For each vial in the phantom, accuracy errors (%bias) were determined by the relative differences in measured T1 and T2 times compared to reference values. Reproducibility was measured by the coefficient of variation (CV) of T1 and T2 measurements across monthly scans. Accuracy and reproducibility were mainly assessed on vials with relaxation times expected to be in physiological ranges at 3T.An International Society of Magnetic Resonance in Medicine/National Institute of Standards and Technology (ISMRM/NIST) System Phantom was scanned monthly on a 3T MRI scanner for 1 year. TR2 > 0.997). Baseline bias (and CV[%]) for T1‐IR, T1‐VFA and T2‐SE sequences were +2.0% (2.1), +6.5% (4.2), and +8.5% (1.9), respectively.A strong linear correlation between measured and reference relaxation times was found for all sequences tested (1 and T2 on the scanner were considered sufficient for the sequences tested. No longitudinal trends of variation were deduced, suggesting less frequent measurements are required following the establishment of baselines.The accuracy and reproducibility of T The T1 of a tissue is generally measured in parallel with dynamic contrast‐enhanced MRI sequences to quantify blood perfusion,2 has been used in applications such as disease diagnosis1 and T2 over time has seen the potential to monitor treatment responses.Quantitative magnetic resonance imaging (qMRI) utilizes MR methods that allow for measurements of physiological changes in physical units. Longitudinal  methods has also been assessed using the phantom: single center results found that accuracy and reproducibility of T1 varied pre‐ and post‐scanner upgrade.1 relaxation time, magnetic field strength, and sequence choice.The International Society of Magnetic Resonance in Medicine/National Institute of Standards and Technology (ISMRM/NIST) System Phantom is commercially available for the execution of qMRI QA programs. It can measure both clinical scanner properties  and a wide range of human relevant T1 and T2 accuracy and reproducibility acquired measurements at infrequent and/or over short time periods,1 and T2 times by longitudinally monitoring the parameters on a 3T MRI scanner. This was completed by imaging the System Phantom over the course of 1 year at monthly intervals using standardized sequences. Quantifying the changes in parameters such as T1 and T2 over time is essential for advancing the use of qMRI clinically .Previous longitudinal studies assessing T22.11‐weighted inversion recovery (T1‐IR) and variable flip angle (T1‐VFA) sequences were utilized for T1‐mapping, while a multi‐echo spin echo (T2‐SE) sequence was used for T2‐mapping. Sequence and parameter selections  was imaged monthly for 1 year (at least 2 weeks apart) using a 3T MRI scanner . Imaging was completed using a 20 channel Head/Neck coil. T2.21 and T2 sequences imaged the T1‐ and T2‐arrays embedded within the phantom, respectively. Each array contains 14 spherical (15 mm ID) vials filled with high purity water doped with either varying concentrations of NiCl2 (T1) or MnCl2 (T2). Nuclear magnetic resonance (NMR) IR methods have been used by NIST in the past to characterize these solutions under 3T and 20°C conditions  shell Figure . The T1 1 = 121 ms to 1884 ms and T2 = 30 ms to 79 ms.The phantoms’ arrays covered a large range of relaxation times, including those found in the human body at 3T: TTemperature of the surrounding deionized water in the phantom was measured both before and after each scanning session using an NIST‐traceable thermometer (supplied with the phantom).2.31‐IR dataset. These locations along with all datasets were imported into an inhouse‐developed Python script. This automatically positioned a 10‐pixel (∼9.8 mm) diameter circular region of interest (ROI) to be at the center of each vial and on the central slice of the respective T1 and T2 array. The average signal for each ROI was calculated and fit to the corresponding signal equations for the respective pulse sequences  was initially used to manually identify the center pixel locations of each array vial on the shortest time of inversion (TI) (35 ms) image of the T1 and T2 times, the %bias was calculated for each monthly acquisition and each vial using a comparison to the NIST measured reference vial value:To assess the accuracy error of the measured T1 and T2 times in the phantom, a coefficient of variation (%CV) was calculated using the individual vials’ mean (μ) and standard deviation (SD) (σ), calculated over the 12 monthly repetitions:To assess the reproducibility over the range of T31 and T2 arrays were imaged monthly using the respective T1‐IR/T1‐VFA and T2‐SE imaging