Impact of Chest Wall Conformation on the Outcome of Primary Mitral Regurgitation due to Mitral Valve Prolapse.

Background: The possible influence of chest wall conformation on cardiovascular (CV) outcome of patients with mitral regurgitation (MR) due to mitral valve prolapse (MVP) has never been previously investigated.
Methods: This retrospective study included all consecutive symptomatic patients with MVP and moderate MR who underwent exercise stress echocardiography at our institution between February 2014 and February 2021. Modified Haller Index (MHI; chest transverse diameter over the distance between sternum and spine) was noninvasively assessed. During the follow-up, we evaluated the occurrence of any of the following: (1) CV hospitalization, (2) mitral valve (MV) surgery, and (3) cardiac death or sudden death.
Results: Four hundred and twenty-four consecutive patients (66.8 ± 11.5 years, 48.3% men) were retrospectively analyzed. Overall, MVP patients had concave-shaped chest wall (MHI = 2.55 ± 0.34) and were found with small cardiac chamber dimensions. During a mean follow-up time of 3.2 ± 1.7 years, no patients died, 55 patients were hospitalized due to CV events, and 20 patients underwent MV surgery. On multivariate Cox analysis, age (heart rate [HR] 1.05, 95% confidence interval [CI] 1.03-1.06), diabetes mellitus (HR 3.26, 95% CI 2.04-5.20), peak exercise-E/e' ratio (HR 1.07, 95%CI 1.05-1.09), and peak exercise-effective regurgitant orifice area (HR 2.53, 95% CI 1.83-3.51) were directly associated to outcome, whereas MHI (HR 0.15, 95%CI 0.07-0.33) and beta-blocker therapy (HR 0.26, 95% CI 0.19-0.36) showed strong inverse correlation. An MHI ≥2.7 showed 80% sensitivity and 100% specificity for predicting event-free survival (area under the curve = 0.98). Conclusions: Symptomatic patients with moderate MR due to MVP and MHI ≥2.7 have an excellent prognosis over a medium-term follow-up. Noninvasive chest wall shape assessment should be encouraged in clinical practice. Copyright:

INTRODUCTION

Primary mitral regurgitation (MR) is the most frequent valvular heart disease in developed countries.[1]

The most common cause of primary MR is mitral valve prolapse (MVP) related to myxomatous degeneration of the mitral valve.[2] Other causes of primary MR include rheumatic heart disease and infective endocarditis.[2]

Resting transthoracic echocardiography is the principal diagnostic tool used to assess the severity and mechanism of primary MR, its consequences on the left ventricle (LV), left atrium and pulmonary circulation, as well as the potential indication for surgery.[34] However, the decision for intervention is primarily based on exercise-induced symptoms.[34]

Exercise stress echocardiography (ESE) plays a pivotal role in patients with chronic MR, particularly in circumstances where a discrepancy exists between the patients' symptoms and the severity of valvular regurgitation.[56]

Despite the large number of prognostic indicators assessed by ESE,[7891011121314] patients with primary MR have widely heterogeneous outcomes, with marked discrepancies in reported risks of complications and of mortality.[151617] Therefore, it is also important to identify participants at lower risk of cardiovascular (CV) events.

We have recently reported that chest wall shape, as noninvasively assessed by Modified Haller Index (MHI),[18] may apparently modify and affect myocardial strain parameters in participants with pectus excavatum (PE),[19] in those with MVP[20] and healthy pregnant women,[21] despite normal biventricular systolic function. In particular, participants with concave-shaped chest wall (defined by MHI >2.5)[2223] have shown a significantly greater impairment in LV functional parameters than participants with normal chest wall shape (MHI ≤2.5) and this impairment was attributed to compressive phenomena and dislocation of the heart leading to dyssynchrony rather than intrinsic myocardial dysfunction.

The hypothesis that a concave-shaped chest wall may select a group of participants with primary MR with a lower risk of CV events has never been previously tested.

Accordingly, in the present study, we aimed at evaluating the influence of chest wall conformation on the occurrence of adverse CV events over a medium-term follow-up in a consecutive population of symptomatic patients with moderate primary MR due to MVP who had undergone ESE.

METHODS

Patient selection

A monocentric retrospective observational study was conducted on all consecutive symptomatic patients with moderate primary MR resulting from MVP who were referred to our institution to perform a semisupine ESE between February 2014 and February 2021.

