Left Atrial Dynamics During Exercise in Mitral Regurgitation of Primary and Secondary Origin

JACC: CARDIOVASCULAR IMAGING

VOL.

-, NO. -, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ORIGINAL RESEARCH

Left Atrial Dynamics During Exercise in Mitral Regurgitation of Primary and Secondary Origin Pathophysiological Insights by Exercise Echocardiography Combined With Gas Exchange Analysis Tadafumi Sugimoto, MD,a,b Francesco Bandera, MD, PHD,a,c Greta Generati, MD,a Eleonora Alfonzetti, RN,a Marta Barletta, MD,a Maurizio Losito, MD,a Valentina Labate, MD,a Marina Rovida, MD,a Michela Caracciolo, MD,a Carlo Pappone, MD,d Giuseppe Ciconte, MD,d Marco Guazzi, MD, PHDa,c

ABSTRACT OBJECTIVES The aim of this study was to identify the pattern of exercise left atrial (LA) dynamics, its gas exchange correlates, and prognosis in mitral regurgitation (MR) of primary and secondary origin. BACKGROUND The adaptive response and clinical significance of LA function during exercise in MR is undefined. METHODS A total of 196 patients with MR (81 with primary MR, 115 with secondary MR) and 54 control subjects underwent exercise stress echocardiography and cardiopulmonary exercise testing with LA function assessment. Patients with MR were divided into 4 groups according to etiology and severity using a cutoff of 3þ. RESULTS LA dynamics was studied using speckle-tracking echocardiography. Compared with control subjects, patients with MR had a lower LA strain and strain rate at rest. Exercise LA strain and LA strain rate progressively worsened from primary MR <3þ through secondary MR $3þ. In primary MR, some reserve in exercise LA strain and LA strain rate was observed, but not in secondary MR. In secondary MR, LA strain at rest and during exercise (18.1  5.7 s1, 18.3  6.9 s1, 18.6  5.5 s1, 13.9  3.8 s1) and peak oxygen consumption (11.7  3 ml/min/kg) were decreased compared with the other groups. In secondary MR $3þ, the slope of ventilation versus carbon dioxide was higher compared with the other groups: 35.1 (interquartile range [IQR]: 29.0 to 44.2) compared with control subjects: 26.5 (IQR: 24.4 to 29.0); patients with primary MR <3þ (26.9; IQR: 24.0 to 31.9); those with primary MR >3þ (25.5; IQR: 23.4 to 29.0); and those with secondary MR <3þ (29.5; IQR: 26.5 to 33.7) (p < 0.05 for all). A progressive impairment in exercise LA mechanics combined with limited cardiac output increase and right ventricular–to–pulmonary circulation uncoupling was observed from primary to secondary MR. LAS during exercise was predictive of all-cause mortality and hospitalization for heart failure. CONCLUSIONS In MR of any origin, exercise LA reservoir and pump function are impaired. For similar MR extent, secondary MR exhibits worse atrial function, resulting in the lowest exercise performance, limited cardiac output increase, impaired right ventricular–to–pulmonary circulation coupling, and the highest event rate. (J Am Coll Cardiol Img 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.

From the aCardiology University Department, Heart Failure Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy; b

Department of Clinical Laboratory, Mie University Hospital, Tsu, Japan; cDepartment for Biomedical Sciences for Health,

University of Milano, Milan, Italy; and the dArrhythmology Department, Scientific Institute for Research, Hospitalization, and Health Care, Policlinico San Donato University Hospital, San Donato Milanese, Milan, Italy. This study was supported by a grant to Dr. Guazzi from the Monzino Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received September 13, 2018; revised manuscript received December 16, 2018, accepted December 20, 2018.

ISSN 1936-878X/$36.00

https://doi.org/10.1016/j.jcmg.2018.12.031

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Left Atrial Dynamics in Mitral Regurgitation

ABBREVIATIONS AND ACRONYMS CO = cardiac output CPET = cardiopulmonary

S

exercise testing

EF = ejection fraction HR = heart rate LA = left atrial LV = left ventricular LVOT = left ventricular outflow tract

MR = mitral regurgitation PASP = pulmonary artery systolic pressure

PC = pulmonary circulation RV = right ventricular SV = stroke volume TAPSE = tricuspid annular plane systolic excursion

VE = minute ventilation

evere mitral regurgitation (MR) of pri-

loops, which requires an invasive approach not

mary

mainly

easily available in clinical practice. Nonetheless,

when emphasized by exercise, is a pre-

measures of LA strain and strain rate obtained by

dictor of cardiovascular events (1–3). By defi-

speckle-tracking echocardiography have been proved

nition,

(LA)

to be sensitive and reproducible methods to evaluate

enlargement because of volume and pressure

LA mechanics (11,12). Interestingly, this analysis may

overload, which imposes increased pulsatile

be reliably performed during exercise (13) and has

loading on the pulmonary circulation (PC),

been recently proposed by our group as an additional

an effect that precipitates pulmonary hyper-

tool to determine the putative role of LA function in

tension and right ventricular (RV)–to–PC

left and right heart functional adaptations during

uncoupling, especially during exercise (4–6).

exercise in patients with reduced and those with

VO2 = oxygen uptake

MR

secondary

induces

origin,

left

atrial

Whereas the importance of LA dynamics

preserved ejection fraction (13).

and its adaptations to physiological settings

Because most of cardiovascular adaptations to ex-

has been long recognized (7) and the role of

ercise can be quantified through the measure of ox-

LA function in cardiovascular disorders is

ygen uptake (V O2) and gas exchange analysis, the

receiving attention in modern times (8–10), a

contemporary

challenging and quite unexplored area of

testing (CPET) and stress echocardiography seems

investigation is the study of the effects of

quite attractive to comprehensively detect and inte-

different types and severity of MR on LA

grate physiological and clinical information (14).

dynamics during progressive exercise and the underlying pathophysiology.

VCO2 = carbon dioxide production

or

use

of

cardiopulmonary

exercise

On the basis of these premises, we aimed to explore how LA dynamics during exercise might

The gold standard for assessing LA function is the generation of pressure-volume

mutually change in the presence of MR of different origin

(primary

vs.

secondary)

and

severity,

T A B L E 1 Clinical Characteristics and Therapy Distribution

All (n ¼ 250)

Control* (n ¼ 54)

Primary MR <3þ† (n ¼ 42)

Primary MR $3þ† (n ¼ 39)

Secondary MR <3þ† (n ¼ 75)