sequences described in Table 1 and T2 value derived for each vial and their SDs are listed in Table The phantoms’ T1 and T2 measurements existed over the full vial range. Visualization of this variability can be seen in Figure 1‐IR had the smallest bias when all vials were included (median = +3.6%), compared to T1‐VFA (+5.0%) and T2‐SE (+5.8%) sequences. In terms of reproducibility, CV's over the full vial range  were calculated between recorded temperature and measured T1 for IR and VFA sequences , and for T2 (ρ = 0.007). Similar calculations showed that there was no clear relationship between systematic variations over time with the T1 or T2 measurements (ρ < |0.001|).Monthly changes in T41 and T2 relaxation time parameters, derived using a 3T MRI scanner.According to the quantitative imaging biomarkers alliance (QIBA), the accuracy and precision of a quantitative parameter determine its reliability to diagnose disease or monitor a tissue response.1 and T2 relaxation times at monthly measurement intervals. Accuracy and reproducibility results were comparable to previous studies completed using the same phantom type and similar sequences when including all vials.This study expands knowledge in the field of qMRI by longitudinally monitoring samples with a wide range of T2 analysis was at the recommendation of the manufacturer. They believe there were probable mixing or labelling errors that occurred during the manufacturing of vial 5. The issues with vial 1 most likely derived from the storage of the vials’ MnCl2 solution prior to manufacturing the phantom: It was stored in glass, and It is suspected that the Mn within plated onto its glass storage bottle.2 than expected. These issues have since been resolved by the manufacturer; however, this highlights the need for monitoring qMRI systems and phantoms.Note that the advice to remove specific vials from the T1 and T2 times. This was expected for the NiCl2 solutions in the T1‐array, with known minimal fluctuations within these temperature ranges.2 T2‐array solutions.ρ = 0.007).Due to limited scanner time availability, imaging could not be completed on the same day of each month. Instead, a time constraint of at least 2 weeks between imaging sessions was implemented, achieving a 4‐week average spacing. Temperature variations between 18 and 22°C had no observed effect on the measured T1 and T2 measurements in the human vial range of the phantom compared to the full range. The CV of T1 and T2 in this range for all sequences tested was less than 5%. Further, Bland–Altman plots in Figure 1‐IR, T1‐VFA and T2‐SE, respectively) were far less in magnitude (<20%) than those likely to cause erroneous outcomes if used in applications like tissue discrimination .Reproducibility was improved for T1‐IR, a gold standard T1‐mapping method, had a greater accuracy and reproducibility compared to T1‐VFA, in agreement with the literature.1, along with have increased sensitivity to B1‐inhomogenieity effects compared to IR and often require a correction technique.1‐VFA with 2–3 flip angles is preferred over IR methods due to shorter acquisition times.1‐mapping and compare scanner baseline %bias and reproducibility.TR2 > 0.997). It can be seen in Figure 1‐array, vials 13 and 14 had reference times of approximately 30 ms and 21 ms, respectively; shorter than that of the first TI (35 ms) used in the T1‐IR pulse sequence. Similarly, for the T2‐array, vials 13 and 14 had reference times of 7 ms and 5 ms; less than the shortest TE (10 ms) used in the T2‐SE sequence. Detecting shorter T1 and T2 times is often a challenge to scanner's gradient hardware and available sequence acquisition parameters.There was a strong linear correlation between the reference and measured vial relaxation times R2 > 0.9972‐array, signals for shorter T2 vials often approached the noise floor  was observed to have signal saturation. This was especially the case for larger flip angles (20°–30°). Thus, only magnitude images for FA's 2°, 5°, and 10° were used to calculate T1 for the saturated vials, similar to Keenan et al.  and 11 (−2.3%)  Figure . HoweverWith the high repeatability of the accuracy measurements observed, similar to Ihalainen et al., it is predicted that future measurements using this scanner would yield similar results.51 and T2 times on a radiotherapy dedicated 3T MRI scanner. Baseline bias (and CV [%]) for T1‐IR, T1‐VFA and T2‐SE sequences were +2.0% (2.1), +6.5% (4.2), and +8.5% (1.9) respectively. Shorter sample relaxation time vials had increased measurement instability; however, no systematic variations in accuracy over time were observed. For this scanner, it was