- Academic Editor
Background: Some patients with hypertrophic obstructive cardiomyopathy
(HOCM) still exhibit systolic anterior motion (SAM) and mitral regurgitation (MR)
even after undergoing an isolated ventricular septectomy. Currently, there are
disputes regarding whether to perform a mitral valve intervention and which type
of operation is more effective. Methods: By searching PubMed, Cochrane,
Embase, Web of Science, FDA.gov, and ClinicalTrials.gov, as well as other
resource databases, we obtained all articles published before December 2022 on
ventricular septal myectomy combined with mitral valve intervention for
hypertrophic cardiomyopathy. Demographic information and outcome variable data
were extracted from 10 screened studies on ventricular septal resection combined
with mitral valve repair. The risk of bias was assessed using methodological
index for non-randomized studies (MINORS). Student’s t-test was used for
comparisons of continuous variables, and the chi-square or Fisher’s exact test
was used for dichotomous variables. A total of 692 patients across 10 studies
were analyzed. Results: There were 5 (0.7%) deaths in the perioperative
period. The average cardiopulmonary bypass time was 64.7
Hypertrophic obstructive cardiomyopathy (HOCM) is a hereditary disease characterized by left ventricular outflow tract obstruction, the systolic anterior motion of the mitral valve, and moderate to severe mitral regurgitation, with typical clinical symptoms such as dyspnea, angina pectoris, and syncope. The incidence of HOCM is about 0.2% [1], and the disease is associated with a high risk of sudden death. Ventricular septal resection is currently the most common and effective treatment for HOCM in patients whose clinical symptoms cannot be improved by drugs [2, 3]. It has a good effect on relieving left ventricular outflow tract obstruction, relieving symptoms, improving quality of life, and reducing the risk of sudden death.
The main cause of HOCM is abnormal hypertrophy of the ventricular septum, and abnormalities of the anterior mitral valve leaflet, papillary muscle, and secondary chordae may also play an important role in its pathogenesis [4, 5]. These abnormal structures may bind the anterior leaflet of the mitral valve, making it difficult to completely improve the outflow tract obstruction and mitral regurgitation by isolated septal myectomy. About 2.5% of HOCM patients have residual left ventricular outflow tract gradient after septal myectomy [6]. For patients with severe left ventricular outflow tract obstruction accompanied by obvious systolic anterior motion of the mitral valve and mitral valve regurgitation, there may be a mitral valve, papillary muscle, or chordal abnormalities that are difficult to accurately assess by preoperative echocardiography, and septal resection combined with mitral valve surgery may be considered [7]. However, whether combined mitral valve surgery is necessary and what the best mitral valve surgery method is still controversial. The mainstream mitral valve repair includes plication or extension of the anterior leaflet [8, 9], secondary chordal cutting [10], papillary muscle reorientation [11], and edge-to-edge repair [10].
In this study, we integrated patient characteristics, preoperative, postoperative, and follow-up clinical and echocardiographic findings from published reports on septal myectomy combined with sub-mitral valve repair for HOCM. Our aim is to determine whether septal resection combined with subvalvular management can improve clinical outcomes and reduce the incidence of adverse events in patients with HOCM.
This systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [12, 13] and was registered on the International Platform of Registered Systematic Review and Meta-Analysis Protocols (number INPLASY202320116). We selected relevant studies published before December 2022 by searching PubMed, Cochrane, Embase, Web of Science, FDA.gov, and ClinicalTrials.gov, with no language restrictions. We used the following combined text and MeSH terms: (((((((((((((((Insufficiency, Mitral Valve) OR (Valve Insufficiency, Mitral)) OR (Mitral Valve Regurgitation)) OR (Regurgitation, Mitral Valve)) OR (Valve Regurgitation, Mitral)) OR (Mitral Regurgitation)) OR (Regurgitation, Mitral)) OR (Mitral Valve Incompetence)) OR (Incompetence, Mitral Valve)) OR (Valve Incompetence, Mitral)) OR (Mitral Incompetence)) OR (Incompetence, Mitral)) OR (Mitral Insufficiency)) OR (Insufficiency, Mitral)) OR (“Mitral Valve Insufficiency”[Mesh])) AND ((“Cardiomyopathy, Hypertrophic”[Mesh]) OR (((((((((Cardiomyopathies, Hypertrophic) OR (Hypertrophic Cardiomyopathies)) OR (Hypertrophic Cardiomyopathy)) OR (Cardiomyopathy, Hypertrophic Obstructive)) OR (Cardiomyopathies, Hypertrophic Obstructive)) OR (Hypertrophic Obstructive Cardiomyopathies)) OR (Hypertrophic Obstructive Cardiomyopathy)) OR (Obstructive Cardiomyopathies, Hypertrophic)) OR (Obstructive Cardiomyopathy, Hypertrophic))).