Secondary MR $3þ† (n ¼ 40)

p Value

64.9  13.2

59.5  13.3

64.3  14.5

64.5  14.0

68.4  12.3‡

66.7  10.2‡

0.004

56

50

45

51

64

65

0.17

25.9  4.3

25.8  3.8

25.2  4.2

25.0  4.5

26.9  4.4

25.7  4.6

0.13

Systolic BP, mm Hg

127  18

129  18

131  14

132  16

126  18

121  21

0.053

Heart rate, beats/min

68  12

70  10

68  12

66  14

67  12

71  12

0.23

Hypertension

65

63

71

56

67

65

0.71

Diabetes mellitus

21

17

2

6

33†‡

35§k

<0.001

Dyslipidemia

49

39

34

31

68‡§k

60

<0.001

Current or ex-smoker

35

26

37

25

40

45

0.15

HFrEF

26.4

—

—

—

48

75

—

HFmrEF

12.0

—

—

—

28

22.5

—

HFpEF

7.6

—

—

—

24

2.5

—

Primary mitral regurgitation

32.4

—

100

100

—

—

—

Noncardiac etiology

21.3

100

—

—

—

—

—

Age, yrs Male Body mass index, kg/m2

Etiology

Therapy ACE inhibitors or ARBs

66

51

54

69

75

78

0.01

Beta-blockers

60

25

56‡

51

79‡k

88‡§k

<0.001

Calcium channel blockers

14

15

22

18

15

0

0.058

Loop diuretics

59

26

46

46

78‡§k

95‡§k

<0.001 <0.001

Aldosterone blockers

28

2

15

10

44‡§k

63‡§k

Ivabradine

6

2

0

0

10

15

0.005

Statins

45

32

29

13

67‡§k

68‡§k

<0.001

Nitrates

8

4

5

5

14

8

0.21

Values are mean  SD or %. *Non-MR patients with left atrial volume index <34 ml/m2 and left atrial strain >23%. †MR during exercise. ‡p <0.05 versus control. §p < 0.05 versus primary MR <3þ. kp < 0.05 versus primary MR $3þ. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; BP ¼ blood pressure; HFmrEF ¼ heart failure with midrange ejection fraction; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; MR ¼ mitral regurgitation.

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Left Atrial Dynamics in Mitral Regurgitation

F I G U R E 1 Left Atrial Strain and Strain Rate at Rest, During Exercise, and in Recovery in the 5 Groups

A

B

0

50 †

*

*

LA Strain (%)

† 30

† †

20

†

†

*

†

*

†

*

†

*

†

*

†

LA Strain Rate (/s)

40 †

†

†

–1

†

† ††

–2

*

†

* * ††

††

–3 *

† 10

–4 † P < 0.05 vs Control

† P < 0.05 vs Control

* P < 0.05 vs Rest

* P < 0.05 vs Rest

0

–5 Rest

Control N = 54

* *

Exercise

Recovery

Primary MR <3+ MR during exercise N = 42

Rest

Primary MR ≥3+ MR during exercise N = 39

Exercise

Secondary MR <3+ MR during exercise N = 75

Recovery

Secondary MR ≥3+ MR during exercise N = 40

Error bars indicate standard error of the mean. LA ¼ left atrial; MR ¼ mitral regurgitation.

addressing the impact that changes in LA function

measurements. Primary and secondary MR groups

may have on functional status and clinical pheno-

were divided according to the severity of MR during

types by using exercise gas exchange analysis and

exercise using cutoff value of 3þ. The origin of MR

echocardiography-derived measures of left and right

was degenerative type II for primary MR (90% pro-

heart hemodynamic status. We also explored the

lapse, 10% flail) and type IIIb for secondary MR. Jet

event-free survival rate on the basis of MR etiology

orientation was eccentric in 80% of patients with

and LA dynamics.

primary MR and concentric in 65% of those with secondary MR.

METHODS

Exclusion criteria consisted of recent myocardial infarction (<3 months), unstable angina, inducible

STUDY POPULATION. Consecutive patients referred

myocardial ischemia, acute MR, causes of mixed

to our center between January 2013 and February

origin, atrial fibrillation, peripheral artery disease,

2018 for functional assessment were considered for

significant anemia (hemoglobin <10 g/dl), respiratory

study recruitment. The population comprised 196

diseases of at least moderate degree, and poor echo-

patients with MR (81 with primary MR, 115 with sec-

cardiographic image quality for LA-strain analysis

ondary MR), who were categorized according to the

(Supplemental Figure 1). All patients signed 2

European Society of Cardiology and European Asso-

informed consent forms, one for the execution of the

ciation for Cardio-Thoracic Surgery guidelines (15),

test and the other for the research use of clinical and

and 54 control subjects with normal left ventricular

instrumental data, approved by our local ethics

(LV) function

committee. Habitual therapy was maintained during

(left ventricular

ejection

fraction

[LVEF] >50%), LA size, reservoir function, LA volume

evaluation.

index <34 ml/m 2, and LA strain peak during LA

REST

relaxation >23% (13,16,17) who were referred for CPET

The echocardiographic evaluation was performed

AND

EXERCISE

ECHOCARDIOGRAPHY.

for quantification of their maximal exercise perfor-

using a Philips iE33 (Philips Medical Systems, And-

mance. According to the guidelines (15), the severity

over, Massachusetts), recording standard images to

of MR at rest was assessed by qualitative measure-

assess LV systolic, diastolic, and valvular function.

ments using a scale of 4 degrees (1 ¼ mild, 2 ¼ mild to

Our exercise echocardiographic methodology has

moderate, 3 ¼ moderate to severe, and 4 ¼ severe),

been previously described (6,13). LA dynamics was

as

assessed by using LA strain (reservoir function) and

well

as

semiquantitative

and

quantitative

3

4

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T A B L E 2 Left Atrial Strain and Strain Rate According to Groups at Rest, During Exercise, and in the Recovery Period

Control* (n ¼ 54)

Primary MR <3þ† (n ¼ 42)

Primary MR $3þ† (n ¼ 39)

Secondary MR <3þ† (n ¼ 75)

Secondary MR $3þ† (n ¼ 40)

p Value

Left atrial strain at rest, % Apical 4- and 2-chamber views

36.0  8.5

27.1  10.6‡

29.7  11.7‡

20.1  10.2‡§k

13.5  9.4‡§k¶

<0.001

Apical 4-chamber view

35.4  8.0

26.2  9.9‡

29.0  12.2‡

20.6  10.9‡§k

13.4  9.1‡§k¶

<0.001

Left atrial strain during exercise, %

40.7  10.9

29.8  13.6‡

30.5  12.7‡

19.5  9.6‡§k

13.4  9.8‡§k

<0.001

Left atrial strain in recovery period, %

43.2  10.6

31.5  14.6‡

33.7  14.6‡

22.7  13.4‡§k

15.9  12.9‡§k

Left atrial strain rate at rest, s1

<0.001 <0.001

Apical 4- and 2-chamber views

3.0  0.8

1.8  0.7‡

1.8  0.8‡

1.8  1.1‡

0.9  0.9‡§k¶

Apical 4-chamber view

2.9  0.9

1.6  0.7‡

1.7  0.9‡

1.7  1.1‡

0.9  0.9‡§k¶

Left atrial strain rate during exercise, s1

3.2  1.0

2.1  1.0‡

2.1  1.0‡

1.5  1.0‡§k

0.9  0.8‡§k¶

<0.001

Left atrial strain rate in recovery period, s1

3.7  1.3

2.2  1.3‡

2.1  1.3‡

1.7  1.2‡

1.0  0.9‡§k

<0.001

Values are mean  SD. *Non-MR patients with left atrial volume index <34 ml/m2 and left atrial strain >23%. †MR during exercise. ‡p < 0.05 versus control. §p < 0.05 versus primary MR <3þ. kp < 0.05 versus primary MR $3þ. ¶p < 0.05 versus secondary MR <3þ. MR ¼ mitral regurgitation.

