Sympathetic Activity in Patients With Secondary Symptomatic Mitral Regurgitation or End-Stage Systolic Heart Failure

JACC: CARDIOVASCULAR INTERVENTIONS

VOL.

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

-, NO. -, 2016

ISSN 1936-8798/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jcin.2016.06.032

Sympathetic Activity in Patients With Secondary Symptomatic Mitral Regurgitation or End-Stage Systolic Heart Failure Can Öztürk, MD,a Robert Schueler, MD,b Marcel Weber, MD,a Armin Welz, MD,a Nikos Werner, MD,a Georg Nickenig, MD,a Christoph Hammerstingl, MDa

ABSTRACT OBJECTIVES This study shows the impact of secondary mitral regurgitation (sMR) and transcatheter mitral valve repair (TMVR) with the MitraClip system on sympathetic nerve activity (SNA). BACKGROUND An increase in SNA is associated with worse outcomes and limited survival in patients with chronic heart failure (CHF). METHODS Twenty CHF-patients without relevant sMR and 30 CHF patients with symptomatic sMR were enrolled prospectively. All patients underwent standardized laboratory testing and microneurography. Sixteen patients from the sMR group underwent the MitraClip procedure; 10 patients after TMVR and 9 untreated sMR patients completed 6 months of follow-up. RESULTS Comparing groups according to presence of sMR, we found no differences in left ventricular dimensions, and serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and noradrenaline; sMR was associated with increased MSNA (106
60 vs. 74
48 burst/min, d ¼ 0.58), an impaired sympathetic baroreflex gain (10
7 vs. 5
5 burst/mm Hg, d ¼ 0.61), and a higher heart rate (90
27/min vs. 78
12/min, d ¼ 0.58). TMVR led to improved New York Heart Association functional class (d > 0.05), reduced levels of NT-proBNP (5,251
3,760 vs. 3,710
2,464 pg/ml; d ¼ 0.58) improvement in 6-minute walk test (204
33 vs. 288
45 m, d ¼ 0.64), but unchanged levels of noradrenaline. TMVR decreased MSNA burst-frequency (130
78 vs. 74
21 bursts/min; d ¼ 0.58) and baroreflex gain (7
4 vs. 4
1 burst/mm Hg; d ¼ 0.61). CONCLUSIONS In patients with CHF, concomitant sMR is associated with increased sympathetic nerve activity, which was independent from measured levels of NT-proBNP, noradrenaline, and left ventricular dimensions. Reduction of sMR with the MitraClip procedure reduced SNA and improved baroreflex gain, in line with improvements of functional capacity. (J Am Coll Cardiol Intv 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.

I

n patients with severe chronic heart failure (CHF)

leading to arterial hypertension and impaired periph-

low cardiac output triggers an increase in sympa-

eral perfusion. This effect potentially promotes

thetic nerve activity (SNA) to maintain sufficient

hydropic decompensation, pulmonary congestion,

circulation. Increased SNA, on the other hand,

and progressive left ventricular (LV) dilatation. SNA

has been shown to be associated with worse prognosis

can be determined by measurement of muscle SNA

in CHF patients (1,2). SNA stimulates the production of

(MSNA),

renin, which leads to increased natrium retention from

have been proven to be independent markers for

and

baroreflex

gain.

Both

the renal tubuli. It induces systemic vasoconstriction

adverse outcomes in different patient populations

From the aDepartment of Medicine II, Heart Center Bonn, University Hospital Bonn, Bonn, Germany; and the bDepartment of Cardiovascular Surgery, Heart Centre Bonn, University Hospital Bonn, Bonn, Germany. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. öztürk and Schueler contributed equally to this work. Manuscript received March 22, 2016; revised manuscript received May 20, 2016, accepted June 20, 2016.