recommended that only annual qMRI QA measurements need be taken combined with before and after any major scanner upgrades following baseline establishment. Further investigations are required to determine deviations in T1 and T2 when using department‐specific sequences and to find the cause of the signal saturation fluctuations in T1‐VFA acquisitions for shorter reference time vials.In conclusion, our study found high accuracy and long‐term reproducibility in physiologically relevant TCertain commercial equipment, instruments, or materials are identified in this paper in order to specify the experimental procedure adequately. Such identification is not intended to imply recommendation or endorsement by NIST, nor is it intended to imply that the materials or equipment identified are necessarily the best available for the purpose.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.Madeline Carr performed the measurements, analyzed the data, and wrote the manuscript with support from all the authors. Kathryn Keenan, Robba Rai, Peter Metcalfe, Amy Walker, and Lois Holloway were involved in experiment planning and supervising the work.Supporting informationClick here for additional data file.


Mitral valve disease surgery is an evolving field with multiple possible interventions. There is an increasing body of evidence regarding the optimal strategy in secondary mitral regurgitation where the pathology lies within the ventricle. We conducted a systematic review to identify the benefits and limitations of each surgical option.  A systematic review of the literature was performed to identify pertinent randomized controlled trials (RCTs), propensity-matched observational series, and meta-analyses which were considered initially and followed by unmatched observational series using the MEDLINE, Ovid EMBASE, and Cochrane Library.  We identified 6 different strategies for treating secondary mitral valve regurgitation: mitral valve replacement, restrictive mitral annuloplasty, surgical revascularization , subvalvular procedures , and procedures directly targeting the mitral valve (edge-to-edge repair and anterior leaflet enlargement) alongside transcatheter heart valve therapy. We also highlighted the role of left ventricular assist devices in the management of this condition. The benefits and limitations of each intervention are highlighted.  There is currently no unanimous and shared strategy for the optimal treatment of patients with secondary IMR. The management of patients with secondary mitral regurgitation must be entrusted to a multidisciplinary Heart Team to ensure ideal intervention and patient matching for the best outcomes. Following the recommendations of the current guidelines, the use of mitral valve replacement (MVR) for secondary mitral regurgitation (S-MVR) has been widely adopted by the surgical community, and the vast majority of patients currently receive valve-sparing surgery to replace the ischemic mitral valve , 2. In tResistance among surgeons to the use of subvalvular repair (SR) combined with RMA can be explained, at least in part, by the fact that clinical benefit of additional handling the subvalvular apparatus which has been reported in observational studies –8 has beWe systematically reviewed the literature to identify pertinent randomized controlled trials (RCTs), propensity-matched observational series, and meta-analyses that were considered initially and followed by unmatched observational series.The criteria for considering the eligibility and inclusion of manuscripts in the study were patients aged ≥ 18 years and the mechanical intervention including mitral valve replacement, repair, and transcatheter mitral valve therapy.Exclusions are consisted of studies involving animal or pediatric studies and nonprimary studies . Another exclusion criterion for manuscripts included the inability to obtain a translation or when articles were published only as abstracts.The search was carried out on February 1, 2021, using the following databases: Ovid MEDLINE (1946 to the present), Ovid EMBASE (1947 to the present), and the Cochrane Library .Three investigators  searched papers published between January 1, 1987, to present using the following terms: “secondary mitral regurgitation,” “ischemic mitral regurgitation,” and “functional mitral regurgitation.” These terms were coupled with « mitral valve replacement », « mitral valve repair », “restrictive mitral annuloplasty,” and “transcatheter heart valve implantation.” For completion, the following terms were added: subvalvular repair, papillary muscle approximation, papillary muscle relocation, and papillary muscle sling. Randomized