LA strain rate (pump function) according to the

4-chamber view. Finally, to assess the severity of RV-

American Society of Echocardiography and European

PC uncoupling, we calculated the PASP/TAPSE ratio,

Association of Cardiovascular Imaging guidelines

both at rest and during peak exercise.

(18).

from

CPET. Symptom-limited CPET was performed on a

myocardial analyses of the left atrium in a longitu-

cycle ergometer for all subjects. Incremental ramp

dinal direction in the apical 4- and 2-chamber views

protocols were designed to obtain a standard of exer-

and using QRS onset as the reference point. During

cise. Ventilatory expired gas analysis was performed

exercise and in the recovery period, LA strain and LA

using a metabolic cart (Vmax, SensorMedics, Yorba

strain rate were obtained by averaging all segment

Linda, California). Twelve-lead electrocardiography

strain values from the apical 4-chamber views. LV

and cuff blood pressure were obtained at rest, each

These

measurements

were

derived

diastolic function was assessed by early (E) to late (A)

minute during exercise, and for $4 min during recov-

mitral Doppler wave velocity and LV filling pressure

ery. Baseline metabolic evaluation was performed

by the ratio between E and early tissue Doppler ve-

during a 1-min rest period and during the active cool-

locity wave (e 0 ). LA stiffness was estimated by the ratio between E/e 0 and LA strain (19). The prevalence of abnormal LA stiffness was assessed using a cutoff

down period for $1 min. Measures of CPET-derived variables were defined as previously detailed (13) and are reported in the Supplemental Appendix.

value of 0.55 (11). Intraobserver variability for LA strain rate and LA

STATISTICAL ANALYSIS. All data are presented as

strain was 9% and 6% (intraclass correlation co-

mean  SD, number (percentage), or median (inter-

efficients, 0.94 and 0.93, respectively), on the basis of

quartile range) as appropriate. Group differences

a sample size of 20 subjects (Supplemental Figure 2)

were evaluated using the Student’s t test for normally

(13). In addition, we assessed stroke volume (SV)

distributed continuous variables, the Mann-Whitney

applying the equation SV ¼ VTI LVOT  CSALVOT, where

U test for skewed continuous variables, and the chi-

VTI LVOT is the velocity-time integral of pulsatile

square or Fisher exact tests for categorical variables.

Doppler obtained at the level of the LV outflow tract

One-way analysis of variance or Kruskal-Wallis tests

(LVOT), and CSA LVOT is the cross-sectional area of the

were used to compare >2 groups. When a significant

LVOT, determined using the circumference area for-

difference was found, post hoc testing with Bonfer-

mula. Cardiac output (CO) was obtained as: SV  heart

roni comparisons for identified specific group differ-

rate (HR), both at rest and during peak exercise. Pul-

ences was used. Paired Student t tests or Wilcoxon

monary artery systolic pressure (PASP) was estimated

tests were used to compare differences within groups.

by measuring the peak velocity of transtricuspid

Pearson’s correlation coefficient was used to examine

continuous Doppler and calculating the gradient as:

relationships between continuous variables. For all

4  (peak velocity) (2); right atrial pressure during

tests, 2-sided p values of <0.05 were considered to

exercise was estimated as a fixed value of 10 mm Hg, as

indicate statistical significance. Data were analyzed

previously suggested (3). Longitudinal systolic func-

using the open-source statistical software package R

tion of the right ventricle was measured by tricuspid

version 3.1.1 (R Foundation for Statistical Computing,

annular plane systolic excursion (TAPSE) from the

Vienna, Austria).

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Left Atrial Dynamics in Mitral Regurgitation

F I G U R E 2 Representative Cases of Left Atrial Strain and Strain Rate Patterns at Rest and During Exercise in Primary and Secondary Mitral

Regurgitation $3þ

Primary

Secondary

BAL 93

ApL 15

Apice 10

MIS 9

MAL 9 ApL -7

ApS 26

Strain 32%

60

BAL 10

MIS 20

MAL 19

Rest

BIS 9

BIS 45

Rest 8 4

ApS 13 Apice 7

Strain 6%

30

Strain Rate -0.7 /s

Strain Rate -1.6 /s -0.5 -1

-1 -2 ERO 45 mm2

Exercise 50

Strain 47%

ERO 18 mm2

Exercise

Strain 9%

12 6

25

Strain Rate -0.8 /s

Strain Rate -2.5 /s -0.5 -1

-2 -4

EXERC

ERO ¼ effective regurgitant orifice.

ERO 67 mm2

EXERC4 ’

ERO 25 mm2

5

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Left Atrial Dynamics in Mitral Regurgitation

age, prevalence of diabetes mellitus and dyslipide-

F I G U R E 3 Estimation of Left Atrial Stiffness in the 5 Groups

mia, and the prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers,

20.0

beta-blockers,

Q3 + 1.5 IQR 10.0

Q1

agents,

aldosterone

and received beta-blockers, loop diuretic agents,

*†‡

aldosterone blockers, and statins at higher rates

Q1 – 1.5 IQR LA Stiffness

diuretic

Patients with secondary MR <3þ and $3þ were older

Q2 5.0

loop

blockers, ivabradine, and statins among all groups.

*†‡§

Q3

compared with control subjects. Patients with sec-

2.0

ondary MR $3þ were receiving beta-blockers, loop *

1.0

diuretic agents, and aldosterone blockers at higher

*

rates compared with those with primary MR. LA

0.5

STRAIN

AND

STRAIN

RATE

ANALYSIS.

Figures 1a and 1b show the changes in LA dynamics in each group. In both control subjects and patients with 0.2

primary MR <3þ, LA strain during exercise and in the

0.1

with rest. In patients with primary MR $3þ and those

recovery period was significantly increased compared Control

Primary MR Primary MR Secondary MR Secondary MR <3+ MR during ≥3+ MR during <3+ MR during ≥3+ MR during exercise exercise exercise exercise

with secondary MR, LA strain in recovery period was significantly higher than at rest. In patients with primary MR, despite impaired LA strain and LA strain

*p < 0.05 versus control, †p < 0.05 versus primary mitral regurgitation (MR) <3þ,

rate during exercise and in the recovery period, a

‡p < 0.05 versus primary MR $3þ, and §p < 0.05 versus secondary MR <3þ. IQR ¼

tendency to increase during exercise was still

interquartile range; LA ¼ left atrial; Q ¼ quartile.

observed, at variance with secondary MR. Moreover, patients with primary MR $3þ had lower exercise LA

RESULTS

strain compared with control subjects. Secondary MR <3þ showed lower LA strain compared with control subjects and primary MR group. Patients with

Clinical characteristics and therapy distribution of control subjects and patients with MR are summa-

secondary MR $3þ had lower LA strain compared

rized in Table 1. There were significant differences in

with the other groups (Table 2, Figure 1A). Patients

T A B L E 3 Cardiopulmonary Exercise Testing Variables

Control* (n ¼ 54)

