Diagnostic algorithms in asymptomatic valvular heart

diseases

Kyriakos Yiangou MD, MSc, FESC, FACC

Cardiologist

p President, Cyprus Society of Cardiology

Joınt Sessıon ACC / Hellenic – Cyprus Chapter

No conflict of ınterest

Introduction

• Symptomatic severe valvular heart diseases (VHD) have a straight forward indication for surgical intervention.

• In asymptomatic individuals with severe VHD things are not so clear.

• Need for diagnostic algorithms and risk stratification models to clarify higher risk / need-to-operate patients.

How to improve risk stratification?

Is the patient really asymptomatic?

Is the function really preserved/normal?

Are there other early VHD consequences-

related markers –indices ?

Three Fundamental Questions!

• Clinicalassessment

• Exercise Test• Peak VO2,

VE/VCO2

• Beyond LVEF / LV diameter

• GLS, LV index? LV myocardial fibrosis, biomarkers?

• AF• LA size• sPAP,

Biomarkers?

Aortic Stenosis

Baumgartner et al. EHJ, 2017

AS and Symptoms✓ Identification of “subtle” symptoms

• Difficult• Ambiguous• Dyspnea or functional limitation

o Deconditioning?o Sedentary lifestyle?o Obesity?o Comorbidities?o Aging?

• Concealed by adaptation

✓ Exercise testing is recommended in AS ✓ Limited value >70yo

• “Patients with symptoms provoked by exercise testing should be considered symptomatic…”

AS and LV ejection fractionn=2 017 severe AS with AVR and TTE

Dahl et al., Circ CVI, 2015

LV Ejection Fraction in AS

ESC 2017 Guidelines

Asymptomatic severe AS, LVEF<50% Class I C< 1-3% of AS patients

Bohbot Y et al. JACC ımagıng, 2019

Early Intervention

Initial conservative management

Adjusted HR=3.70 p=0.002

Asymptomatic, LVEF>50%, low risk

No or mild symptoms

AS and myocardial function

Ng*, Delgado* et al., Eur H J, 2011

62±6% 59±6% 62±6% 61±6%LVEF, % 62±6%

Delgado et al., Eur H J, 2011

Yingchoncharoen et al. Circ CV Img, 2012

n=79 Asymptomatic severe AS with preservedLV ejection fraction (63±8%)

AS and LV function

Marwick et al. Circ Cardiovasc Imaging 2012;5:719-725

EACVI R&I Committee

VariablesWhole pooled cohort

(n=1 067)Age, years 74±10Body surface area, m² 1.79±0.26Male gender, % 56

ComorbiditiesCoronary artery disease, % 26Hypertension, % 63Diabetes, % 28Dyslipidemia, % 44

Echocardiographic dataIndexed Aortic valve area,

cm²/m²0.49±0.17

LVEF, % 63.5±8LVEF >60%, % 65LV global longitudinal strain, % -16.2±3.6

Magne J et al. JACC CVI, 2019

Prognostic Value of GLS in AS: IPD Meta-Analysis

Distribution of GLS

Prognostic Value of GLS in AS: IPD Meta-Analysis

AUC=0.68Sensitivity=0.60Specificity=0.70

Cut-Off Value for Mortality

Best cut-off: -14.7

Magne et al. JACC CVI, 2019

Prognostic Value of GLS in AS: IPD Meta-Analysis

Survival according to GLS>14.7% in pts with LVEF >60%

Pooled effect (REM) of GLS>14.7% on death

Magne et al. JACC CVI, 2019

Prognostic Value of LV mechanical dispersion

LV mechanical dispersion: • time interval between onset of QRS and peak LV

longitudinal strain• SD of the 16 LV segments: < 70ms

Klaeboe et al., JASE, 2017

Prognostic Value of LV mechanical dispersion

Klaeboe et al., JASE, 2017Prihadi et al. EHJ CVI, 2019

LV mechanical dispersion <62ms

LV mechanical dispersion ≥62ms

n=630, various degrees of AS

Static PressureLVSP

SAP

∆PMG

AA

Flow axis

Valvular Load

Arterial Load

EOASV

}}

Valvulo-Arterial Impedance

Zva = =LVSP MG + SAP

SVi SVi

Left Ventricular Afterload in AS = Valvular Load + Arterial Load

Courtesy from Dr Philippe Pibarot, Quebec Heart and Lung Institute.