Two independent researchers screened relevant literature by reviewing titles and abstracts. Any disagreements that arose were resolved by a third researcher through negotiation. After the initial screening, the full literature was obtained and further examined. The inclusion criteria for the study were: (1) patients with clinically symptomatic HOCM; and (2) myectomy combined with sub-mitral valve repair was performed. Exclusion criteria included clinical studies of isolated septal myectomy, incomplete clinical and echocardiographic data, outcome variables that did not fit the study’s purpose, and study types such as reviews, case reports, and animal experiments. When multiple studies were published by the same author in different years, only the latest one was included (see Fig. 1). We used the MINORS tool to assess the risk of bias and the quality of the included studies (Supplementary Table 1) [14].
Study selection process.
Two researchers independently reviewed and screened to extract relevant study population baseline data, including patient number, age, sex, medication history, New York Heart Association functional class, implantable cardioverter defibrillator (ICD) implantation, and related surgical history. They also noted any abnormal papillary muscle and chordae found during operation and treatment techniques, preoperative and postoperative echocardiographic indicators, such as left ventricular diastolic diameter, ejection fraction, interventricular septal thickness, maximum left ventricular outflow tract pressure gradient, mitral valve regurgitation degree, and pacemaker implantation. Additionally, they recorded perioperative mortality, reoperation rates during the follow-up period, and New York Heart functional class.
A systematic review was performed using Review Manager 5.4 (Nordic Cochrane
Center, Copenhagen, Denmark). Continuous variables were reported as mean
The study included 692 patients, of whom 52.2% were male. The average age was
53.0
Author | N | Age | Male | Hypertension | Atrial fibrillation | NYHA class III/IV | Beta/Ca |
Family history |
Afanasyev 2021 [10] | 24 | 54.1 |
14 (58.3%) | NA | NA | 24 (100%) | 24 (100%) | NA |
Liu 2022 [15] | 40 | 53.7 |
15 (37.5%) | 15 (37.5%) | 5 (12.5%) | 37 (92.5%) | 40 (100%) | 3 (7.5%) |
Ram 2021 [16] | 60 | 61.0 |
30 (50.0%) | 24 (40.0%) | 20 (33.3%) | 44 (73.3%) | NA | NA |
Minakata 2004 [17] | 56 | 42.0 |
23 (41.1%) | NA | 11 (19.6%) | 46 (82.1%) | 37 (66%) | 19 (33.9%) |
Raffa 2022 [18] | 66 | 58.4 |
29 (43.9%) | NA | 37 (40.9%) | 51 (77.3%) | 66 (100%) | 22 (33.3%) |
Bogachev-Prokophiev 2019 [19] | 40 | 49.6 |
14 (35.0%) | NA | NA | 27 (67.5%) | 40 (100%) | NA |
Dorobantu 2022 [20] | 83 | 52.0 |
51 (61.4%) | NA | 26 (31.3%) | 49 (59.0%) | 83 (100%) | NA |
Ferrazzi 2015 [21] | 39 | 58.0 |
NA | NA | 13 (33.3%) | 32 (82.1%) | 39 (100%) | NA |
Schoendube 1995 [22] | 58 | 48.2 |
38 (65.5%) | NA | 2 (3.4%) | 53 (91.3%) | 58 (100%) | NA |
Zyrianov 2023 [23] | 226 | 53.1 |
127 (56.2%) | NA | 44 (19.5%) | 178 (78.8%) | NA | NA |
Total | 692 | 53.0 |
341/653 (52.2%) | 39/100 (39.0%) | 158/628 (25.2%) | 541/692 (78.2%) | 387/406 (95.3%) | 44/162 (27.2%) |
N, number; NA, not available; NYHA, New York Heart Association.