Primary MR <3þ† (n ¼ 42)

Primary MR $3þ† (n ¼ 39)

Secondary MR <3þ† (n ¼ 75)

Secondary MR $3þ† (n ¼ 40)

p Value

Maximal work, W

90 (71–120)

88 (67–108)

86 (71–120)

68 (56–86)‡§k

54 (36–64)‡§k¶

<0.001

Peak VO2, ml/kg/min

18.4  5.6

17.9  6.8

17.9  6.2

13.6  3.9‡§k

11.5  3.2‡§k

<0.001

70  19

74  21

73  23

62  21§

50  16‡§k¶

<0.001

3,320 (2,630–4,270)

3,370 (2,540–4,270)

3,330 (2,570–4,440)

2,180 (1,770–2,760)‡§k

1,830 (1,260–2,210)‡§k¶

<0.001

1.20  0.12

1.18  0.12

1.16  0.12

1.18  0.13

1.11  0.12‡¶

0.011

10.1  2.8

10.0  2.8

10.1  3.6

9.2  2.8

8.0  2.8‡§k

0.003 <0.001

Percentage predicted peak VO2, % Peak circulatory power, mmHg ml/kg/min Peak RER Peak oxygen pulse, ml/beat HRR, beats/min VE/VCO2 slope Peak end-tidal carbon dioxide, mm Hg

16.9  8.8

13.9  10.1

14.7  9.7

8.8  7.1‡§k

8.1  6.4‡§k

26.5 (24.4–29.0)

26.9 (24.0–31.9)

25.5 (23.4–29.0)

29.5 (26.5–33.7)‡k

35.1 (29.0–44.2)‡§k¶

<0.001

37.7  4.1

35.9  4.9

38.8  4.4

33.9  5.2‡k

32.2  5.7‡§k

<0.001

0.15  0.05

0.17  0.06

0.16  0.06

0.18  0.04‡

0.20  0.05‡§k

<0.001

EOV, %

13

7

13

37‡§

53‡§k

<0.001

DVO2/DWR flattening, %

2

12

13

23‡

23‡

0.009

Dyspnea, %

9

38‡

46‡

59‡

70‡§

<0.001

Fatigue, %

9

19

21

25

30

0.041

Peak VD/VT

Symptoms

Values are median (interquartile range), mean  SD, or %. *Non-MR patients with left atrial volume index <34 ml/m2 and left atrial strain >23%. †MR during exercise. ‡p < 0.05 versus control. §p < 0.05 versus primary MR <3þ. kp < 0.05 versus primary MR $3þ. ¶p < 0.05 versus secondary MR <3þ. CPET ¼ cardiopulmonary exercise testing; EOV ¼ exercise oscillatory ventilation; HRR ¼ heart rate recovery; MR ¼ mitral regurgitation; RER ¼ respiratory exchange ratio; VD/VT ¼ dead space/tidal volume ratio; VCO2 ¼ carbon dioxide production; VE ¼ minute ventilation; VO2 ¼ oxygen uptake; WR ¼ work rate.

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F I G U R E 4 Correlations Between Left Atrial Strain and Strain Rate and Cardiopulmonary Exercise Testing Data (Peak Oxygen Uptake and

Minute Ventilation/Carbon Dioxide Production Slope)

45

45 y = 0.22x + 10.0 R = 0.54 P < 0.001

Peak VO2 (mL/kg/min)

40

y = 2.1x + 11.6 R = 0.44 P < 0.001

40

35

35

30

30

25

25

20

20

15

15

10

10

5

5

0

0 0

20

40

60

80

0

LA Strain During Exercise (%)

90

2

3

4

5

6

90 y = –5.0In(x) + 45.5 R = –0.48 P < 0.001

80

VE/VCO2 Slope

1

LA Strain Rate During Exercise (/s) [Absolute Value]

y = –4.1In(x) + 31.7 R = –0.47 P < 0.001

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0 0

20

40

60

80

0

LA Strain During Exercise (%) Control

Primary MR <3+ MR during exercise

1

2

3

4

5

6

LA Strain Rate During Exercise (/s) [Absolute Value] Primary MR ≥3+ MR during exercise

Secondary MR <3+ MR during exercise

Secondary MR ≥3+ MR during exercise

LA ¼ left atrial; MR ¼ mitral regurgitation; VCO2 ¼ carbon dioxide production; VE ¼ minute ventilation; VO2 ¼ oxygen uptake.

with secondary MR $3þ had lower LA strain rate

primary MR $3þ. When data on LA dynamics were

compared with the other 4 groups and, interestingly,

stratified according to tertiles of LVEF, LA strain and

the other 3 MR groups had lower LA strain rate

LA strain rate at rest, during exercise, and in the

compared with control subjects at rest, during exer-

recovery period showed a between-groups statisti-

cise, and in recovery (Figure 1B). Figure 2 depicts 2

cally significant difference according to etiology

representative cases of LA strain and LA strain rate

and MR severity but did not differ among tertiles

patterns at rest and during exercise in primary and

(Supplemental Table 1).

secondary MR $3þ. Figure 3 reports group differences in LA stiffness and shows a progressive increase from

CPET. Compared with control subjects and patients

control subjects through patients with secondary

with primary MR, those with secondary MR of

MR $3þ. Interestingly, patients with secondary

both <3þ and $3þ reached lower maximal work load,

MR <3þ had worse LA stiffness than those with

peak V O2, and peak circulatory power (Table 3).

7

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Left Atrial Dynamics in Mitral Regurgitation

T A B L E 4 Physiological and Echocardiographic Parameters According to Groups at Rest and Peak Exercise

Primary MR <3þ† (n ¼ 42)

Control* (n ¼ 54)

Systolic BP, mm Hg

Primary MR $3þ† (n ¼ 39)

Rest

Peak

Rest

Peak

Rest

Peak

129  18

197  30

131  14

192  29

132  16

195  26

Diastolic BP, mm Hg

78  5

80  6

79  4

79  4

79  4

81  3

Heart rate, beats/min

70  10

131  21

68  12

129  24

66  14

127  24

LV mass index, g/m2

83  18

100  29‡

LV end-diastolic volume index, ml/m2

43  8

54  15

63  14‡

Relative wall thickness

0.41  0.07

0.40  0.07

0.37  0.09 1.71  0.69‡§

109  24‡

E/A ratio

1.02  0.26

1.15  0.45

E/e0 ratio

9.9  3.1

12.7  8.9

14.7  7.0

Left atrial volume index, ml/m2

23.1  5.8

39.7  17.7‡

46.9  15.2‡

0.26 (0.19–0.37)

0.41 (0.32–0.56)‡

0.47 (0.30–0.76)‡

6

27

Left atrial stiffness Abnormal left atrial stiffness, %

42‡

LV ejection fraction, %

67  7

74  7

64  9

68  9

65  7

69  7

LV cardiac output, l/min

4.0  1.0

8.8  2.2

3.5  1.1

7.4  3.0‡

3.5  1.1

7.1  2.6‡

LV stroke volume index, ml/m2

31.2  5.8

37.7  6.7

28.6  8.2

33.9  8.3

28.4  7.2

Cardiac power output, mm Hg l/min MR (0–4 degrees)