} Total Load

>3.5: Moderate>4.5: Severe

Z (ω) =𝑭 (ω)

𝑽 (ω)

Retrospective analysis of 544 asymptomatic pts

≥ moderate AS (≥ 2.5 m/s), LVEF ≥ 50%; Follow-up 2.5±1.8 years

Prognostic Impact of Global Afterload

Follow-up (years)

Ove

rall

Surv

ival

, (%

)

Multivariate AnalysisMed Zva: HR=2.3; p=0.03High Zva: HR=2.8; p=0.01

100

80

60

40

20

0

0 2 4 6 8

Zva<3.5

P < 0.001

3 years

88 ± 3%

80 ± 3%

70 ± 5%

3.5≤ Zva<4.5

Zva≥ 4.5

Age-Gender matched generalpopulation

Hachicha et al., JACC, 2009

0

5

10

15

20

25

3021.5±4.8 21.2±5.1 20.6±5.3 20.3±5.3 20.2±5.3

18.8±5.8 17.6±5.715.6±5.3

14.0±5.9 12.3±6.0

p=0.079p=0.014 p=0.007 p=0.008 p=0.006

VO

2m

ax, m

L/kg

/min

Valvulo-Arterial Impedance (Zva), mmHg/mL/m²

Evidence Symptoms

Levy et al. Arch CV Disease, 2014Dulgheru et al. IJC, 2013

Maximal exercise capacity is associated with hemodynamic overload and outcome

Very Severe AS (IIa)n=116

44 patients with AV velocity >5.5m/s96 events: 90 AVR

Rosenhek et al., Circulation, 2010

n=197AVA<0.75m² and

Peak Ao vel>4.5m/s orMPG>50mmHg

Kang et al., Circulation, 2010

1995 to 2008: 13 years 1996 to 2006: 10 years

MSCT can contribute to the evaluation of the severity of the AS either indirectly (quantification of calcification) or directly (AVA planimetry)

Guidelines on the management of valvular heart disease 2017

Agatson Calcium Score > 1100 →severe AS

(sensitivity 93% - specificity 82%)

Messika-Zeitoun et al Circulation 2004;110:356–362.

Cowell SJ, et al Clin Radiol 2013,58:712-716

Rapid progression of AS severity (IIa)

Retrospective, n=129Outcome: AVR or death

Rate of progression: 0.24±0.30 m/s/yr

Rosenhek et al., NEJM, 2000 Rosenhek et al., Eur H J, 2004

Ao Vel >0.3m/s/yearn=34

Progression of AS

Dweck et al., Circ CVI, 2014

Tastet et al. JACC, 2018

PET – Fused radiolabeled sodium fluoride (18F-NAF): calcification activity in the vasculature

LGE and Outcome in AS

Musa et al., Circ, 2018

n=674 severe AS, 6 UK centers

All causes mortality CV mortality

Adjusted HR=2.4, 95%CI: 1.4-4.05

Adjusted HR=3.1, 95%CI: 1.65-5.99

Myocardial Function in AS

Prospective, Mild to severe ASNo exclusion criteria according to LVEFn=166

Chin et al., JACC CVI, 2017

67%

66%

67%

68% 66% 67%

Myocardial Function in AS

Bing et al., JACC CVI, 2019

Preserved LVEF

Fibrosis Type and Outcome in ASNative T1 mapping

Bing et al., JACC CVI, 2019

Lee et al., JACC CVI, 2017

Treibel et al., JACC, 2018

Fibrosis Type and Outcome in AS

Focal non-infarct LGE typical of the replacement fibrosis seen in AS

T1 mapping

Bing et al., JACC CVI, 2019

ImpairedLVEF

????

New Proposed Algorithm

iReview, JACC CVI, 2019

Tastet et al. JACC, 2019Généreux et al. EHJ, 2017

New AS Staging: Extent of Cardiac Damage

Doris et al. JACC CVI, 2019

Brain Natriuretic Peptide in Asymptomatic AS

Severity of AS

LV mass

Symptomatic status

NYHA Class

Systolic dysfunction

Symptom free survival Bergler-Klein Circulation 2004 Nessmith AJC 2005

Weber EHJ 2004 Lim, EHJ 2004

Kupari, Eur JHF 2007 Lancellotti, AJC, 2010

Mıtral Regurgıtatıon

Baumgartner et al. EHJ, 2017

Is the patient really asymptomatic?n=134 asymptomatic primary MR, 19% of reduced exercise capacity(<84% of predicted VO2); 13% of MR-related

Determinants of reduced Exercise capacity: high E/E’ ratio, low LV stroke volume

Messika-Zeitoun, JACC, 2006

Is the function really preserved/normal?