MVP was defined as a systolic billowing of one or both mitral leaflets >2 mm above the mitral annulus in the long-axis parasternal view.[24] A maximal leaflet thickness of ≥5 mm was defined as classic MVP and otherwise was defined as nonclassic MVP.

Moderate primary MR was defined as Grades 2 or 3 regurgitation according to the Recommendations for Noninvasive Evaluation of Native Valvular Regurgitation.[25]

The main indication for ESE was the discordance between symptomatic status (resting and/or exercise-induced dyspnea, chest pain, and/or palpitations) and standard echocardiographic measurements suggesting a moderate MR.

The criteria of exclusion were as follows: (1) history of coronary artery disease (CAD); (2) ischemic MR, defined as MR caused by chronic changes of LV structure and function due to ischemic heart disease;[26] (3) MR due to rheumatic heart disease and infective endocarditis; (4) resting severe primary MR; (5) concomitant more than mild aortic stenosis or regurgitation; (6) hemodynamic instability; (7) relevant comorbidities; (8) poor echocardiographic acoustic windows; and (9) inability to perform physical exercise.

The following parameters were recorded: age, gender, body surface area, presence of CV risk factors, and the current medical treatment.

Each patient underwent resting blood pressure measurement with a semiautomatic sphygmomanometer (Omron 705IT; Omron, Kyoto, Japan), electrocardiogram (ECG), MHI assessment, and ESE.

All procedures were in accordance with the ethical standards of our Institutional Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants, and the protocol was approved by the Local Ethics Committee.

Modified Haller index assessment

MHI measurement has been developed in our echo laboratory and has been previously validated in a comparative study of transthoracic ultrasound and chest X-ray.[18] It is calculated by dividing the maximum latero-lateral (L-L) external thoracic diameter by the minimum anteroposterior (A-P) internal thoracic diameter. Both thoracic diameters are measured at the end of inspiration. This approach yields the values of chest shape comparable to those obtainable through Chest X-rays, without exposing the subject to radiations.[18] Considering the PE definition based on a Haller index value >2.5,[2223] a normal MHI should be ≤2.5, whereas a concave-shaped chest wall is defined by an MHI >2.5.

Exercise stress Doppler echocardiography

Patients underwent incremental exercise test on a semisupine bicycle ergometer (Ergoselect 1200 ELP; Ergoline, Bitz, Germany), with initial workload set at 25 W, increased by 25 W every 2 min.[27]

A 12-lead ECG was continuously monitored. Heart rate (HR), blood pressure, and peripheral arterial oxygen saturation (SaO2) were measured at rest, every 2 min during the test, at peak exercise, and during recovery.

All stress echocardiograms were performed by the same cardiologist using a commercially available Philips Sparq ultrasound machine (Philips, Andover, Massacchusetts, USA) with a 2.5 MHz transducer, with the patient positioned on a semirecumbent cycle ergometer.

All conventional echo Doppler measurements were performed according to the recommendations of the American Society of Echocardiography and the European Association of CV Imaging.[2829]

The following echo Doppler parameters were collected at rest, during the second minute of each stage, and at peak exercise: LV ejection fraction (LVEF), LV diastolic function assessed by the E/A ratio and the average E/e' ratio, degree of MR severity, tricuspid annular plane systolic excursion, and finally systolic pulmonary artery pressure (SPAP). For each measurement, at least three cardiac cycles were averaged.

A hypercontractile response in all wall segments was considered normal (negative ESE), regardless of exercise ECG results. Ischemia was defined as new or worsened wall motion abnormalities during stress as indicated by an increase in wall motion score ≥1 grade in ≥2 segments (positive ESE).[27]

Degree of MR severity was assessed by evaluating the regurgitant jet area using color flow Doppler (qualitative assessment) and by quantitative methods, which measured the vena contracta (VC) and the effective regurgitant orifice area (EROA).[30] Exercise-induced severe primary MR was diagnosed in case of an increase in EROA ≥0.13 cm2 during exercise, according to previous studies.[31]

Patient evaluation and follow-up

During the follow-up period, each patient underwent a clinical visit (when possible) and/or a detailed telephonic interview to detect the occurrence of major adverse CV events (MACE). The latter were defined as any of the following:

CV hospitalizations: congestive heart failure (CHF), acute coronary syndromes (ACS), and arrhythmias associated with hemodynamic instability

The recourse to surgical MV repair or replacement due to disease progression

Cardiac death or sudden death.

Statistical analysis

For the whole study population, all the continuous data were summarized as mean ± standard deviation, whereas categorical data were presented as percentage.