2.2 (1.9–2.7)

1.7 (1.4–2.1)‡

32.2  7.7‡ 1.8 (1.4–2.2)‡

80/20/0/0/0

76/22/2/0/0

0/26/71/2/0

2/19/79/0/0

0/3/23/54/21

Effective regurgitant orifice, mm2

—

—

14  7

15  5

30  15§

40  16§

Regurgitant volume, ml

—

—

20.5  11.3

22.7  8.9

45.2  21.7§

54.8  28.0§ 46  14§

Regurgitant fraction, % PASP, mm Hg TAPSE, mm RV fractional area change, % RA area, cm2 RA volume, ml

0/0/0/69/31

—

—

29  11

29  9

47  12§

26  5

42  11

31  13

50  12‡

36  11‡

56  11‡

23.8  3.6

27.7  3.5

23.7  3.7

28.1  4.5

26.0  4.5

27.8  4.6

50  8

55  6

45  9

50  7

46  8

52  8

15.7  3.2

16.7  4.2

17.6  4.1

42.9  14.8

48.0  18.6

52.1  18.0

Values are mean  SD, median (interquartile range), or %. *Non-MR patients with left atrial volume index <34 ml/m2 and left atrial strain >23%. †MR during exercise. ‡p < 0.05 versus control. §p < 0.05 versus primary MR <3þ. kp < 0.05 versus primary MR $3þ. ¶p < 0.05 versus secondary MR <3þ. BP ¼ blood pressure; E/A ¼ ratio of mitral peak velocity of the early filling wave to the atrial contraction wave; E/e0 ¼ ratio of early filling wave to early diastolic mitral annular velocity; LV ¼ left ventricular; MR ¼ mitral regurgitation; PASP ¼ pulmonary artery systolic pressure; RA ¼ right atrial; RV ¼ right ventricular; TAPSE ¼ tricuspid annual plane systolic excursion.

Patients with secondary MR had also lower HR re-

and echocardiographic parameters at rest and peak

covery than control subjects. Patients with secondary

exercise in each cohort. Patients with secondary

MR $3þ exhibited lower percentage predicted peak

MR $3þ had the highest LV mass index, LV end-

V O2 , circulatory power, peak oxygen pulse, HR re-

diastolic volume index, E/e 0 ratio, LA volume index,

covery, and peak end-tidal carbon dioxide and higher

and LA stiffness at rest and the lowest LVEF, SV, and

minute ventilation (VE)/carbon dioxide production

CO at rest. Patients with secondary MR <3þ had

(VCO 2) slope and rate of DV O2/D WR (work rate) flat-

higher E/e 0 ratio, LV mass, and LV end-diastolic vol-

tening compared with control subjects and patients

ume index compared with control subjects and pa-

with primary MR. Significant differences in peak ox-

tients with primary MR <3þ, and LA stiffness in

ygen pulse, exercise oscillatory ventilation, and rate

patients with secondary MR <3þ was higher than in

of V O2 flattening were observed among all groups. In

control subjects and patients with primary MR.

terms of symptoms at peak exercise, patients with

Compared with control subjects, all MR groups

primary MR <3þ and $3þ presented similar rates of

showed greater LA volume index. Patients with pri-

dyspnea and lower fatigue sensation. Figure 4 reports

mary MR $3þ and those with secondary MR <3þ

the correlations between LA strain and strain rate and

showed higher LV mass index and LV end-diastolic

CPET data (peak V O2 and VE/V CO 2 slope). A correlation

volume index. Patients with primary and secondary

was observed in primary and secondary MR by LA

MR $3þ had higher E/A ratios than the other 3

strain and LA strain rate with peak VO2 by dividing the

groups. In patients with secondary MR $3þ, systolic

population according to LA size (34 ml/m2), as shown

blood pressure, LVEF, CO, cardiac power output,

in Supplemental Figure 3.

TAPSE, and RV fractional area change all were the

ECHOCARDIOGRAPHY AND EXERCISE HEMODYNAMIC

lowest values at peak exercise. Peak LVEF and peak

STATUS. Table 4 and Figure 5 describe physiological

TAPSE in patients with MR <3þ were lower than in

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9

Left Atrial Dynamics in Mitral Regurgitation

T A B L E 4 Continued

Secondary MR <3þ† (n ¼ 75)

Secondary MR $3þ† (n ¼ 40)

p Value

Rest

Peak

Rest

Peak

Rest

126  18

167  31‡§k

121  21

154  28‡§k

0.053

76  7

78  6

76  8 †‡

78  8

0.031

0.08

67  12

111  21‡§k

71  12

107  17‡§k

0.23

<0.001

122  30‡§

143  36‡§k¶

73  25‡§

105  33‡§k¶

<0.001

0.39  0.16†‡

0.29  0.07‡§k¶

<0.001

<0.001

1.30  0.92

1.85  1.23द

<0.001

18.3  8.9‡§

27.3  13.6‡§k¶

<0.001

39.2  15.1‡

64.1  28.4‡§k¶

<0.001

0.92 (0.45–1.63)‡§k

2.25 (1.16–4.17)‡§k¶

<0.001

64‡§

Peak

<0.001

<0.001

93‡§k¶

41  14‡§k

43  15‡§k

31  9‡§k¶

34  10‡§k¶

<0.001

<0.001

3.3  0.9‡

6.1  1.9‡

3.2  1.0‡

4.9  1.6‡§k

<0.001

<0.001

31.6  9.2‡

24.4  6.5‡

26.0  7.0‡§k¶

<0.001

<0.001

27.7  7.6

1.5 (1.1–1.8)‡§k

<0.001

1.1 (0.9–1.5)‡§k¶

23/64/13/0/0

0/59/41/0/0

0/5/28/43/25

0/0/0/58/43

<0.001

10  6k

14  7k

22  10§k¶

29  13§k¶

<0.001

<0.001 <0.001

16.6  10.6k

20.8  10.5k

34.8  15.5§k¶

43.8  20.0§¶

<0.001

<0.001

25  11k

25  11k

43  15§¶

48  13§¶

<0.001

<0.001

33  13

52  13‡

42  15द

59  12द

<0.001

<0.001

18.6  4.7‡§k

20.6  5.3‡§k

16.7  5.2‡§k

17.8  5.1‡§k¶

<0.001

<0.001

45  12

40  14‡k

38  15‡k¶

36  14‡§k

<0.001

<0.001

18.1  4.7

20.8  6.6‡§

<0.001

55.1  22.8

67.9  34.4‡§k

<0.001

control subjects and patients with primary MR.

severity-dependent decline from primary to sec-

Compared with control subjects, all MR groups had

ondary MR. These changes in CO occurred with

higher peak PASP, and patients with primary MR $3þ

substantially no changes in LA strain in secondary

exhibited lower peak CO and cardiac power output.