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Sympathetic Activity in MR

ABBREVIATIONS

with CHF (3–5). An activated SNA has been

Kingdom). After local disinfection a tungsten needle

AND ACRONYMS

shown of prognostic relevance in patients

(200 m m) was introduced into the nervus peroneus

CHF = chronic heart failure LV = left ventricular LVEF = left ventricular ejection fraction

MR = mitral regurgitation MSNA = muscle sympathetic nerve activity

NT-proBNP = N-terminal pro-brain natriuretic peptide

and animals with isolated primary mitral

longus close to the caput fibuli to record multiunit

regurgitation (MR) (6,7).

postganglionic sympathetic activity (Figure 1) (11).

Secondary MR (sMR) is a common finding

The recording started after 5 min resting in supine

in CHF patients with ischemic or non-

position to ensure standardization to the setting

ischemic cardiomyopathy. The presence of

(Figure 1). Sympathetic muscle activity is defined by

sMR in heart failure patients is associated

burst frequency (burst/min) and burst incidence

with poor prognosis (8) and the impact of

(burst/100 beats) (12). Neural activity was amplified

surgical treatment of MR on SNA has been

(50,000 to 100,000), band-passed (300 to 3,000 Hz)

shown

and integrated, as described previously (1,11).

previously

(9,10).

It

is

unclear

whether interventional reduction of sMR

sMR = Secondary mitral

During

MSNA

recording

blood

pressure

was

regurgitation

impacts on patient’s prognosis and the ef-

measured non-invasively by use of SOMNOtouch NIBP

SNA = sympathetic nerve

fects of MitraClip procedure on SNA are un-

(SomnoMedics, Randersacker, Germany) consisting of

activity

known.

a 4-channel electrocardiography and pulse meter,

TMVR = Transcatheter mitral

independent

adverse

which was attached to the index finger of the patients

valve repair

outcome in CHF patients, we hypothesized

and enables continuous blood pressure monitoring.

that the presence of MR in CHF patients deteriorates

Results from continuous blood pressure measure-

SNA in CHF patients and that interventional reduc-

ments were used for the calculation of baroreflex gain.

Because

SNA

risk

is

an

marker

established for

tion of MR might lead to amelioration of SNA. The

Cardiovascular reflexes, such as the baroreceptor

objectives of this study were to: 1) compare SNA in

heart rate reflex (baroreflex), regulate the hemody-

CHF patients with and without sMR; and 2) examine

namic response to parasympathetic and sympathetic

the impact of transcatheter mitral valve repair

signals. The baroreflex gain plays an important role in

(TMVR) on SNA.

the development und progress of cardiovascular diseases and can be used for risk stratification after

METHODS

myocardial infarction, heart failure, or arrhythmias (13,14). Baroreflex gain is defined as the slope of the

PATIENTS. Thirty consecutive patients presenting

XY graphic curve from burst incidence and contin-

with symptomatic moderate to severe MR (MR grade

uous diastolic blood pressure. For the determination

>II) and 20 controls with CHF due to LV systolic dysfunction (left ventricular ejection fraction [LVEF] <40%) were prospectively enrolled to the study. Patients with CHF and without relevant MR were

of noradrenaline levels EDTA blood was centrifuged at 3000 RPM for 10 minutes; the supernatant was removed and deep frozen (-79 C). NT-proBNP was determined from lithium heparin plasma.

matched to sMR patients concerning baseline characteristics (age, sex, and body mass index), functional

ECHOCARDIOGRAPHY. Echocardiographic assessment

capacity, and cardiovascular comorbidities. All pa-

of LV function was done following current recom-

tients underwent standardized transthoracic echo-

mendations and guidelines (15). Parasternal long and

cardiography, clinical examination, 6-min walk test,

short axis and apical 4- and 2-chamber, as well as apical

routine laboratory testing, and microneurography. N-

long axis, views were transthoracic recorded (trans-

terminal pro-brain natriuretic peptide (NT-proBNP)

thoracic echocardiogram: transthoracic echocardiog-

and noradrenaline levels were determined from blood

raphy). The LVEF was calculated by Simpsons rule

(EDTA or serum) in each patient. The 6-month follow-

from 4- and 2-chamber views. Assessment of MR con-

up after MitraClip included clinical examination,

sists of determination of proximal isovelocity surface

routine laboratory testing, transthoracic echocardiog-

area, effective regurgitant orifice area, as well as vena

raphy,

contracta width and regurgitant volume, where

6-min

walk

test,

and

repeated

micro-

neurography measurement.