Univariate Cox proportional hazard regression analysis was performed to evaluate the effect of the main demographics, anthropometrics, CV risk factors, stress ECG parameters, stress echo Doppler indices, and medical treatment on the occurrence of the above-mentioned outcome. For each variable investigated, correspondent hazard ratios with 95% confidence intervals (CI) were calculated. Variables with a P < 0.05 were then entered into a multivariate model. However, to avoid the issue of multicollinearity, only the most statistically significant variables at univariate were then included in the multivariate Cox regression analysis.

The receiver operating characteristics (ROC) curve analysis was performed to establish the sensitivity and the specificity of the main statistically significant continuous variables for predicting CV events. Area under the curve (AUC) was estimated.

The event-free survival curves of the variables statistically significant at Cox multivariate analysis were estimated using the Kaplan–Meier method and the survival curves were compared using the log-rank test.

A detailed intra- and interobserver variability analysis of the main conventional echo Doppler parameters measured at rest and at peak exercise, was conducted in a group of 15 randomly selected subjects by two different operators. We used the intraclass correlation coefficient (ICC) with its 95% CI as a statistical method for assessing intra- and interobserver measurement variability. An ICC of 0.70 or more was considered to indicate acceptable reliability.

Values of P < 0.05 were considered to indicate statistical significance.

Statistical analysis was performed using the SPSS software version 25 (SPSS Inc., Chicago, Illinois, USA).

RESULTS

A total of 424 consecutive patients (mean age 66.8 ± 11.5 years, 48.3% men) were retrospectively included in the present study.

All basal demographic, anthropometric and clinical parameters detected in the whole study population are summarized in Table 1. Concerning anthropometrics, great majority of MVP patients (68% of the total) enrolled in the present study showed a concave-shaped chest wall conformation (MHI >2.5). Analysis of CV risk factors revealed a moderate prevalence of hypertension (55% of pts), a mild-to-moderate prevalence of dyslipidemia (34% of pts) and smoking (31% of pts) and a low prevalence of type 2 diabetes (22% of pts). Moreover, systolic and diastolic blood pressure levels were within the normal values and prevalence of sinus rhythm on resting ECG was 93.2%. In addition, less than half of participants (44.3%) were prescribed with Ace-inhibitors/Angiotensin II receptor blockers, approximately one-fourth of the total received beta-blockers (24.3% of pts) and statins (26.1% of pts), whereas antiplatelets (20% of pts) and anticoagulants (6.8% of pts) were more rarely prescribed in these patients.

Table 1

Basal demographic, anthropometric, and clinical parameters detected in the study population

Basal demographic, anthropometric and clinical parameters	All patients (n=424), n (%)
Age (years)	66.8±11.5
Male sex	205 (48.3)
BSA (m2)	1.84±0.16
MHI	2.55±0.34
MHI>2.5	287 (68.0)
Smoking	131 (31.0)
Hypertension	233 (55.0)
Diabetes mellitus	93 (22.0)
Dyslipidemia	144 (34.0)
SBP (mmHg)	132.6±17.0
DBP (mmHg)	81.0±9.1
SaO2 (%)	97.2±1.6
HR (bpm)	71.3±13.4
Sinus rhythm	395 (93.2)
Antiplatelet tp	85 (20.0)
Anticoagulants	28 (6.8)
ACE-i/ARBs therapy	188 (44.3)
Beta-blocker therapy	103 (24.3)
Statins	110 (26.1)

ACE-i=Angiotensin-converting enzyme inhibitors, ARBs=Angiotensin II receptor blockers, BSA=Body surface area, DBP=Diastolic blood pressure, ECG=Electrocardiographic, HR=Heart rate, MHI=Modified Haller Index, SaO2=Arterial oxygen saturation, SBP=Systolic blood pressure

Table 2 describes resting echo Doppler parameters measured in the entire study population. Compared to the accepted reference values,[28] participants were found with decreased cardiac chamber dimensions, particularly the left atrium, and preserved biventricular contractile function. The first degree of diastolic dysfunction was the most frequent LV transmitral filling pattern, with no evidence of increased LV filling pressure (average E/e' ratio 9.4 ± 3.7). Great majority of participants were diagnosed with classic MVP (65% of pts) and mid-late systolic MR (70% of pts), with resting moderate MR, as expressed by VC (3.0 ± 1.5 mm) and EROA (0.20 ± 0.08 cm2) values, with no evidence of pulmonary hypertension (SPAP 29.5 ± 6.8 mmHg).