MR. Lower CO resulted in higher PASP. Progressive

Patients with secondary MR had lower peak HRs than

RV-to-PC uncoupling (PASP/TAPSE) was paralleled

the other 3 groups. Whereas effective regurgitant

by decreasing LA strain (Figure 7A) and LA strain

orifice

rate (Figure 7B).

and

regurgitant

volume

during

exercise

were significantly increased compared with rest, in patients with primary MR $3þ and those with secondary MR, regurgitant fraction was significantly greater only in those with secondary MR $3þ. Supplemental Table 2 reports the physiological and echocardiographic parameters at rest and peak exercise in the primary and secondary MR groups.

OUTCOME ANALYSIS. During the follow-up period

(median 600 days; interquartile range: 310 to 960 days; n ¼ 151), 20 patients (9 [16%] with secondary MR <3þ, 11 [31%] with secondary MR $3þ) reached the composite endpoint of hospitalization for heart failure or mortality among the 4 MR groups. Primary MR groups had no composite events. Mitral valve

MAIN HEMODYNAMIC DIFFERENCES AMONG THE

surgery was performed in 15 patients (n ¼ 2 [7%] with

4

GROUPS. Figure 6 reports changes between

primary MR <3þ, 7 [24%] with primary MR $3þ, 3

rest and exercise of main hemodynamic variables

[5%] with secondary MR <3þ, and 3 [9%] with

MR

(Figure 6A, LA strain vs. CO) (Figure 6B, CO vs. PASP

secondary MR $3þ). Figure 8 depicts event-free

vs. LA strain). For similar CO at rest, irrespective of

Kaplan-Meier survival curves according to type and

etiology, peak exercise CO was lower in patients

degree of MR (Figure 8A) and LA strain cutoff of 16

with MR than control subjects, with a progressive

(Figure 8B).

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Left Atrial Dynamics in Mitral Regurgitation

F I G U R E 5 Different Levels of Severity (From Green to Red) in the 5 Groups

Echocardiographic Parameters at Rest LA volume index (ml/m2)

LA strain rate (/s)

LA strain (%)

E/e’

2 LVEDV index (ml/m )

Control

23.1 ± 5.8

–2.9 ± 0.9

35.4 ± 8.0

9.9 ± 3.1

43 ± 8

67 ± 7

Primary MR <3+

39.7 ± 17.7

–1.6 ± 0.7

26.2 ± 9.9

12.7 ± 8.9

54 ± 15

64 ± 9

Primary MR ≥3+

46.9 ± 15.2

–1.7 ± 0.9

29.0 ± 12.2

14.7 ± 7.0

63 ± 14

65 ± 7

Secondary MR <3+

39.2 ± 15.1

–1.7 ± 1.1

20.6 ± 10.9 †

18.3 ± 8.9

73 ± 25

41 ± 14 †

13.4 ± 9.1

27.3 ± 13.6

105 ± 33

31 ± 9

Secondary MR ≥3+

64.1 ± 28.4

–0.9 ± 0.9

P = NS vs Control

P < 0.05 vs Control

LVEF (%)

P < 0.05 vs Control and the Other 3 MR Groups, Respectively

† P < 0.05 vs Control and both primary MR groups, respectively

Mean of the Differences Between Rest and Exercise (95% CI) LA strain rate (/s)

ERO (mm2)

LA strain (%)

Regurgitant volume (ml)

Regurgitant fraction (%)

Stroke volume (ml)

LVEF (%) 3.3 (0.3 to 6.2) *

Primary MR <3+

–0.5 (–0.7 to –0.2) * 3.6 (0.4 to 6.7) *

1.2 (–2.3 to 4.7)

1.4 (–6.9 to 9.7)

–1.2 (–8.4 to 6.0)

9.0 (5.7 to 12.3) *

Primary MR ≥3+

–0.5 (–0.7 to –0.2) * 1.4 (–2.0 to 4.8)

8.5 (5.1 to 11.9) *

7.1 (2.5 to 11.7) *

–1.1 (–3.6 to 1.5)

6.9 (2.6 to 11.2) *

3.1 (1.1 to 5.2) *

Secondary MR <3+

0.2 (0.1 to 0.3) *

–1.1 (–2.9 to 0.59) 4.4 (1.8 to 7.0) *

5.8 (2.3 to 9.2) *

0.03 (–0.0 to 0.07)

6.8 (4.7 to 8.9) *

2.1 (0.4 to 3.8) *

Secondary MR ≥3+

–0.02 (–0.1 to 0.2)

0.01 (–1.8 to 1.8) 7.9 (5.0 to 10.9) *

9.5 (4.5 to 14.6) *

4.5 (0.0 to 8.9) *

2.5 (–2.4 to 5.3)

3.2 (1.0 to 5.3) *

*P < 0.05 (paired t-test)

Impaired Response at Exercise

Echocardiographic and CPET Parameters During Exercise LA strain rate during exercise (/s)

LA strain Cardiac power output during exercise (%) (mm Hg L/min)

Peak PASP/TAPSE (mm Hg/mm)

Peak VO2 (ml/min/kg)

% predicted peak VO2 (%)

VE/VCO2 slope

Control

–3.2 ± 1.0

40.7 ± 10.9

2.2 (1.9 to 2.7)

1.5 ± 0.4

18.4 ± 5.6

70 ± 19

26.5 (24.4 to 29.0)

Primary MR <3+

–2.1 ± 1.0

29.8 ± 13.6

1.7 (1.4 to 2.1)

1.9 ± 0.7

17.9 ± 6.8

74 ± 21

26.9 (24.0 to 31.9)

Primary MR ≥3+

–2.1 ± 1.0

30.5 ± 12.7

1.8 (1.4 to 2.2)

2.1 ± 0.7

17.9 ± 6.2

73 ± 23

25.5 (23.4 to 29.0)

Secondary MR <3+

–1.5 ± 1.0 †

19.5 ± 9.6 †

1.5 (1.1 to 1.8) †

2.9 ± 1.2 †

13.6 ± 3.9 †

62 ± 21

29.5 (26.5 to 33.7)

Secondary MR ≥3+

–0.9 ± 0.8

13.4 ± 9.8

1.1 (0.9 to 1.5)

3.7 ± 1.5

11.5 ± 3.2 †

50 ± 16

35.1 (29.0 to 44.2)

P = NS vs Control

P < 0.05 vs Control

P < 0.05 vs Control and the Other 3 MR Groups, respectively

† P < 0.05 vs Control and both primary MR groups, respectively

Echocardiographic parameters at rest (top), differences from rest to peak (middle), and cardiopulmonary exercise testing (CPET) parameters during exercise (bottom). CI ¼ confidence interval; ERO ¼ effective regurgitant orifice; LA ¼ left atrial; LVEDV ¼ left ventricular end-diastolic volume; LVEF ¼ left ventricular ejection fraction; MR ¼ mitral regurgitation; PASP ¼ pulmonary artery systolic pressure; TAPSE ¼ tricuspid annular plane systolic excursion; VCO2 ¼ carbon dioxide production; VE ¼ minute ventilation; VO2 ¼ oxygen uptake.