controlled trials (RCT), propensity-matched observational series, and meta-analyses were considered initially and followed by unmatched observational series. Pertinent abstracts were reviewed, and data were extracted independently for all enclosed manuscripts. The correct progression of the study was verified by a fourth investigator (F.N.) to ensure accuracy. The PRISMA Chart and PRISMA 2020 Checklist Item are enclosed in Extracted data were transposed onto a table with the following subheadings: study completion date, number of patients, follow-up period, primary and secondary end points, and study findings.The Cochrane Risk of Bias assessment tool was used for randomized controlled trials. Assessment of bias of the RCTs showed a low risk of reporting, detection, or attrition bias as the outcomes were well reported and the loss to follow-up was low.Given significant heterogeneity in study design across identified studies, formal data synthesis via meta-analysis was not conducted. Hazard Ratios (HR) with 95% CIs were calculated where possible for primary and secondary endpoints as shown in Tables 1This was the largest series of mitral valve replacement and repair operations reported which considered the various mitral valve repair techniques, the reported results for each procedure, and evaluating indications, clinical uses, clinical evidence, and limitations. Follow-up of patients with severe left ventricular function dysfunction for which the use of a left ventricular assistance device (LVAD) was indicated was also included.In the past few years, the use of mitral valve repair has greatly exceeded the use of replacement. However, recently, a randomized trial established the superiority of replacement across a spectrum of patients with severe ischemic mitral regurgitation , 2. The P.0001) and partial chordal sparing mitral valve replacement  at postoperative discharge, preservation of the entire subvalvular apparatus may determine a continuous and progressive reduction of LVEDV that was noted to have fallen further only after 1 year compared to partial preservation . Moreover, compared to partial preservation, the left ventricular end-systolic volume (LVESV) continued to decline over time in patients who received total chordal preservation , but no notable changes were observed in recipients of partial chordal sparing .The improved outcome using the total chordal preservation surgery compared to posterior leaflet only is almost certainly due to its superior long-term reduced left ventricular chamber size and systolic afterload . IndividOnly 1 published RCT has compared outcomes between complete preservation of all chordal structures and mitral valve repair. The CTSN trial  recruited 251 patients in 23 countries. The primary outcome was the degree of left ventricular reverse remodeling, which was defined as the LVESV at 1 year after randomization. An interim analysis at 2 years reported no significant between-group difference of left ventricular reverse remodeling  [n = 416) or MV replacement (n = 184) reported a long-term risk of death that was 35% higher in the replacement group than in the repair group (hazard ratio 1.352 (95% CI 1.131–1.618)) [While awaiting the outcome of the CTSN trial at more than 2 years, there is currently a substantial body of exhaustive evidence to support the use of chordal sparing MV replacement operation, as it appears to offer an additional benefit on mitral regurgitation recurrence over the mitral valve repair , 18. On –1.618)) .P = 0.17; HR, 1.2; 95% CI, 0.7–1.9; P = 0.52) [P = 0.34). The survival benefit of chordal sparing operations was less evident in patients younger than 60 years of age. In recipients of mitral repair, the survival was 81% compared with 55% for those who received valve replacement (P = 0.0001) [In the past 20 years, 2 largely independent studies have supported any definitive conclusions about the relative effects of the two surgical procedures on survival. One study included 370 patients and reported an overall 6-year survival that was not statistically different between MV repair and MV replacement  .The major concern with the use of mitral valve replacement without preservation of valve apparatus during the surgery of IMR is the increased risk of reduced postoperative ejection performance. This pathophysiological condition has been associated with the rapid increase in systolic wall stress leading to the elimination of the low-impedance pathway for ejection into the left atrium and to ventricular dysfunction caused by breaking of the mitral valve apparatus.2 (P < 0.05) in the chordal preservation group and increased from 89 ± 9 to 