Prevalence & Natural History of Tricuspid Regurgitation in Ischemic Mitral Regurgitation Patients

Background Functional tricuspid regurgitation (FTR) is most often secondary to left-sided heart pathology involving the mitral valve. We studied the incidence, clinical impact, risk factors, and natural history of patients who developed FTR due to an ischemic cause of mitral regurgitation (IMR). We conducted a retrospective cohort study based on data collected from January 2012 to December 2014. Patients diagnosed with IMR were eligible for the study. The mean follow-up was ve years. RESULTS The study group consisted of 134 patients with IMR divided into two groups based on FTR development (FTR vs non-FTR group). Forty patients were diagnosed with FTR (30.1%). FTR patients were older (63.0 ± 10.4 vs 57.1 ± 11.0, respectively, p<0.05) with a high incidence of previous coronary artery disease (p<.006). Severe IMR, high pulmonary arterial pressure (PAP), and failed revascularization were signicant predictors of FTR development (p<.001, p<.005, p<.003, respectively). Low systolic left ventricle function was a predictor for FTR progression.


Introduction
Acute myocardial infarction directly affects myocardium viability and functionality and leads to structural remodeling and conduction changes seen immediately after an injury. The remodeling process results in valvular dysfunction and eventually hemodynamic changes. Ischemic mitral regurgitation (IMR) is a complication observed following the remodeling of the injured left ventricle. [1][2][3] IMR is de ned as mitral regurgitation following structural remodeling due to ischemic myocardial injury that is not directly related to valvular or sub-valvular pathologies such as mitral valve prolapse, endocarditis, autoimmune disease, medication, or direct radiation effect. The mechanism of IMR seems to be limited to lea et motion, mainly due to shortening and limited relaxation of the ischemic papillary muscles. IMR is often classi ed as type IIIb of the Carpentier classi cation introduced in 1983, involving a restricted lea et motion, most commonly the posterior lea et. 4 There can also be a widening of the annulus diameter of the failing LV and secondary lea et malcoaptation. Ischemic mitral regurgitation may develop after myocardial infarction in 11-59% of patients. [5][6][7] Functional tricuspid regurgitation (FTR) is the consequence of various structural and functional changes involving the tricuspid annulus and the right ventricle. It is mostly secondary to left-sided mitral pathology in the setting of mitral regurgitation, mitral stenosis, and aortic stenosis. 8-10 patients with FTR and IMR have a three-fold higher risk of developing heart failure and double the risk of mortality. [11][12][13][14][15][16] The prevalence of tricuspid regurgitation in relation to mitral valve disease was described in recent studies addressing general left-sided pathology. [17][18][19][20] The prevalence and natural history of FTR in the setting of mitral regurgitation following myocardial infarction was less known.

PLANNING OF THE STUDY
We conducted an observational cohort study using the computerized database of Emek Medical Center, a university-based secondary care center. Information regarding patient characteristics, demographic, and angiographic details were collected and analyzed using the Clalit health service database. Patients enrolled in the study were admitted to our heart institute for acute myocardial infarction from January 2012 to December 2014. Patients with primary mitral and tricuspid pathology and secondary pulmonaryrelated tricuspid regurgitation were excluded. The study population consisted of patients who developed mitral regurgitation following myocardial infarction. Patients were eligible for the study provided they met the inclusion criteria (Table 1s-

ECHOCARDIOGRAPHIC ANALYSIS
All echocardiograms were performed at the time of hospitalization using General Electric VIVID-75 s, VIVID 95, Philips CVx, and a portable bedside VIVID-1. The echocardiographic reports were prospectively reviewed independently by senior cardiologists using the Carestream Vue imaging system. In case of disagreement, an additional certi ed cardiologist was consulted. Echocardiographic images were assessed based on mitral and tricuspid insu ciency using an integrated approach taking into consideration valvular morphology, width of the proximal jet, color Doppler ow, jet area relative to the atrium, and hepatic and pulmonary ow patterns. LV ejection fraction (LVEF) was visually assessed (eyeball) in multiple acoustic windows and calculated using the biplane Simpson method according to the American Society of Echocardiography guidelines 2017. Systolic pulmonary artery pressures were calculated as the sum of the peak tricuspid regurgitation systolic gradient and the estimated vena cava central pressure (taking into consideration size and respiratory variation).

SAMPLE SIZE
The planned sample size is based on multiple variables such as IMR and FTR prevalence and a group difference of at least about 15% to demonstrate a statistical difference of 80% and alpha of 5% in a twosided test. We had to include a minimum sample size of 164 patients. Preliminary analysis reveals that one out of ve patients will be eligible for the study. Following these analyzes, we extended the duration of recruitment for two years.

ETHICS
The study was approved by Emek Medical Center Ethics Committee following the Helsinki Convention No 0105 − 17 EMC. Informed consent was waived due to the use of anonymous patient data and the retrospective nature of the study.

STATISTICAL ANALYSIS
A chi-square test was performed to analyze the association between the study groups and categorical variables. For continuous variables, we used the t-test (alternatively the Wilcoxon two-sample test).
Categorical variables were presented using frequencies and percentages. Continuous variables were presented using mean ± standard deviation. All con dence intervals are at the 95% level. TR progression was analyzed using the Mantel-Cox multivariant analysis and R-squared analysis. Multivariable models and logistic regression analysis were used to estimate the predictors of FTR. Differences considered statistically signi cant were at the 2-sided p level of 0.05. The statistical analyses were performed using SAS 9.4 software. A p-value < 0.05 was considered signi cant.