Table 2

Main resting echo Doppler parameters measured in the mitral valve prolapse subjects enrolled in the present study

Resting echoDoppler paramaters	All patients (n=424)
LVEDVi (ml/m2)	39.7±7.5
RWT	0.40±0.06
LVMi (g/m2)	97.3±23.2
LVEF (%)	57.0±6.4
E/A ratio*	0.89±0.25
Average E/e’ ratio**	9.4±3.7
LAVi (ml/m2)	24.4±5.1
RVEDD (mm)	24.5±4.2
TAPSE (mm)	22.4±1.9
Classic MVP	276 (65.0)
Nonclassic MVP	148 (35.0)
Holo-systolic MR, n (%)	127 (30.0)
Mid-late systolic MR, n (%)	297 (70.0)
Vena contracta (mm)	3.0±1.5
EROA (cm2)	0.20±0.08
SPAP (mmHg)	29.5±6.8

*Calculated in patients with sinus rhythm, **Measured in all patients. EROA=Effective regurgitant orifice area, LAVi=Left atrial volume index, LVEDVi=Left ventricular end-diastolic volume index, LVEF=Left ventricular ejection fraction, LVMi=Left ventricular mass index, MHI=Modified Haller Index, MR=Mitral regurgitation, MVP=Mitral valve prolapse, RVEDD=Right ventricular end-diastolic diameter, RWT=Relative wall thickness, SPAP=Systolic pulmonary artery pressure, TAPSE=Tricuspid annular plane systolic excursion

Main hemodynamics, ECG changes, echo Doppler parameters, and symptoms recorded at peak exercise in MVP patients are summarized in Table 3. Blood pressure values showed a physiological response to dynamic exercise in all patients. Overall, participants showed a good exercise tolerance (in terms of Watts, percentage of HR maximum, and double product reached). Furthermore, we observed a moderate prevalence of exercise-induced isolated ventricular premature beats (33.8% of pts) and upsloping ST-segment depression ≥2 mm (34.8% of pts) in our study population. Analysis of echo Doppler data obtained at peak exercise revealed that MVP participants showed a low prevalence of both positive ESE (9.8% of cases) and exercise-induced severe MR (defined by a ΔEROA ≥0.13 cm2). In fact, they were found without significant increase in peak exercise-E/e' ratio (13.7 ± 6.5), peak exercise-EROA (0.24 ± 0.09 cm2), and peak exercise-SPAP (46.8 ± 12.2 mmHg). Finally, dyspnea, which occurred in 41.2% of patients, was the most frequent exercise-induced symptom, followed by palpitations (29.2% of pts) and atypical chest pain (20% of pts).

Table 3

Main hemodynamics, electrocardiographic changes, echo Doppler parameters, and symptoms detected at peak exercise in the study population

Hemodynamics, electrocardiographic changes, echoDoppler parameters and symptoms at peak exercise	All patients (n=424), n (%)
Watts reached	95.5±33.1
SaO2 (%)	96.6±1.9
Percentage of HR maximum reached (%)	78.0±11.3
DP (mmHg×bpm)	20912.0±4997.9
Isolated VPBs	143 (33.8)
Upsloping ST depression≥2 mm	147 (34.8)
LVEF (%)	62.8±8.8
Positive ESE	41 (9.8)
E/A ratio*	1.07±0.35
Average E/e’ ratio**	13.7±6.5
Vena contracta (mm)	4.0±2.0
EROA (cm2)	0.24±0.09
∆EROA≥0.13 cm2	56 (13.2)
TAPSE (mm)	28.7±5.4
SPAP (mmHg)	46.8±12.2
Dyspnea	174 (41.2)
Typical chest pain	33 (7.7)
Atypical chest pain	85 (20.0)
Palpitations	124 (29.2)
Syncope	8 (1.9)

*Calculated in patients with sinus rhythm, **Measured in all patients. Δ=Absolute difference between peak exercise and rest data, DP=Double product, ECG=Electrocardiographic, EROA=Effective regurgitant orifice area, ESE=Exercise stress echocardiography, HR=Heart rate, LVEF=Left ventricular ejection fraction, MHI=Modified Haller index, SaO2=Oxygen saturation, SPAP=Systolic pulmonary artery pressure, TAPSE=Tricuspid annular plane systolic excursion, VPBs=Ventricular premature beats

Figure 1 illustrates an example of participant with moderate primary MR due to MVP and concave-shaped chest wall, who was diagnosed with upsloping ST-segment depression >1.5 mm and concomitant hyperkinetic response to exercise (negative ESE).