All patients underwent intraoperative transesophageal echocardiography to evaluate mitral valve structure, function, and the amount of myocardium to be resected. A median sternotomy was performed. Standard cardiopulmonary bypass was established through ascending aortic and right atrial cannulation. For some patients requiring secondary surgery, cardiopulmonary bypass was established through femoral artery cannulation. Myocardial protection was achieved by an intermittent antegrade or retrograde infusion of cardioplegia. All patients underwent aortotomy as an approach, and the aorta was transected about 10 mm above the right coronary artery ostium to allow observation of the left ventricular outflow tract. Septectomy was performed at the nadir of the right cusp, about 5 mm below the aortic valve, to the left of the trigon, and the thickness of the resected wedge-shaped interventricular septum was 1/3 to 1/2 of the base thickness. The excision was extended to the point of insertion of the papillary muscle with minimally invasive instruments [24].
Submitral valve repair mainly includes the following methods: false chordae
and/or secondary chordae amputation, papillary muscle release or accessory
papillary muscle resection, trabeculectomy between the septum and mitral valve
apparatus, and separation of hypertrophic papillary muscles. The attachment to
the leading edge of the anterior mitral leaflet was preserved to avoid iatrogenic
mitral valve injury. After cessation of cardiopulmonary bypass, a provocation
test was performed, and the left ventricular outflow tract gradient, systolic
anterior motion, and mitral regurgitation were evaluated by intraoperative
transesophageal ultrasound. If a residual gradient
During the operation, secondary aortic clipping was performed three times, including the repair of a left ventricular free wall rupture (n = 1) and residual left ventricular outflow track obstruction (LVOTO) (n = 2). Concomitant surgery for the previous etiology included resection of subaortic stenosis (n = 2), aortic valve repair (n = 6), aortic valve replacement (n = 3), radical pericardiectomy (n = 1), repair of Ebstein anomaly (n = 1), coronary artery bypass grafting (CABG) (n = 9), tricuspid valve repair (n = 2), and atrial septal defect closure (n = 2). No patient required mitral valve replacement. There were five (0.7%) deaths in the perioperative period, and the causes of death were infectious multiple organ failure (n = 1), failed septal myectomy combined with coronary artery bypass grafting (n = 1), gastrointestinal bleeding with cardiogenic shock (n = 1), refractory sepsis (n = 1), and left ventricular diastolic failure (n = 1).
The average cardiopulmonary bypass time was 44
Author | LVOT gradient (mmHg) | Ventricular septal thickness (mm) | III/IV mitral regurgitation | Systolic anterior motion | LV ejection fraction (%) | AML-annulus ratio | |
Afanasyev [10] | |||||||
Preoperative | 86.4 |
26.0 |
24 (100%) | 24 (100%) | 71.8 |
NA | |
Follow-up | 11.1 |
18.1 |
0 | 2 (8.3%) | 63.2 |
NA | |
Liu [15] | |||||||
Preoperative | 96.7 |
17.0 |
40 (100%) | 40 (100%) | 66.3 |
NA | |
Follow-up | 8.8 |
13.5 |
0 | 0 | NA | NA | |
Ram [16] | |||||||
Preoperative | 91.0 |
24.8 |
30 (50.0%) | NA | 65.1 |
0.75 | |
Follow-up | 13.0 |
13.0 |
1 (1.7%) | NA | 65.0 |
0.79 | |
Minakata [17] | |||||||
Preoperative | 97.0 |
NA | 36 (64.3%) | NA | 71.0 |
NA | |
Follow-up | 11.0 |
NA | 5 (9.3%) | NA | 72.0 |
NA | |
Raffa [18] | |||||||
Preoperative | 89.7 |
18.9 |
37 (56.1%) | 53 (80.3%) | 64.2 |