111 ± +12 g/cm2 (P < 0.05) in the chordal transection group. Ejection fraction was unchanged before and after mitral valve surgery (from 0.63 ± 0.01 to 0.61 ± 0.02) in patients who received chordal sparing operation instead showing a marked reduction in those without the use of chordal sparing (from 0.60 ± 0.02 to 36 ± 0.02).Rozich et al.  showed t2, rather than LVEDD greater than 64 mm and LVESD greater than 54 mm, significantly reduces the risk of persistent or recurrent MR when chordal-sparing MV replacement is used [However, the incidence of serious ventricular function problems can be significantly reduced by well-advised patient selection and choice of surgical technique for IMR correction. In young patients, consideration should be given to avoiding total chordal sparing mitral valve replacement in favor of RMA with subvalvular repair if they have preoperatively echocardiographic asymmetric leaflet tethering, posterior leaflet tethering angle of <45°, tenting height < 11 mm, absence of a basal aneurysm/dyskinesis, no greater degree of LV dilation (LVEDD < 60 mmHg), and LV sphericity index . Moreove is used .Introduced in mitral surgery in the 1980s , the useThe mechanism of restrictive mitral annuloplasty, by bringing the leaflets closer together, is to reduce the anteroposterior diameter to minimize the tenting area and favor normalization of the coaptation length. A consistent addition to appropriate-sized annular correction with RA is to reduce the LVES dimension or volume. Therefore, the abolition of MR and the decrease of the size of the left ventricle consequently favor reduced stress of the LV wall, inducing an improvement of LV reverse remodeling .In patients with moderate IMR, the use of RMA combined with CABG remains a point of discussion. Penicka and colleagues demonstrated that improvements in global and regional wall motion, as well as reverse LV remodeling after CABG alone, are indicative of viable myocardium. In their series of patients with moderate IMR and who received CABG alone, the resolution of MR after surgery was associated with more viable segments and less LV dyssynchrony at baseline. The role of CABG and the presence of viable myocardium are emphasized in the results of the CTSN trial where 25% of patients did not undergo CABG operation thus eliminating the possibility of improved regional wall motion. Hence, the RMA was rendered ineffective leading to the inability of the leaflets to establish the appropriate zone of coaptation to reduce the tenting height and tenting area , 2.Tables The most widely used dogma in RMA is to downsize by 2 ring sizes . The overcorrection by undersizing MV repair and the technique using rigid versus partial bands or flexible complete rings affect MR recurrence rates. Although some evidence has shown that recurrent MR is more frequent in recipients of partial bands or flexible complete rings , 28, 29.The concept of “the tighter, the better” tenaciously advocated by most surgeons , 30, 31 The largest echocardiographic series report an MR recurrence range from 15% of patients at 6 months to 56.8% of patients at 24 months , 23. TheP.097; mean change from baseline, −16.1 ml and – 19.1 ml, respectively). Similarly, Nappi et al. [X; P = Y; mean change from baseline, − X ml and – Y ml, respectively).Kron et al.  showed ti et al.  found a The use of restrictive mitral annuloplasty alone is the valve repair operation for which there is the most evidence derived from individual studies. Several reports have compared the RMA with mitral valve replacement . All stun = 416) versus partial or total chordal sparing operation (n = 106) over a 20-year period (from 1986 to 2006) increased in later years (from 2000 to 2006). The use of MV repair vs. MV replacement seemed to be related to surgeon choice and preference highlighting that the judgment of the operating surgeons was by far the most important factor determining the choice of repair versus replacement . Nevertheless, the severity of MR , P = 0.0001) was a factor influencing the choice of surgeon with a higher percentage of MVR compared to RMA in patients with moderate to severe MR. Additionally, patients selected for replacement tended to have better ejection fractions , P = 0.0007) [The Duke group  showed t 0.0007) .The main limitation to RMA is the excessive geometric distortion of the left ventricle and an accentuating tethering of the leaflets with the unfavorable remodeling of mitral leaflets . SeveralThere is currently no single surgical management of moderate ischemic mitral regurgitation at the time of CABG which is based on a widely diffused consensus-oriented towards a single procedural direction. Two points of view are compared.Some experts believe that revascularization alone for moderate ischemic mitral regurgitation can reduce rates of mitral regurgitation. The principle is related to the fact that there is an improvement in regional and global left ventricular function and geometry after CABG , 44.The detractors of this choice support the use of RMA combined with CABG and therefore intervene directly on the MR. In this case, further unfavorable remodeling can be avoided, and the risk of heart failure decreased , 46.Observational studies addressing the differences in the MR recurrence of the 2 surgical strategies.