Figure 1

Example of subject with concave-shaped chest wall (MHI = 2.8) and moderate primary MR due to MVP, who was diagnosed with upsloping ST-segment depression >1.5 mm and concomitant hyperkinetic response to exercise (negative ESE). (a) The L-L maximum external thoracic diameter, obtained by using the measuring device. (b) The A-P minor internal thoracic diameter, assessed by transthoracic echocardiography. (c) ECG at peak exercise showing upsloping ST-segment depression >1.5 mm in left precordial leads (V4-V6). (d) Parasternal long-axis view, recorded at peak exercise, demonstrating moderate MR due to MVP. Ao = Aorta. A-P = Antero-posterior, ECG = Electrocardiogram, LA = Left atrium, L-L = Latero-lateral, LV = Left ventricle, MHI = Modified Haller Index, MVP = Mitral valve prolapse

Predictors of outcome

The mean follow-up time was 3.2 ± 1.7 years. During follow-up, there were no deaths and 75 CV events were recorded. A total of 55 patients were hospitalized due to: (1) CHF (24 patients); (2) ACS (11 patients); (3) arrhythmias associated with hemodynamic instability (20 patients); and 20 patients underwent surgical MV repair or replacement due to disease progression.

The univariate Cox proportional hazard ratio analysis [Table 4] showed several clinical, ECG and echo Doppler variables that were strongly associated with the occurrence of MACE during the follow-up period. Interestingly, MHI showed a statistically significant inverse correlation with the outcome (HR 0.14, 95%CI 0.07-0.31, P < 0.001). In other terms, the greater was the MHI value, the lower was the prevalence of MACE during follow-up.

Table 4

Univariate and multivariate Cox regression analysis for identifying the main demographics, anthropometrics, cardiovascular risk factors, stress electrocardiographic parameters, stress echo Doppler variables and medical treatment independently associated with the occurrence of major adverse cardiovascular events during the follow-up period

Variables	Univariate cox regression analysis			Multivariate cox regression analysis
	HR	95% CI	P	HR	95% CI	P
Demographics
Age (years)	1.04	1.02-1.07	<0.001	1.05	1.03-1.06	0.03
Male sex	1.13	0.72-1.79	0.59
Anthropometrics
BSA (m2)	1.04	0.25-4.32	0.96
MHI	0.14	0.07-0.31	<0.001	0.15	0.07-0.33	<0.001
Cardiovascular risk factors
Smoking	2.92	1.85-4.61	<0.001
Hypertension	2.79	1.65-4.75	<0.001
Diabetes mellitus	3.83	2.43-6.04	<0.001	3.26	2.04-5.20	<0.001
Dyslipidemia	3.23	2.04-5.14	<0.001
Stress ECG variables
Percentage of heart rate maximum reached (bpm)	0.98	0.96-1.00	0.09
Exercise-induced VPBs	1.06	0.65-1.71	0.82
Stress echo LV systolic and diastolic indices
Peak exercise LVEF (%)	0.95	0.94-0.96	<0.001
Peak exercise average E/e’ ratio	1.12	1.10-1.14	<0.001	1.07	1.05-1.09	<0.001
Stress echo MR severity indices
Peak exercise EROA (cm2)	6.90	5.17–9.22	<0.001	2.53	1.83-3.51	<0.001
Peak exercise SPAP (mmHg)	1.06	1.05–1.07	<0.001
Medical treatment
Beta-blocker therapy	0.27	0.20-0.38	<0.001	0.26	0.19-0.36	<0.001
Statin therapy	0.85	0.79-0.91	0.13

Significant P values are in bold. BSA=Body surface area, CI=Confidence interval, EROA=Effective regurgitant orifice area, HR=Hazard ratio, LV=Left ventricular, LVEF=Left ventricular ejection fraction, MHI=Modified Haller Index, MR=Mitral regurgitation, SPAP=Systolic pulmonary artery pressure, VPBs=Ventricular premature beats, ECG=Electrocardiographic

On multivariate Cox regression analysis [Table 4], age (HR 1.05, 95% CI 1.03–1.06, P = 0.03), diabetes mellitus (HR 3.26, 95% CI 2.04–5.20, P < 0.001), peak exercise-E/e' ratio (HR 1.07, 95% CI 1.05–1.09, P < 0.001), and peak exercise-EROA (HR 2.53, 95% CI 1.83–3.51, P < 0.001) were directly associated to outcome, whereas MHI (HR 0.15, 95% CI 0.07–0.33, P < 0.001) and beta-blocker therapy (HR 0.26, 95% CI 0.19–0.36, P < 0.001) showed strong inverse correlation.