NA | |
Follow-up | 15.4 |
14.0 |
1 (1.5%) | 2 (3.1%) | NA | NA | |
Prokophiev [19] | |||||||
Preoperative | 92.3 |
26.8 |
40 (100%) | 40 (100%) | 76.2 |
NA | |
Follow-up | 9.1 |
15.4 |
4 (10.0%) | 2 (5.0%) | 66.2 |
NA | |
Dorobantu [20] | |||||||
Preoperative | 93.0 |
24.0 |
32 (38.6%) | NA | 63.0 |
NA | |
Follow-up | 13.0 |
13.0 |
1 (1.2%) | NA | 59.0 |
NA | |
Ferrazzi [21] | |||||||
Preoperative | 82.0 |
17.0 |
9 (23.1%) | NA | 68.0 |
0.45 | |
Follow-up | 9.0 |
14.0 |
1 (2.5%) | NA | 63.0 |
0.57 | |
Schoendube [22] | |||||||
Preoperative | 79.0 |
25.0 |
38 (65.5%) | 24 (100%) | NA | NA | |
Follow-up | 5.0 |
13.0 |
0 | 5/49 (10.2%) | NA | NA | |
Zyrianov [23] | |||||||
Preoperative | 70.3 |
23.0 |
65 (28.8%) | NA | 65.7 |
0.43 | |
Follow-up | 11.0 |
16.1 |
4 (1.8%) | NA | 63.0 |
0.55 | |
Total | |||||||
Preoperative | 83.6 |
22.5 |
351/692 (50.7%) | 181/194 (93.3%) | 66.7 |
0.49 | |
Follow-up | 11.0 |
14.7 |
17/675 (2.5%) | 11/215 (5.1%) | 63.4 |
0.60 | |
p |
p |
p |
p |
p |
p |
NA, not available; LVOT, left ventricular outflow tract; LV, left ventricle; AML, anterior mitral leaflet.
Author | Perioperative mortality | NYHA functional class III/IV | Pacemaker implantation | Hospital stay (days) | Unplanned reoperation | Atrial fibrillation |
Afanasyev [10] | 0 | 0 | 0 | NA | 0 | NA |
Liu [15] | 0 | 0 | 2 (5.0%) | 5.9 |
2 (5.0%) | 2 (5.4%) |
Ram [16] | 0 | 5 (8.3%) | 5 (8.3%) | 6.0 |
0 | 20 (33.3%) |
Minakata [17] | 0 | 0 | 3 (5.4%) | 12 |
0 | 11 (20.4%) |
Raffa [18] | 1 (1.5%) | 3 (4.6%) | 3 (4.6%) | 10.6 |
1 (1.5%) | 33 (50.8%) |
Prokophiev [19] | 0 | 0 | 2 (5.0%) | NA | 1 (2.5%) | NA |
Dorobantu [20] | 1 (1.2%) | 0 | 8 (9.8%) | NA | 0 | 13 (15.8%) |
Ferrazzi [21] | 0 | 0 | NA | NA | 0 | 3 (7.7%) |
Schoendube [22] | 2 (3.4%) | 4 (7.1%) | 3 (5.4%) | NA | 0 | 3 (5.4%) |
Zyrianov [23] | 1 (0.4%) | 2 (0.9%) | NA | NA | 0 | 15 (6.7%) |
Total | 5 (0.7%) | 14/682 (2.1%) | 26/427 (6.1%) | 8.7 |
4/687 (0.6%) | 100/618 (16.2%) |
NA, not available; NYHA, New York Heart Association.
During the follow-up period, 10 patients died, and the causes of death included: chronic respiratory failure (n = 1), congestive heart failure (n = 6), and renal failure (n = 3). There were 4 unplanned reoperations: one patient was readmitted for mitral annuloplasty and posterior leaflet plication due to residual left ventricular outflow tract gradient and mitral regurgitation (n = 1); endocarditis (n = 1); repair of aortic perforation (n = 1); and repair of ventricular septal perforation (n = 1).
The postoperative and follow-up data from ten studies were pooled, and it was found that: (1) Ventricular septal myectomy combined with sub-mitral valve repair significantly reduces the pressure gradient of the left ventricular septal outflow tract, eliminates the SAM phenomenon, improves mitral regurgitation, and relieves heart failure in patients with HOCM with severe left ventricular outflow tract obstruction and mitral valve regurgitation. (2) Patients do not require additional mitral valve intervention, and only 0.6% of patients require reoperation for secondary mitral valve surgery after the procedure. (3) Retaining a certain thickness of the ventricular septum during the operation can also effectively eliminate the obstruction and avoid surgical adverse events such as ventricular septal perforation and ventricular septal rupture. (4) However, after ventricular septal resection combined with subvalvular management, the proportion of patients requiring permanent pacemaker implantation is high.