applicable, to specify severity of MR. MR was graded

The study was approved by the ethics committee of

according to the recommendations of the European

the University of Bonn and in concordance with the

Society of Cardiology as “mild,” “moderate,” “mod-

Declaration of Helsinki. All patients had to provide

erate to severe,” or “severe” (16,17). Transthoracic

written informed consent before study inclusion.

echocardiography were performed with a commer-

ASSESSMENT

cially available echocardiographic system (iE 33,

OF

SNA. SNA

was determined by

measuring MSNA, baroreflex gain and neurohormonal

Philips Medical Systems, Andover, Massachusetts).

activity. MSNA was assessed with microneurography

sMR was defined as mostly central MR with global

(ADInstruments, Neuro Amp EX, Oxford, United

(symmetric) or regional (eccentric) LV dilatation and

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Sympathetic Activity in MR

F I G U R E 1 Microneurography

(A) Setting of MSNA assessment. Two tungsten microelectrodes are inserted at the caput fibuli and 1 reference electrode is attached to the skin. (B) Setup of ADInstruments neuroamplifier and SomnoMedics finometer. (C) MSNA recording example of a patient with secondary mitral regurgitation before MitraClip implantation. (D) MSNA recording example of a control patient with chronic heart failure. (E) MSNA recording of the MitraClip patient 6 months after clip procedure with normalized MSNA values. MSNA ¼ muscle sympathetic nerve activity.

reduced

LVEF

despite

structurally

normal

MV

leaflets.

chosen patients were analyzed by the same investigator twice. Intraobserver variability was evaluated by intraclass correlation coefficient for total agree-

STATISTICAL ANALYSIS. Exploratory data analysis

ment, with good agreement being defined as >0.80.

was performed and no adjustment was made for

Mean values and standard deviations between the

multiple tests. Normal distribution of continuous

measurements were obtained and total agreement

variables was examined using the Kolmogorov–

among the observation was calculated using intra-

Smirnov test. Continuous data were expressed as

class correlation analysis.

mean
SD. Because of the small patient number and to prevent inflating type I error rate we did not

RESULTS

calculate p-values from any kind of test. Calculated standardized differences were calculated as the mean

From January 2014 to July 2015, 50 consecutive

divided by the standard deviation of a difference

CHF patients were enrolled, including 20 patients

between 2 values from the 2 groups. Following Cohen

(71.3
8.5 years; 85% male) without relevant MR

(18), 3 effect size indices (0.2, 0.5, 0.8) were chosen to

(CHF group) and 30 patients (79.2
7.4 years; 73.3%

represent small, medium, and large effect sizes. Ac-

male) with CHF and symptomatic sMR (sMR group).

cording to current evidence, large and medium ef-

Sixteen patients underwent successful TMVR with

fects ($0.5) can be assessed with the “naked eye,” a

the

small effect (#0.2) is more difficult to estimate and

with unsuitable anatomy for MitraClip procedure

MitraClip

system.

Six

patients

presented

obviously not of clinical relevance (18,19). The

(insufficient coaptation length [n ¼ 3], leaflet calcifi-

method of Bland and Altman was used for the

cation [n ¼ 1], inability to perform transesophageal

assessment of interobserver agreement. For the

echocardiography due to esophageal stenosis [n ¼ 1],

assessment of intraobserver variability, 20 randomly

and insufficient transesophageal echocardiography

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Sympathetic Activity in MR

image quality [n ¼ 1]). In 4 patients, the heart team

MSNA IN PATIENTS WITH AND WITHOUT

decision voted for surgical MV treatment. The

When compared with normal values, we found

remaining 4 patients declined either surgical or

increased MSNA (93
57 burst/min [normal values:

interventional treatment. During follow-up, 2 of the

20
3]) and impaired baroreflex gain (7
4 burst/

patients treated with MitraClip died and 4 patients

mm Hg [normal values: 2
0.2]), the average heart

declined further study participation. Finally, 10

rate was 85 beats/min.