DISCUSSION

sustain reservoir

This was the first study to systematically address LA

valve

incompetence;

function

reserve

2)

LA

during

pump

and

exercise

are

maintained only in patients with primary MR,

adaptations during exercise in a large cohort of

especially without significant exercise-induced MR;

patients with MR of both primary and secondary

3)

origin. A thorough analysis of LA dynamics at rest,

depressed CO response to exercise and more severe

during exercise, and in recovery provided evidence

RV-to-PC uncoupling; 4) LA reservoir function and

that exercise further challenges and rapidly ex-

peak VO2 were significantly more impaired in pa-

hausts the atrial reservoir and booster pump func-

tients with secondary MR $3þ compared with those

tions, which are already compromised at rest. The

with primary MR; and 5) significant exercise venti-

impaired

LA

dynamics

are

paralleled

by

a

main study results are as follows: 1) changes in LA

lation inefficiency was observed only in patients

dynamics parallel the degree of MR, but for similar

with secondary MR $3þ and severely depressed

MR severity, they consistently depend on the eti-

global LA dynamics (i.e., reservoir function and

ology and related functional determinants that

booster pump function).

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Left Atrial Dynamics in Mitral Regurgitation

LA REMODELING AND IMPAIRED DYNAMICS IN THE

induced quite early in the natural history of the

PRESENCE OF MR. The left atrium is exquisitely

disease.

sensitive to volume and pressure overload, which are

The aforementioned reasons offer a relevant

the most frequent triggers of chamber remodeling, a

background also for explaining the observed differ-

phenomenon that refers to the pathophysiological

ences in reservoir and booster pump function (29).

changes in atrial structure and mechanical function

There is a clear perception now that increased LA

(20). LA remodeling is the overall reflection of ab-

dimension may not necessarily reflect functionally

normalities in LV filling pressure and diastolic func-

compromised LA dynamics (9). In this respect, it is

tion (9,21) unless atrial fibrillation, high-output

interesting to note that in primary MR of any severity,

states, and especially MR coexist. Indeed, once MR

despite a clear reduction in reservoir function and

develops, it becomes a major hemodynamic deter-

booster pump at rest, the exercise LA pump function

minant of changes in LA size and impaired dynamics,

reserve (change in LA strain rate from rest to exercise)

basically contributing to trigger the transcription of

is preserved, which reinforces the concept of a quite

unfavorable

different atrial myopathy progression in comparison

prohypertrophic

and

profibrotic

signaling, whose extent may vary according to the

with secondary MR (27).

ischemic or nonischemic origin of mitral incompetence, the duration of valvular disease, and the

HEMODYNAMIC

severity of MR itself (22,23). Accordingly, the study of

ALTERED

LA geometry and dynamics in the presence of MR of

PRIMARY MR. Given that the left atrium functions as

different origin and stages has been the matter of

a cushion between the left and the right heart, there

intense investigation for a long time in both experi-

are forward (CO) and backward (pulmonary pressures

mental (24–26) and clinical settings (27).

and RV function) hemodynamic consequences that

LA

CHANGES DYNAMICS:

RELATED

TO

SECONDARY

THE

VERSUS

Our results suggest that the left atrium is consid-

need to be considered. All patients showed similar CO

erably more sensitive to changes in loading condi-

at rest irrespective of MR etiology, which, however,

tions due to secondary than primary MR. Notably, in

was accompanied by a progressive reduction in LA

secondary MR and severe primary MR, LA dysfunc-

strain from primary through MR. Remarkably, MR

tion was not different once the population was

compromised the exercise CO reserve, and patients

divided according to LVEF, very likely suggesting that

with MR <3þ of secondary origin had increases in CO

changes in LA dynamics are not influenced by systolic

even lower than those with primary MR $3þ.

cardiac reserve function.

These data confirm and extend the finding that

In the present subpopulations, for similar degrees of

atrial dysfunction and superimposed mitral insuffi-

MR, differences in LA dimensions and function were

ciency prevent adequate CO increase during physical

detected between secondary and primary MR, reaching

challenge.

statistical significance for MR $3þ, suggesting overall a

In parallel to this pattern, an unfavorable increase

maladaptive response to exercise load for secondary MR.

in PASP has been observed for the progressively lower

The differences in terms of dimensions may be

extent of CO increase, leading to some loss of exercise

explained by a 2-fold mechanism: a higher degree of

RV contractile reserve and RV-to-PC uncoupling

atrial myopathy (i.e., higher array of structural,

(TAPSE/PASP ratio) (30).

architectural, contractile, and electrophysiological

Although previous findings have shown that the

changes of the atria [28]) and a loss of atrioventricular

rate of pulmonary hypertension and RV dysfunction

synchrony (29). Although a direct measure of LA

is lower among patients with primary than secondary

fibrosis is unavailable, the progressive loss of atrial

MR (4,31,32), in either condition exercise-induced MR

compliance and increase in stiffness from low to high

(1–3) and dynamic exercise pulmonary hypertension

degrees of MR suggest more severe atrial myopathy in

(4,5,33) have been reported as prognostic in primary

secondary MR, potentially triggered by a primary

and secondary MR. It is nevertheless difficult to

pressure-overload sustained mechanism, as inferable

compare

from a significantly greater E/e 0 ratio in secondary

the differences in their background, etiology, and

versus primary MR. This has been observed even if

treatment. The present data show that exercise ca-

secondary MR during exercise is not significant,

pacity, LA reservoir function during exercise, and RV-

suggesting that the type of load exerted on LA prop-

to-PC

erties turns from purely volumetric to pressure

secondary MR in

the

2

conditions

directly,

coupling during exercise comparison

are

because

of

impaired in

with primary MR

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F I G U R E 6 Changes From Rest to Exercise in Left Atrial Strain and Pulmonary Artery Systolic Pressure Versus Cardiac Output in the 5

Groups

A

B 12

80

*†

60 *† *† 6

*†

4

*† *†

*†

8

PASP (mm Hg)

Cardiac Output (L/min)

10

*† 40

20 2 0

0 0

10

20

30

40

50

0

2

LA Strain (%)

4

6

8

10

12

Cardiac Output (L/min)

* P < 0.05 vs Control in LA strain

* P < 0.05 vs Control in Cardiac output

† P < 0.05 vs Control in Cardiac output

† P < 0.05 vs Control in PASP

Control N = 54

Primary MR <3+ during exercise N = 38

Primary MR ≥3+ during exercise N = 39

Secondary MR <3+ during exercise N = 77

Secondary MR ≥3+ during exercise N = 40

(A) Left atrial strain; (B) pulmonary artery systolic pressure. Empty circles ¼ rest; filled circles ¼ exercise. LA ¼ left atrial; MR ¼ mitral regurgitation; PASP ¼ pulmonary artery systolic pressure.

F I G U R E 7 Changes From Rest to Exercise in Left Atrial Strain and Left Atrial Strain Rate Versus Tricuspid Annular Plane Systolic

Excursion/Pulmonary artery Systolic Pressure in the 5 Groups

A

B

† P < 0.05 vs Rest in PASP/TAPSE

5

PASP/TAPSE (mm Hg/mm)

12

†

4

4

†

3

† P < 0.05 vs Rest in PASP/TAPSE * P < 0.05 vs Rest in LA strain rate

5

* P < 0.05 vs Rest in LA strain

†

*†

3

*†

† 2

2

*†

*† †

*† 1

1

0

0 0

10

20

30

40

LA Strain (%)

50

0

1

2

3

4

5

LA Strain Rate (/s) [Absolute Value]

(A) Left atrial strain; (B) left atrial strain rate. Open circles ¼ rest; filled circles ¼ exercise. LA ¼ left atrial; PASP ¼ pulmonary artery systolic pressure; TAPSE ¼ tricuspid annular plane systolic excursion.