The ROC curve analysis revealed the following cutoff for age (≥70 years, 70% sensitivity and 69% specificity, AUC = 0.75), peak exercise-E/e' ratio (≥13, 81% sensitivity and 80% specificity, AUC = 0.87) and peak exercise-EROA (≥0.35 cm2, 86% sensitivity and 71% specificity, AUC = 0.86) as the cutoff values with maximum sensitivity and specificity for predicting outcome and an MHI ≥2.7 (80% sensitivity and 100% specificity, AUC = 0.98) as the best cutoff for predicting event-free survival over a medium-term follow-up.

The Kaplan–Meier event-free survival curves, obtained for the six strongest independent predictors of outcome, are depicted in Figure 2.

Figure 2

The Kaplan–Meier event-free survival curves, obtained for the six variables with the strongest independent correlation with adverse CV events. (a) age, (b) MHI, (c) type 2 diabetes mellitus, (d) peak exercise average E/e' ratio, (e) peak exercise EROA, (f) beta-blocker therapy, CV = Cardiovascular, EROA = Effective regurgitant orifice area. MHI = Modified Haller Index

Measurement variability

Intra- and interobserver agreement between the raters, expressed as ICCs with 95% CIs, ranged from 0.77 to 0.93 and from 0.76 to 0.90, respectively [Supplemental Table 1].

Supplemental Table 1

Detailed intra- and interobserver variability analysis of the main conventional echo Doppler parameters, measured at rest and at peak exercise, in a group of 15 randomly selected participants by two different operators

Patient list	LVEF (%)
	Rest			Peak stress
	Initial measurement	Remeasurements		Initial measurement	Remeasurements
		Rater 1	Rater 2		Rater 1	Rater 2
1. A.S.	60	61	61	69	70	70
2. A.V.	58	58	59	66	66	66
3. S.H.	65	66	65	70	69	68
4. G.G.	58	58	59	66	65	63
5. M.Z.	60	61	61	67	66	67
6. M.F.	58	58	57	66	66	66
7. M.L.	58	58	57	65	65	65
8. E.R.	60	61	59	66	65	66
9. C.R.	60	59	59	68	67	69
10. C.B.	60	60	61	66	67	65
11. G.T.	60	56	57	69	70	70
12. S.B.	60	59	58	67	66	65
13. G.S.	58	57	57	67	65	68
14. S.R.	60	60	60	68	68	69
15. R.C.	60	60	61	69	68	69
ICC (95% CI)		0.81 (0.53–0.93)	0.79 (0.49–0.92)		0.84 (0.59–0.94)	0.76 (0.42–0.91)
Patient list	Average E/e’ ratio
	Rest			Peak stress
	Initial measurement	Remeasurements		Initial measurement	Remeasurements
		Rater 1	Rater 2		Rater 1	Rater 2
1. A.S.	8	10	11	10	11	9
2. A.V.	5,5	7	4	7,5	6	5
3. S.H.	13	15	16	16	14	13
4. G.G.	10	11	8	14	11	10
5. M.Z.	11	12	9	16	15	11
6. M.F.	14	10	9,5	20	18	15
7. M.L.	13	10	9	20	17	12
8. E.R.	13	10	9	19	17	14
9. C.R.	9	7	6	21	20	18
10. C.B.	17	14	11	29	25	21
11. G.T.	13	11	10	22	20	15
12. S.B.	9,6	7,5	7	11,6	9,5	7
13. G.S.	9	7	6	12	10	15
14. S.R.	9	7	5	12	9	15
15. R.C.	23	20	18	33	27	21
ICC (95% CI)		0.86 (0.63-0.95)	0.80 (0.50-0.93)		0.84 (0.60-0.94)	0.78 (0.46-0.92)
Patient list	EROA (cm2)
	Rest			Peak stress
	Initial measurement	Remeasurements		Initial measurement	Remeasurements
		Rater 1	Rater 2		Rater 1	Rater 2
1. A.S.	0.35	0.25	0.25	0.41	0.32	0.31
2. A.V.	0.16	0.2	0.1	0.22	0.3	0.31
3. S.H.	0.16	0.1	0.1	0.22	0.26	0.25
4. G.G.	0.18	0.16	0.15	0.25	0.21	0.33
5. M.Z.	0.11	0.1	0.13	0.15	0.14	0.11
6. M.F.	0.11	0.09	0.13	0.15	0.13	0.1
7. M.L.	0.29	0.26	0.25	0.35	0.31	0.3
8. E.R.	0.13	0.1	0.09	0.18	0.15	0.13
9. C.R.	0.19	0.16	0.15	0.24	0.22	0.21
10. C.B.	0.25	0.25	0.22	0.3	0.27	0.26
11. G.T.	0.18	0.16	0.15	0.24	0.21	0.2
12. S.B.	0.13	0.11	0.1	0.17	0.18	0.16
13. G.S.	0.11	0.1	0.13	0.17	0.15	0.14
14. S.R.	0.29	0.24	0.22	0.33	0.27	0.26
15. R.C.	0.31	0.27	0.26	0.35	0.31	0.3
ICC (95% CI)		0.92 (0.77-0.97)	0.88 (0.70-0.96)		0.86 (0.63-0.95)	0.79 (0.49-0.92)
Patient list	SPAP (mmHg)
	Rest			Peak stress
	Initial measurement	Remeasurements		Initial measurement	Remeasurements
		Rater 1	Rater 2		Rater 1	Rater 2
1. A.S.	30	24	23	45	35	51
2. A.V.	40	33	30	70	55	50
3. S.H.	45	34	31	70	60	55
4. G.G.	25	23	19	60	66	51
5. M.Z.	22	20	19	40	35	30
6. M.F.	25	22	21	60	55	65
7. M.L.	30	28	27	60	56	55
8. E.R.	37	35	32	47	42	40
9. C.R.	35	33	39	50	46	43
10. C.B.	27	25	24	37	33	31
11. G.T.	25	22	21	50	47	45
12. S.B.	27	23	21	42	40	38
13. G.S.	28	25	23	38	35	33
14. S.R.	30	27	26	55	51	50
15. R.C.	30	28	25	45	42	40
ICC (95% CI)		0.90 (0.72-0.96)	0.79 (0.48-0.92)		0.90 (0.74-0.97)	0.81 (0.52-0.93)