S MR.

patients with implanted MitraClip and 9 untreated

The presence of sMR alone was associated with

sMR patients completed 6 months of follow-up pro-

increased MSNA (sMR: 106
59 burst/min; CHF: 74


cedures, including microneurography measurement

48.1 burst/min; d ¼ 0.58), an impaired sympathetic

(Figure 2).

baroreflex gain (sMR: 10
7 burst/mm Hg; CHF: 5
5

The CHF and sMR patients did not differ relevantly

burst/mm Hg; d ¼ 0.61), and a higher heart rate

characteristics,

(sMR: 90
27/min; CHF: 78
12/min; d ¼ 0.58)

blood pressure, medication, and New York Heart

(Table 3). The MSNA burst incidence was increased in

Association functional class (Table 1).

sMR patients but not different to the CHF group (sMR:

concerning

demographic

baseline

119
63; CHF: 93
58 burst/100 beats; d ¼ 0.48). ECHOCARDIOGRAPHY. As determined by echocar-

Levels of NT-proBNP (88,323
13,907 pg/ml) and

diography, the LVEF was 37.6
15.8% in the overall

noradrenaline serum levels (883
493 ng/l) were

cohort. Patients with sMR presented with better

increased in the overall cohort without differences

LV systolic function as compared with the CHF group

between groups regarding levels of NT-proBNP (sMR:

(sMR: 43
18%; CHF: 29
7%; d ¼ 0.64; Table 2). Patients

with

sMR

underwent

treatment

for

6,577
6,816 pg/dl; CHF: 13,010
21,495 pg/dl; d ¼ 0.37) and noradrenaline (sMR: 882
531 ng/l; CHF:

moderate-severe MR in 93.3% and severe MR in 10% of

885
452 ng/l; d ¼ 0.03). Increased MSNA was asso-

cases (effective regurgitant orifice area: 0.3
0.1 cm;

ciated with an elevated NT-proBNP (r ¼ 0.69; p ¼ 0.03),

vena contracta width: 0.7
0.1 cm; regurgitant

but not with renal function (r ¼ 0.03; p ¼ 0.9)

volume: 53
19 ml/beat; Table 2).

(Figures 3A and 3B).

F I G U R E 2 Study Flow Chart

sMR ¼ secondary mitral regurgitation; CHF ¼ chronic heart failure; EF ¼ ejection fraction; MV ¼ mitral valve; NYHA ¼ New York Heart Association; other abbreviation as in Figure 1.

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Sympathetic Activity in MR

T A B L E 1 Baseline Demographics of the Study Cohort

sMR (n ¼ 30)

Female (%)

CHF (n ¼ 20)

T A B L E 2 Echocardiographic Characteristics of the Study Cohort

Standardized Difference

CHF (n ¼ 20)

0.30

LVEDV (ml)

161.7
62.3

0.19

LVESV (ml)

87.7
60.6

113.4
55.3

0.37

25.9
4.4

0.03

LV ejection fraction (%)

43.3
17.5

29.2
7.2

0.77

7.8
9.8

0.07

Left atrial volume (ml)

91.7
39.5

65.7
28.2

0.64

128
12

132
15

0.51

94
14

88
16

0.15

15

79.2
7.4

71.3
8.5

BMI (kg/m2)

25.9
4.5

EuroScore II (%)

8.3
6.8

Systolic Diastolic

146.6
73.2

Standardized Difference

0.30

26.7

Age (yrs)

3
0.4

MR grade (%)

BP (mm Hg)

Medication (%)

b-Blockers

sMR (n ¼ 30)


1.1
0.7

0

$II

1.01

100

1.05

100

0

1.05

PISA (cm)

0.8
0.2

—

—

100

95

0.11

Vena contracta (cm)

