometric patterns of remodeling. Adapted with permission.83

Figure 2. Pathophysiologic mechanisms of left ventricular (LV) remodeling.

Figure 3. The progression of left ventricular (LV) remodeling in aortic stenosis. LVH = LV

hypertrophy

Figure 4. Event-free survival curves in patients with appropriate (dotted line) or inappropriately

high (continuous line) left ventricular (LV) mass in asymptomatic severe aortic stenosis.

Reproduced with permission.26

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