The classic Morrow operation involves making two parallel incisions in the interventricular septum. However, due to the limited field of view and operating range of surgical exposure, some patients with non-outflow tract hypertrophy, such as apical hypertrophy, cannot achieve the expected results. Later, an extended myectomy was proposed, which involves extending the range of the surgery to both sides and the apex. Currently, modified Morrow surgery is the preferred surgical strategy for patients with HOCM [24]. Sufficient ventricular septal resection is effective for most patients, but there are some limitations, especially for patients with a thin ventricular septum and subvalvular structural abnormalities. Mitral valve replacement has also been proposed as an alternative treatment for HOCM, but due to the durability of artificial valves and the high incidence of infection, thromboembolism, and other problems, it is used less frequently at present [25].
Hypertrophy of the papillary muscles, shortening and thickening of the secondary chordae, and fibrosis in patients with hypertrophic cardiomyopathy may lead to abnormal tethering of the anterior mitral leaflet and poor coaptation of the anterior and posterior mitral leaflets. During systole, mitral commissures move toward the left ventricular outflow tract, increasing SAM-mediated mitral regurgitation [23, 26, 27, 28]. In particular, for patients with insignificant ventricular septal hypertrophy but with left ventricular outflow tract obstruction, ventricular septal hypertrophy may not be the primary cause of the obstruction [29]. Moreover, the SAM phenomenon cannot be fully explained by the Venturi effect [30]. The contribution of the mitral valve device and all its components to the dynamic obstruction of the LVOT varies; thus, surgical correction is recommended in addition to extended myectomy for optimal results [31, 32]. After subvalvular repair, the anterior mitral leaflet-annulus ratio increases, and the tenting area decreases. This helps the anterior leaflet of the mitral valve move backwards and promotes the coaptation plane of the anterior and posterior leaflets to move backwards away from the left ventricular outflow tract, thereby eliminating the SAM phenomenon, relieving mitral valve regurgitation, preventing left ventricular outflow tract obstruction, and avoiding mitral valve replacement [21].
The study conducted by Liu et al. [15] compared the one-year follow-up results
of the combined group (n = 40) and the isolated septal myectomy group (n = 106).
The study found that when there was no significant difference in postoperative
ventricular septal thickness, the combined group could better improve the SAM and
mitral regurgitation (MR) levels, and the left ventricular outflow tract gradient was lower. These
results are consistent with the results of [19, 21]. There was no significant
difference in aortic clipping time between the combined group and the isolated
septal myectomy group (38.0
Aortic regurgitation is a common complication after septal resection, and the incidence in this study was found to be only 1.2% (n = 8). The incidence of mitral valve replacement was even lower, at only 0.3% (n = 2). Despite a wider scope of surgical intervention, the incidence of ventricular septal perforation and defect was also low, at 0.3% (n = 2). During the follow-up period, the incidence of atrial fibrillation was 16.2%. These clinical outcomes were comparable to those seen after isolated septal myectomy [33, 34, 35]. For patients with mild septal hypertrophy but severe SAM and MR, subvalvular management is a better option than mitral valve replacement. Combined surgery can effectively eliminate LVOTO and alleviate MR, reducing the risk of iatrogenic ventricular septal perforation or defect. Additionally, it can lower the incidence of intraoperative repeat aortic clipping [19, 29, 36]. However, due to the wider range of myocardium involved in combined surgery, it can have a greater impact on the normal rhythm conduction of the ventricle. The rate of permanent pacemaker implantation during hospitalization for surgical patients was 6.1%, which is higher than the rate of 3.5% seen in patients with a simple septal myectomy. Excluding the patients with preoperative right bundle branch block, only 1.1% of patients with normal preoperative ECG evaluation required permanent pacemaker implantation [37]. Therefore, surgeons need to screen for right bundle branch block before combined surgery to avoid sudden complete atrioventricular block after surgery.