0.7
0.1

—

—

95

98

0.07

EROA (cm2)

0.3
0.1

—

—

100

100

0.003

Regurgitation volume (ml)

53.1
18.5

62

65

0.23

Tricuspid regurgitation grade

100

90

0.47

sPAP (mm Hg)

II

17

55

III

77

35

IV

6

0

CHF

90

100

0.36

DCMP

45

65

0.19

85

0.29

ACE inhibitors/ARB Diuretics Aldosterone receptor blockers NYHA functional class (%) $II

—

2.1
0.8 1.6
0.4

TAPSE (mm)

43.4
13

—

1.3
0.8

0.64

1.8
0.3

0.37

29.7
12

0.64

Values are mean
SD or %. EROA ¼ effective regurgitant orifice area; LV ¼ left ventricular; LVEDV ¼ left ventricular enddiastolic volume; LVESV ¼ left ventricular end-systolic volume; MR ¼ mitral regurgitation; PISA ¼ proximal isovelocity surface area; sPAP ¼ systolic pulmonary artery pressure; TAPSE ¼ tricuspid annular systolic excursion; other abbreviations as in Table 1.

CHD

66.7

Arterial hypertension

90

100

0.19

History of stroke

20

5

0.36

(TMVR: 90
33 mm Hg; sMR: 92
48 mm Hg; d ¼ 0.07)

PAD

20

15

0.19

in

Hyperlipidemia

70

20

0.29

treatment.

Nicotine Creatinine (mg/dl)

patients

with

sMR,

regardless

of

MitraClip

23

20

0.03

Concerning MSNA measurements, sMR patients

1.5
0.5

1.6
0.7

0.15

that underwent TMVR showed decreased MSNA burst-

Values are % or mean
SD. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass index; BP ¼ blood pressure; CHD ¼ coronary heart disease; CHF ¼ chronic heart failure; DCMP ¼ dilatative cardiomyopathy; PAD ¼ peripheral artery disease; NYHA ¼ New York Heart Association; sMR ¼ secondary mitral regurgitation.

frequency (130
78 vs. 74
21 bursts/min; d ¼ 0.58), baroreflex gain (7
4 vs. 4
1 bursts/mmHg; d ¼ 0.64) and burst incidence (143
88 vs. 113
34 bursts/100 beats; d ¼ 0.48). Patients with untreated sMR showed no changes in MSNA (d < 0.5) (Table 4). NT-proBNP levels (6,577
6,816 vs. 3,710
2,464

SYMPATHETIC ACTIVITY AND FUNCTIONAL OUTCOMES AFTER 6 MONTHS OF FOLLOW-UP. Ten patients of the

sMR group who underwent TMVR with the MitraClip and 9 untreated patients with sMR completed 6 months of follow-up procedures with complete

pg/ml; d ¼ 0.58) and noradrenaline levels were reduced in patients 6 months after MitraClip treatment (882
530 vs. 624
351 ng/l; d ¼ 0.30). In untreated patients, we found no relevant changes regarding NT-proBNP (6,577
6,816 vs. 6,784
2,789;

assessment of SNA. Medical treatment remained unchanged during follow-up.

T A B L E 3 Assessment of Sympathetic Activity

Echocardiography showed stable MR reduction in

sMR (n ¼ 30)

CHF (n ¼ 20)

NT-proBNP (ng/l)

6576.6
6,815.8

13,009.6
21,495.4

0.37

Noradrenalin (pg)

881.7
530.4

885.3
452.1

0.03

all patients after the MitraClip procedure (effective regurgitant orifice area: 0.3
0.1 vs. 0.2
0.1 cm 2; d ¼ 0.48; regurgitant volume: 53
19 vs. 30
8 ml/beat; d ¼ 0.64) (Figure 4) and decrease in left atrial volumes (131
63 vs. 78
23 ml; d ¼ 0.58); LVEF and LV volumes remained unchanged after 6 months. Functional New York Heart Association class improved during follow-up (2.8
0.4 vs. 1.6
0.5;

MSNA Burst-incidence (burst/100 beats)