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Left Atrial Dynamics in Mitral Regurgitation

F I G U R E 8 Kaplan-Meier Curve of Event-Free Survival According to the Type and Degree of MR (A) and LAS During Exercise (Cutoff 16 %, B)

A

LAS during exercise >16%

B

1.0 Event-Free Survival Rate

Event-Free Survival Rate

1.0 0.8 0.6

*

0.4 Log-rank test P = 0.037 *P = 0.013 vs Primary MR

0.2

0.8 0.6

LAS during exercise ≤16%

0.4 AUC = 0.74, 95% CI (0.62 to 0.86) Log-rank test p = 0.013

0.2 0.0

0.0 0

1

2

3

0

1

Time (Years)

2

3

Time (Years)

Number of patients at risk

Number of patients at risk

LAS during exercise

Primary MR

58

24

11

5

>16%

91

47

29

13

Secondary MR <3+ during exercise

57

41

26

14

≤16%

60

43

28

15

Secondary MR ≥3+ during exercise

36

25

20

9

Composite endpoint was defined as all-cause mortality and hospitalization for heart failure. There was no significant difference in age among the 3 groups. AUC ¼ area under the curve; CI ¼ confidence interval; LAS ¼ left atrial strain; MR ¼ mitral regurgitation.

irrespective of the presence or absence of significant

is

dynamic MR.

utilization.

IMPACT OF SEVERE MR ON EXERCISE V O 2 AND VE/ VCO2

SLOPE. The

entire

set

of

a

pattern

indicative

of

impaired

oxygen

Interestingly enough, patients with secondary

hemodynamic

MR, especially of severe degree, exhibited a truly

derangement well explains the finding of a prognostic

pathological exercise ventilatory response (i.e., VE/

definition by LA strain. Especially in the setting of

VCO 2 slope of 35) and a high rate of exercise oscil-

severe MR, the ability to augment LA reservoir

latory ventilation pattern in more than 50% of

capacity and booster pump function becomes critical

cases. These abnormal gas exchange phenotypes are

for preserving cardiac filling and CO (34). The

typical of elevated pulmonary pressure and RV-to-

observed loss of LA mechanical properties combines

PC uncoupling (35).

with lower peak V O2 with advancing degrees of MR

STUDY LIMITATIONS. We used a quantitative evalu-

and LA size.

ation of MR severity based on color scale, avoiding

This expected hemodynamic effect, however, was

effective regurgitant orifice evaluation for 2 reasons:

at work only in patients with secondary MR of

it does not quantify minimal or mild MR, and it is

either mild to moderate or severe valve disease.

inaccurate in cases of eccentric jets. Actually, a

Indeed, looking at percentage predicted VO2, pa-

qualitative assessment of MR severity during exercise

tients with primary MR were able to maintain >70

by effective regurgitant orifice was successfully per-

of their maximum predicted value. Because VO 2 is

formed in 88 of 196 patients with MR (50%).

the product of CO and oxygen arteriovenous dif-

The evidence for a pressure load as a major

ference, we may postulate and speculate that pa-

determinant of the progressive increase in LA stiff-

tients with primary MR are less deconditioned,

ness and impaired functional reserve of the left

being able to maintain normal type I versus type II

atrium in secondary versus primary MR should have

muscle fiber distribution and, in consequence, a

been confirmed by direct LA pressure measures, but

better ability to extract oxygen. This explanation,

further research is warranted to obtain conclusive

although not directly proved, may be supported by

results. We excluded patients with atrial fibrillation

the observation that patients with secondary MR

to specifically dissect the role of MR as a unique

had a quite high rate of DV O2/D WR flattening, which

initiator of impaired atrial function. Certainly, a

13

14

Sugimoto et al.

JACC: CARDIOVASCULAR IMAGING, VOL.

-, NO. -, 2019 - 2019:-–-

Left Atrial Dynamics in Mitral Regurgitation

significant portion of patients with MR may develop

functional properties rather than just mitral valve

atrial fibrillation, and the information obtained in

competence as a meaningful additional target of our

pure MR may not apply to this subset. In addition, we

interventions.

were unable to detect differences, if any, in terms of the different effects of eccentric versus concentric

ADDRESS

MR jets.

Guazzi, University of Milano School of Medicine,

FOR

CORRESPONDENCE:

Dr.

Marco

Given that MR begets atrial myopathy, we were

Cardiology University Department, IRCCS Policlinico

unable to differentiate how much a progressive loss

San Donato, Piazza E. Malan 1, San Donato Milanese,

in LA chamber dynamics may depend on atrial myo-

20097 Milan, Italy. E-mail: [email protected].

cyte remodeling compared with the amount of regurgitant flow. LA dynamics substantially mirror LV

PERSPECTIVES

dynamics. However, MR becomes a modifier of this physiological

parallelism.

On

a

technical

basis

COMPETENCY IN PATIENT CARE AND

we were unable to simultaneously analyze LV defor-

PROCEDURAL SKILLS: The pathophysiology of LA

mation by global longitudinal strain and gain infor-

dynamics in MR of primary and secondary origin

mation on this subject, which remains an issue to be

shows major differences according to etiology and

addressed in future studies.

degree. There is progressive worsening of LA strain and LA strain rate from primary MR <3þ through

CONCLUSIONS

secondary MR $3þ during exercise. This maladapta-

In patients with MR of any origin, reservoir function

tion translates in a progressive loss of CO, induction of

and LA booster pump reserve play a key role in the

RV-to-PC uncoupling, impaired exercise performance,

abnormal response to exercise, with direct implica-

and ventilation inefficiency. The impairment in exer-

tions on right heart hemodynamic status, CO in-

cise LA strain defines a worse event-free survival rate.

crease, and ventilation efficiency. For primary MR, there is still a reserve in LA dynamics during exercise. This reserve is exhausted in MR of secondary origin according to the extent of regurgitant flow. The impairment in LA strain defines worse eventfree survival, and LA functional assessment by exercise stress echocardiography and its correlates obtained by CPET analysis provide a new approach for

studying

the

pathophysiology

and

clinical

impact of MR. The present findings highlight the

TRANSLATIONAL OUTLOOK: On the basis of the present observations, further studies are needed to determine the utility of unmasking the abnormalities in LA dynamics during exercise in MR. Although no specific interventions are planned to restore atrial dynamics by mitral valve repair, the findings appear helpful to pave the way to a more detailed characterization of LA function and its reversibility in MR of either primary and secondary origin.

importance of considering the restoration of LA

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KEY WORDS exercise, left atrial dynamics, mitral regurgitation

29. Zakeri R, Moulay G, Chai Q, et al. Left atrial A PP END IX For supplemental methods, tables, and figures, please see the online version of this paper.

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