Results Of The Study
During the study period, 960 patients were admitted to the intensive cardiac unit due to acute MI. Of these, 275 patients were excluded from the study: 260 patients due to non-ischemic originating mitral regurgitation or previous known mitral regurgitation, ve patients due to primary mitral disease (two due to rheumatic heart disease, two due to mitral valve prolapse and one due to chest radiation), and nine patients due to secondary non-IMR-related tricuspid pathology.
Of the 685 eligible patients, 175 (25.6%) developed ischemic mitral regurgitation. Thirty-ve patients were excluded due to a lack of adequate follow-up TTE exams and poor imaging quality. Thus, 134 patients were in the nal study cohort (Fig. 1).
Forty patients (29%, 95% CI: 22.75-38.07%) developed functional tricuspid regurgitation (FTR) during follow-up. Demographic characteristics of the two groups revealed that patients who developed FTR were older (63.0 ± 10.4 and 57.1 ± 11.0, respectively, p < 0.05) with a high incidence of vascular disease either coronary (p < 0.006) or peripheral (p < 0.009). Failed coronary revascularization was a strong positive predictor of FTR development (p < .003). No gender difference was found between the groups. Smoking, hyperlipidemia, diabetes, and chronic kidney failure were not predictive of FTR development (Table 1).  (Table 1). We did not nd a signi cant statistical correlation between the infarct-related artery involved and the development of FTR. Our analysis did not cover the correlation of multivessel disease with the development of FTR. Pulmonary arterial pressure (mean) and left ventricular systolic function as estimated by ejection fraction appeared to have a signi cant effect on FTR progression (p < 0.05, p < 0.02, respectively) but did not affect FTR development (p < 0.5, p < 0.54, respectively) (Table 2s and Table 3s). The distribution of incidence events and their severity among IMR patients appear to be directly and linearly linked to FTR development and progression (Fig. 2). During follow-up, the development of new FTR was observed in almost third of the patients. FTR progressed in one-fth of patients within 1.67 years (1.8 ± SD). The development of FTR was strongly associated with elevated pulmonary arterial pressure and reduced left ventricular ejection fraction (LVEF) (Fig. 3). Atrial Fibrillation was found to be associated with TR severity 2 (χ2 = 0.96, p > .62).
Patients who developed FTR had a lower overall survival rate than patients who did not have FTR. Multivariable models to predict FTR in IMR patients indicated a statistically signi cant difference in survival between the two groups at the time to progression to severe FTR (Mantel Cox χ2 = 5.02, p < .025).
FTR progression was associated with heart failure at admission. There were statistically signi cant greater odds of FTR progression among patients with heart failure compared to patients with no heart failure at admission (OR: 8.09; 95% CI: 3.30-19.89, p < .001).

Discussion
The results of our study support recent reports of bivalvular deterioration in heart failure patients with reduced ejection fraction (HFrEF) and the interconnection between the mitral and tricuspid apparatuses.
Our study highlights a speci c group of patients with ischemic-related mitral regurgitation and its effect on the development of functional TR.
Multivalve involvement was described in the past regarding rheumatic heart disease and congenital heart disease and not extensively in the context of ischemic heart disease.
Myocardial infarction is still the most common cause of HFrEF and until recently it was thought that its major effect was directed toward left-sided pathology through an extensive remodeling process.
IMR is a common complication after myocardial infarction that requires adequate follow-up regardless of the appearance of clinical symptoms. Mild asymptomatic IMR usually tends to be neglected; however, our study demonstrates a linear relationship between the development of mitral regurgitation and the development of functional tricuspid regurgitation as a result of myocardial infarction. This linear connection, we believe, seems to involve volume and pressure overload, shifting from the left to the right side through the pulmonary vasculature.
Nearly one-third of IMR patients developed FTR during the ve-year follow-up period. Elderly patients with extensive myocardial damage were at particularly high risk. Almost one-fth of patients who developed IMR and LV dysfunction had a signi cantly high risk of FTR deterioration.
Bivalvular regurgitation, particularly with involvement of the tricuspid valve, greatly in uences the prognosis of heart failure, limits therapeutic options, and substantially increases the overall mortality.
IMR should be properly monitored and followed up regardless of symptoms. FTR should be assessed annually to avoid signi cant deterioration and to start prompt treatment for heart failure before the rst signs of heart failure appear.

Limitation Of The Study
Our study is designed in a retrospective fashion. The data were analyzed retrospectively based on computerized patient medical records. Echocardiographic images were assessed according to the ASE criteria.
Quanti cation of the severity of mitral and tricuspid regurgitation was based on qualitative grading (visual assessment) using parameters such as color ow, jet area; CWD jet; LV and RV size, function, and volume; PA pressure; MV and TV morphology; and LA and RA size. These assessment methods may be confounded by several technical and hemodynamic factors, including the eccentricity of the jets and atrial size. However, we cannot accurately apply quantitative or semiquantitative methods because this is a retrospective study.
The in uence of heart failure medical therapy and its contribution to valvular dysfunction could not be evaluated here. Larger samples are needed to evaluate these factors.

Conclusion
One-third of patients who develop ischemic mitral regurgitation (IMR) will develop functional tricuspid regurgitation (FTR) at a ve-year follow-up. The incidence and severity of FTR are highly in uenced by the severity of the IMR. Elderly patients with ischemic heart disease who had extensive myocardial damage and for whom revascularization failed are at high risk of IMR and FTR development. LV function signi cantly in uences FTR deterioration. Declarations 1. Ethics approval and consent to participate -The study was approved by Emek Medical Center Ethics Committee in accordance with the Helsinki Convention. Informed consent was waived due to the con dentiality of the patient data and the methodology of the study.

Consent for publication
-N/A 3. Availability of data and materials -The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Study design