118.7
63

93.4
57.6

0.48

Burst-frequency (burst/min)

105.7
59.3

73.6
48.1

0.58

Heart rate (beat/min)

89.5
26.7

77.7
12.3

0.58

Baroreflex gain

10.2
6.5

5.4
4.7

0.61

d ¼ 0.61), as well as the 6-minute walking distances (204
33 vs. 288
45 m; d ¼ 0.64). There was no difference in systolic (TMVR: 129
65 mm Hg; sMR: 139
44 mm Hg; d ¼ 0.07) or diastolic blood pressure

Standardized Difference

Values are mean
SD. MSNA ¼ muscle sympathetic nerve activity; NT-proBNP ¼ N-terminal pro-brain natriuretic peptide; other abbreviations as in Table 1.

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F I G U R E 3 Boxplot Diagrams

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Sympathetic Activity in MR

F I G U R E 4 Boxplot Diagram

Mitral regurgitation at baseline and 6 months after MitraClip procedure.

improved to comparable levels of patients with CHF but without relevant MR. Because impaired SNA has been shown to be associated with worse prognosis in CHF patients, these findings may help to explain the impact of sMR on survival in typical CHF patients. IMPACT OF SYMPATHETIC ACTIVITY ON PROGNOSIS.

MSNA is a known independent marker of adverse clinical outcome in patients with CHF, obstructive sleep apnea syndrome, arterial hypertension, and chronic anemia (20–22). Mehta et al. (6) found an activation of SNA in patients with MR compared with healthy controls as a compensatory mechanism for chronic LV volume overload. However, changes in SNA after surgical repair were not homogenous and related to systolic LV function and dimensions before surgery, but not procedural success. Because all pa(A) Comparison of MSNA frequency and incidence at baseline and follow-up after

tients in our study had impaired LV function, the

MitraClip. (B) Comparison of baroreflex gain at baseline and follow-up after MitraClip.

results are not comparable to the study by Metha

Abbreviations as in Figure 1.

et al. (6). Furthermore, microneurography was not used in the studies by Mehta et al. for the determination of SNA (9).

d ¼ 0.03) or noradrenalin (882
530 vs. 746
99; d ¼ 0.17) serum levels.

Elevated SNA induces tachycardia and arterial hypertension due to amplified stimulation of adrenergic receptors. Therefore, increased SNA potentially de-

DISCUSSION

creases myocardial tissue perfusion, increases the heart rate, and thus deteriorates systolic LV function.

The main findings of our study were that concomitant

Tsutsui et al. (7) found a chronic b-blockade to have

sMR in CHF patients promotes impaired SNA as

beneficial effects on LV function in dogs with chronic

determined by microneurography, whereas laboratory

MR. Ahmed et al. (10) showed that b-blockers improve

measures on neurohumoral activity were not altered

systolic function in patients with asymptomatic

relevantly in the presence of sMR. After TMVR, SNA

primary MR, indicating on activated SNA in primary

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Sympathetic Activity in MR

MR patients and proving a negative influence of activated SNA on LV function in those patients.

T A B L E 4 Baseline and Follow-Up Findings

Because b-blocker therapy was not different in the patient groups included in our study, we are reluctant to compare our findings with the study by Ahmed et al. (10). Of note, Barretto et al. (11) examined 22 patients

MitraClip

No MitraClip

Standardized Difference

LVEDV (ml)

128
66.1

130.2
50.8

0.07

LVESV (ml)

70.2
58.8

65.5
44.3

0.07

Ejection fraction (%)

42.2
17.47

39.3
11.2

0.30

78
22.8

145.2
49.8

0.58

3.2
0.9

0.77

Left atrial volume (ml)

with CHF and showed that impaired MSNA was an

MR

independent

BP, systolic (mm Hg)

129.3
65.4

138.9
44.2

0.07

Furthermore, Leimbach et al. (2) demonstrated

BP, diastolic (mm Hg)

91.5
48.3

90.3
40.8

0.07

elevated SNA in 16 moderate to severe CHF patients

Mean mitral gradient (mm Hg)

2.5
0.2

1.9
0.5

0.11

sPAP (mm Hg)

44
9.1

48.7
12.3

0.48

NYHA

1.6
0.5

3.1
0.2

predictor

for

increased

mortality.

in comparison with 19 healthy controls. They showed a significant correlation between plasma norepinephrine and SNA levels. SNA AFTER INTERVENTIONAL VALVE TREATMENT.