According to the Mayo Clinic’s experience [38], only 2.1% of patients without
intrinsic mitral valve disease required additional mitral valve intervention. In
a comparison of Doppler echocardiographic findings before and after 1830 isolated
diaphragm resections without congenital mitral valve disease, the number of class
III/IV patients decreased from 54.3% to 1.7%. In 2019, the American Society of
Thoracic Surgeons analyzed septal myectomy data from over 2300 patients, of whom
approximately one-third (n = 801) underwent septal myectomy combined with mitral
valve intervention. Mitral valve repair was performed in 62% of cases, while
mitral valve replacement was performed in the remaining 38% [39]. For mitral
valve intervention, mitral valvuloplasty is prioritized over mitral valve
replacement, and the 2-year survival rate of mitral valve repair is much better
than that of mitral valve replacement (96.7% vs. 87.2%, p
Zyrianov et al. [23] retrospectively analyzed 212 patients with HOCM who
underwent septal myectomy combined with secondary chordal cutting. Based on the
thickness of the ventricular septum, the patients were divided into two groups:
the mild ventricular septal hypertrophy group (
In a randomized controlled study, 48 patients were assigned to undergo either
ventricular septal myectomy with edge-to-edge repair or secondary chordal cutting
[10]. Postoperative Doppler echocardiography revealed no significant difference
in the left ventricular outflow tract gradient (15.4
The secondary chordae play an important role in maintaining the geometry of the
left ventricle, and their resection may affect ventricular contraction [45, 46].
From pooled data, although the left ventricular ejection fraction is reduced
(66.7
Isolated septal resection generally requires a resection of 40%–50% of the
maximum septal thickness [47], and even in some institutions, only 10 mm of the
septum is preserved [48]. This often represents a great surgical difficulty and
increases the risk of septal perforation or even rupture in patients. In
contrast, combined surgical resection of 30% of the ventricular septum was
considered sufficient in Zyrianov’s study [23], even in patients with moderate to
severe hypertrophy (IVS
The limitation of this study is that it included 8 retrospective analyses and 2 randomized controlled trials. Most of them were retrospective studies, and there was no control group. Moreover, the sample size was limited, and the inclusion criteria were not absolutely uniform, leading to certain selection bias, attrition bias, and missing outcome variable bias. Individual patients had concomitant surgery, which also had a certain impact on the statistics of the outcome. Randomized controlled trials represent a higher level of evidence, but they are less feasible and less ethical for surgical studies. In this case, non-randomized and observational studies are also valuable evidence.
Sub-mitral valve repair surgery has greater flexibility, and surgeons mostly operate according to personal experience and preference. When experienced surgeons perform ventricular septal myectomy, the mortality rate is less than 1%, and the clinical success rate is 90%–95%. Maron summarized five major North American clinics from 2000 to 2014, including the Mayo Clinic and Cleveland Clinic [49]. Among the 3695 patients in high-volume hypertrophic cardiomyopathy surgery centers, the mortality rate was only 0.4%, while the mortality rate of patients in low-volume HCM surgery centers in the United States was about 5.9% (n = 665) during the same period [50]. Surgical outcomes and adverse event rates in cardiac surgery centers with different volumes are quite different. Accurately judging whether septal resection combined with sub-mitral valve repair has significant advantages compared with other surgical methods requires a larger sample size and longer follow-up.
The mechanism of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy is very complex. It involves different factors such as the segmental hypertrophic interventricular septum, hypertrophic and displaced papillary muscles, fibrotic and shortened chordae, thickened and elongated mitral valve leaflets, and even deranged myocardial trabeculae. A septal myectomy combined with sub-mitral management represents a comprehensive surgical approach to correct left ventricular outflow tract obstruction and mitral regurgitation. This approach targets pathological mechanisms such as septal hypertrophy and sub-mitral structural abnormalities, resulting in good surgical results and long-term survival.
SAM, systolic anterior motion; LVOT, left ventricular outflow tract; MR, mitral regurgitation; IVS, interventricular septum; AML, anterior mitral leaflet; LVOTO, left ventricular outflow track obstruction; ICD, implantable cardioverter defibrillator; E2E, edge to edge; TPG, transmitral pressure gradient; RPR, resection-plication-release; RCT, Randomized Controlled Trial; CABG, coronary artery bypass grafting; CMR, cardiac magnetic resonance; TEE, trans esophageal echocardiography.
All data and materials were from published researches.
MYS, RL, and XW designed the research study. MYS, RL, and CHL data analysis. MYS, RL, and XW assessment and results. MYS, RL wrote the manuscript. MYS, RL, XW, and CHL contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Not applicable.
Not applicable.
This research received no external funding.
The authors declare no conflict of interest.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.