CI=Confidence interval, EROA=Effective regurgitant orifice area, ICC=Intraclass correlation coefficient, LVEF=Left ventricular ejection fraction, SPAP=Systolic pulmonary artery pressure

DISCUSSION

The present study demonstrated that the patient's chest wall conformation, as assessed by MHI value, might be related to a different prevalence of CV events over a medium-term follow-up in a consecutive population of symptomatic patients with moderate primary MR. Notably, participants with moderate primary MR and concave-shaped chest wall (MHI ≥2.7) had a significantly lower prevalence of MACE during the follow-up period.

Differently from previous studies,[7891011121314] the present study retrospectively evaluated not only the conventional ESE-derived prognostic factors but also a new anthropometric variable, that is the MHI, in a consistent group of symptomatic participants with moderate primary MR who had undergone ESE. The MHI, noninvasively assessed by a nonradiological technique[18] was tested as a potential additive factor independently correlated with the prevalence of MACE over a medium-term follow-up period.

Majority of the symptomatic patients with primary MR included in the present study were found with a concave-shaped chest wall conformation; had a moderate prevalence of hypertension and a low prevalence of other CV risk factors; had good blood pressure control; were diagnosed with small cardiac chamber dimensions, particularly the left atrium; frequently showed exercise-induced ST-segment changes, especially upsloping ST-segment depression ≥2 mm, with concomitant atypical chest pain and/or palpitations; had good exercise tolerance, high prevalence of negative ESE, and low prevalence of exercise-induced worsening of MR.

Consistent with literature data,[3233] our survival analysis confirmed that traditional demographics (higher age), CV risk factors (type 2 diabetes), stress echo Doppler variables (lower peak exercise-LVEF, higher peak exercise-E/e' ratio and higher peak exercise-EROA) and clinical indices (undertreatment with beta-blockers) were independently correlated with a higher prevalence of MACE during the follow-up period in symptomatic patients with moderate primary MR who had undergone ESE.

In addition, univariate and multivariate Cox regression analysis revealed that concave-shaped chest wall, as noninvasively defined by an MHI >2.5, was inversely correlated with the occurrence of the outcome.