Studies on SNA in patients with sMR are scarce. Hu et al. (23) found SNA to be related to myxomatous

1.5
0.5

288
45.4

6-MWT (m) Noradrenalin (pg/l)

624
351.3

NT-proBNP (pg/ml)

3,709.6
2,464.4

0.64

622.4
99.4

0.03

6,784
2,789.1

0.58

MSNA frequency (burst/min)

74.4
20.9

132.1
71.2

0.58

MSNA incidence (burst/100 beats)

113.1
33.8

142.3
68.9

0.48

4.1
1.2

7.1
2.8

0.64

Baroreflex gain (burst/mm Hg)

degeneration in mitral valve prolapse, which propagates the disease severity. In an early study, Ashino et al. (24) demonstrated decreased MSNA and

Values are mean
SD. 6MWT ¼ 6-min walk test; other abbreviations as in Tables 1, 2, and 3.

normalized baroreflex gain in a subset of 10 patients with mitral stenosis 1 week after interventional mitral

(i.e., levels of noradrenaline) were small, which could,

valvuloplasty. In concordance with our findings, this

as well, be due to the small sample size of the study

group found no difference in noradrenaline levels

groups.

between patients with mitral stenosis and a healthy group (24).

CONCLUSION

More recently, Dumonteil et al. (25) examined 14 patients

undergoing

transcatheter

aortic

valve

In patients with CHF, sMR is associated with increased

replacement and found normalized MSNA values 30

SNA, which was independent from measured levels of

days after transcatheter aortic valve replacement. The

NT-proBNP and noradrenaline. Reduction of MR with

impact of TMVR on SNA in sMR patients is not known.

the MitraClip system reduces SNA and improves bar-

Interventional edge-to-edge repair with the Mitra-

oreflex gain.

Clip system (Abbott Vascular, Abbott Park, Illinois) is a treatment option in surgical high-risk patients with

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

symptomatic MR. MitraClip procedure improves heart

Christoph Hammerstingl, Medizinische Klinik und

failure symptoms in sMR and primary MR (26). The

Poliklinik II, Universitätsklinikum Bonn, Sigmund-

impact of MitraClip procedure on survival is discussed

Freud-Str.

controversially and the underlying mechanisms for a

[email protected].

25,

53105

Bonn,

Germany.

E-mail:

beneficial influence on survival are unclear. In our study, we found evidence that sMR is asso-

PERSPECTIVES

ciated with impaired SNA in patients with CHF and TMVR by use of the MitraClip system decreased SNA in treated patients. These findings were independent of changes in LV dimensions and laboratory measures

WHAT IS KNOWN? In patients with severe CHF, low cardiac output triggers an increase in SNA to maintain sufficient circulation.

on neurohumoral activity. STUDY LIMITATIONS. Our study is limited by its single

side character and limited patient number; the presented results, therefore, are preliminary and must be reconfirmed in independent patient cohorts. We, furthermore, completed follow-up only in a small number of patients. A longer follow-up time and greater patient numbers might result in different results. Differences in specific measures of SNA

0.61

199.4
35.6

WHAT IS NEW? Patients with sMR had higher sympathetic activity levels when compared with patients with CHF but without MR. SNA improved after interventional edge-to-edge repair. WHAT IS NEXT? Determination of SNA might contribute to a better understanding of the effects of interventional treatment of sMR on patient’s functional outcome and survival.

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Sympathetic Activity in MR

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KEY WORDS MitraClip, muscle sympathetic nerve activity, TMVR, mitral regurgitation, sympathetic nerve activity