0 2 4 6 1080

20

40

100

60

80

Impact of LVEF on Postoperative Outcome

Enriquez-Sarano et al. Circulation , 1994

Post

op

erat

ive

Surv

ival

, %

Follow-up, years

p=0.0001

72±4%

53±9%

32±12%LVEF ≥60%

LVEF <50%LVEF 50-60%

LVEF ≥60% Excellent survival as compared to reference population

LV Forward EF𝑳𝑽 𝑭𝒐𝒓𝒘𝒂𝒓𝒅 𝑬𝑭 = 𝟏𝟎𝟎 ×

𝑳𝑽 𝑺𝑽

𝑳𝑽𝑬𝑫 𝒗𝒐𝒍𝒖𝒎𝒆

Dupuis et al., JAHA, 2017

LVEF: 65%LV forward EF: 35%

0 6 12 18 24 30 36 42 48

0

20

40

60

80

100

Car

dia

c Ev

en

t-fr

ee

Su

rviv

al, %

Follow-up, months

GLS >20%

GLS <20%

p<0.0001

66±7%

28±8%

Adjusted HR=3.3 (1.1-9.9) p=0.03

n=135

LV Longitudinal Function and Outcome

Magne et al. Heart 2012

In asymptomatic degenerative MR, reduced LV longitudinal function is

associated with 3-fold increase in risk of cardiac-event.

Bi-centric study, n=135 asymptomaticMR (moderate & severe) with no LV

dysfunction/dilatation

Tribouilloy et al. JACC, 2009;54:1961–8

Impact of LV Dilatation on Survival

MIDA registry

739 patients with flail leaflet, follow-up: 6.1±3.7 years

Only 33% of asymptomatic pts with

LVESD >40mm

0 2 4 6 100

20

40

100

60

80

Ad

just

edPo

sto

p S

urv

ival

, %

8Follow-up, years 30 35 40 45 50

LV ESD (mm)

Haz

ard

Rat

io

10

3.2

1.0

0.3 40 or 22 mm/m²

LVESD <40mmLVESD ≥40mm

p=0.019

73±4%

65±7%

LV Remodeling in Primary MRn=94 MR patients, LVEF>60%, LVES d<40mm

Control group: n=51

Schiros et al. Circulation, 125:2334-2342; 2012

LV Ejection IndexComposite echo marker of LV dilatation and ejection

43mm23.9mm/m²

LVOT TVI=21cm

1.14(Indexed)

Or 2.04

(non-indexed)

Best Cut-off value= 1.13 (indexed) or 2.35 (non-indexed)

Magne et al EHJ CVI 2015

LV Ejection Index

In patients with “normal” LVEF & no LV dilatation

Postop. overall survival Postop. CV mortality

Magne J et al Circ Cardiovasc Imaging. 2015

Risk stratification using Clinical Score – in MR

Grigioni et al. EHJ, 2018

The MIDA mortality risk scoreDerivation cohort, n=2472; validation cohort, n=1194

0

20

40

60

80

100

Primary MR and LV Myocardial Fibrosis

LV

eje

cti

on

fra

cti

on

, %

67±4% 68±5%LV fibrosis (n=11, 30%)

No LV fibrosis (n=29, 70%)

p=NS

0

10

20

30

40

50

LV

ES

dia

mete

r 39±434±5

21±1.518±3

LVESd, mm Ind LVESd,

mm/m²

p=0.007

p=0.002

n=40 asymptomatic pts, LVEF>60%,

LVESd<45mm

Van de Heyning et al. Eur J Clin Invest, 2014

Primary MR and LV Myocardial Fibrosis

Edwards et al. Circ CVi, 2014

n=35 asymptomatic primary MR; 31% of LGE

LV Contractile Reserve

GLS= -24.3%

Exercise

PSLA view 4ch view 2ch view

GLS = -18%

Rest

EDV=140ml, ESV=51ml LVEF= 64%

EDV=153ml, ESV=36ml LVEF= 76% Lancellottı et al EHJ CVI 2014

0 6 12 18 24 30 36 42 48 54 60

0

10

20

30

40

50

Car

dia

c Ev

en

t-fr

ee

Su

rviv

al, %

60

70

80

90

100

Impact of LVCR on Outcome

74±8%

45±8%

68±7%

42±8%

p=0.003

Follow-up, months

Adjusted HR=2 (1.0-4.1) p=0.04

CR+

CR-

Magne et al EHJ CVI 2014

-15 -10 -5 0 5 10 15

1

2

3

4

5

6

7

Log

BN

P

Ex-induced changes in GLS

r= -0.48, p<0.0001

LV contractile reserve using GLS

Are there others early MR consequences-related markers ?

LA size and Prognosis in Primary MR

Le Tourneau et al., JACC, 2010, 56: 570-8

ESC 2012 Guidelines for the Management of VHD: primary MR

Magne et al., Heart, 2012

ESC 2017 Guidelines for the Management of VHD: primary MR

ESC 2017 Guidelines / Stress Echo

2012 2017

AS

MR

Stress echocardiography-derived parameters in Asymptomatic patients

Vahanian et al. EHJ, 2012Baumgartner et al. EHJ, 2017

Take Home Messages!

- Guidelines derived imaging parameters are crucial!• LVEF, LVES diameter, LA volume

- In patients with no LV dysfunction/dilatation, further advanced parameters are required:• LV global longitudinal strain, LA strain, LV ejection index• CMR: LV fibrosis assessment

No golden single measurement – method but global assessment as well as ındıvıdualızatıon is required