Overall, our results demonstrated that moderate primary MR is a benign condition in participants with MVP which is often associated to concave-shaped chest wall conformation (MHI >2.5). It is known that thoracic deformity has a predominant role in generating mitral valve malformation; notably, the continuous mechanical stress induced by a concave-shaped chest wall and/or PE would promote degeneration, mitral annular distortion, shrink leaflet gradually, and would cause mitral prolapse and secondary regurgitation as well.[3435]

A number of hemodynamic and anthropometric factors detected in MVP participants were responsible for our findings. First, the great majority of MVP participants were found with optimal blood pressure levels and therefore was protected from augmented mechanical stress, higher left ventricular pressure and increased regurgitation volume induced by arterial hypertension.[36] Second, the majority of MVP patients (70%) were diagnosed with mid-late systolic MR rather than holo-systolic MR. It is known that the latter is associated with adverse outcomes.[14] Third and perhaps most importantly, MR severity may be overestimated by resting transthoracic echocardiography (TTE) in participants with concave-shaped chest wall, due to the small size of all cardiac chambers, mostly the left atrium as the receiving chamber. In our study population, MVP participants were found without LV eccentric hypertrophy, not only for the extrinsic compression exerted on cardiac chambers and dislocation of the heart by a narrow A-P chest diameter but probably also because MR degree was, in absolute terms, less than moderate. Overestimation of MR severity may be related to the use of techniques that rely on single-frame measurements, such as VC width or proximal isovelocity surface area;[3738] in participants with MVP, jets are often very eccentric and poor alignment with an eccentric jet may lead to overestimation of both VC and EROA, especially when left atrial size is small. MVP can also induce increased coaptation length of redundant leaflets with tunneling of the jets and “spray effect” in a relatively small receiving chamber, contributing to overestimation of MR.

The present study demonstrated that a chest wall shape assessment might be very helpful, if added to the preliminary evaluation of patients with moderate primary MR referred to echo laboratory for performing ESE due to resting and/or exercise-related symptoms. In the centers where a rigid ruler in centimeters coupled to a level is not available, it could be useful to measure the A-P chest diameter by TTE only, in order to identify or exclude a concave-shaped chest wall or a PE. In most cases, a narrow A-P chest diameter or an MHI >2.5 might suggest the clinician to search more carefully for the possibility of overestimation of MR degree of severity, mostly if LV and LA size are not large enough to be considered concordant with the severity of MR itself, and MR is not holosystolic.

The clinician should even consider to not require ESE for determining the functional response to MR and for diagnosing obstructive CAD, because of the low probability of MACE over a medium-term follow-up and the excellent prognosis of these participants.[394041]

Finally, our results revealed a 64% of reduction of CV events over a medium-term follow-up in those MVP participants who were on beta-blocker treatment. As observed by previous authors,[4243] the protective role of beta-blockers on the survival was primarily related to the reduction of the sympathetic nervous system activity which is typically increased in MVP participants. Therefore, beta-blocker prescription should be considered in these participants.

Main limitation of the present study is its retrospective nature. Moreover, a detailed analysis of mitral annular disjunction (MAD) was not performed in our study population for the following reasons: no patient with severe MR due to MVP was included in the study; only 33.8% of MVP participants had exercise-induced isolated ventricular premature beats and 29.2% of them were symptomatic for palpitations; furthermore, during the follow-up period, there were no deaths and only 75 CV events were recorded. All these data suggested that our study population was a low risk population. On the other hand, the presence of MAD has been mostly associated to severe MR, redundant floppy mitral valve and increased risk of MACE and complex ventricular arrhythmias.[4445]

In addition, brain natriuretic peptide levels, which have been associated with lower survival and higher combined adverse events in patients with organic MR,[464748] were not systematically measured in our study population. Finally, maximum HR reached was close to sub-maximal, probably because some patients did not adequately discontinue beta-blockers before ESE.

CONCLUSIONS

Chest wall conformation appears to be related with the prevalence of MACE in symptomatic patients with moderate primary MR who had undergone ESE. Participants with moderate primary MR and concave-shaped chest wall have in fact a significantly lower prevalence of MACE over a medium-term follow-up. An MHI ≥2.7 might potentially indicate to not perform ESE, due to the excellent prognosis of these participants.

A noninvasive chest shape assessment should then be encouraged in clinical practice, especially in the preliminary evaluation of symptomatic patients with moderate primary MR.

Ethical clearance

Committee's reference number CE-24.2021.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.