(CABG +/- RMA) and a nonsignificant tendency to better event-free survival for the RMA are discordant and usually have major methodological or sample-size limitations. The reliability of retrospective cohort studies, even if improved by a statistical analysis based on the propensity score, is bound by variables that are often not measurable. The most important is the surgeon's decision to consider with surety, a safety margin to permit restoration of the IMR after myocardial revascularization which leads to a favorable remodeling of the left ventricle , 44.P = 0.316), LVESV (P = 0.427), and left ventricular function (P = 0.204). The assessments of heart failure using the Minnesota QOL score and BNP measurements were not discriminatory of better improvement with either CABG alone or combined strategy.Four recent randomized clinical trials –48 of moP < 0.001). There was no significant survival benefit for the patients who underwent combined CABG plus RMA as compared with those who CABG alone , 0.45 to 1.83; P = 0.78). Likewise, there were no differences between the 2 groups in New York Heart Association functional class, LV ejection fraction, survival, or major adverse cardiac and cerebrovascular events at 2 years. The investigators noted that the RMA group had a longer hospital stay after surgery, a higher incidence of postoperative supraventricular arrhythmias during the first year , and more postoperative neurologic events , which included metabolic encephalopathy, seizures, transient ischemic attack, and stroke [In a study from the National Heart, Lung, and Blood Institute-sponsored Cardiothoracic Surgical Trials Network (CTSN) , CABG ald stroke .P < 0.001). In RIME trial [Both POINT and RIME  , 46 reven = 1515) or CABG combined with mitral valve surgery (n = 964). The authors reported no benefit for long-term survival  0.90 to 1.14; P = 0.73); however, patients who had RMA decreased the MR grade more than those who underwent CABG-alone operation . NYHA class improvement was not statistically demonstrated  [Two meta-analyses pooled data from RCTs, and large observational studies have compared the use of RMA plus CABG-to-CABG alone , 50. Aga = 0.30) .P = 0.014). Patients who had coupled CABG and MV surgery showed a significantly lower incidence of moderate-to-severe MR at follow-up . Late mortality was similar between the surgical approaches in RCTs (hazard ratio (HR) 1.20, 95% CI, 0.57-2.53) and OS . There were no significant differences in echocardiographic outcomes [The only comparative meta-analysis of 4 RCTs and 15 observational studies (OS), with clinical and echocardiographic endpoints, has compared patients with moderate-to-severe IMR who received CABG alone and those who underwent CABG and mitral valve surgery (18 RMA and 5 MVR). The use of combined CABG and MVS was not associated with an increased perioperative mortality (RCTs: relative risk (RR) 0.89, 95% confidence interval (CI), 0.26-3.02; OS: RR 1.40, 95% CI, 0.88-2.23) but reduced cardiac events  for the RA  or improve survival , 51. ConSubvalvular procedures are commonly used in addition to annuloplasty with the purpose to recondition both the functionality and configuration of the subvalvular apparatus. The main effect of subvalvular repair is the reduction of tethering forces exerted on both leaflets of MV due to lateral and posterior dislocation of PMs. Unlike the RMA which can indirectly influence the recovery of LV geometry through a favorable reverse remodeling, subvalvular repair has a targeted action in improving left ventricular geometric disorder. There are different surgical techniques for handling the subvalvular apparatus referring to peculiar concepts, and each procedure should be selected considering the direction of MV tethering . Here, we will discuss three techniques with possible variations: the papillary muscle approximation, the papillary muscle relocation, and the ring + string procedure , 60–62 .The principle that strengthens the three main surgical techniques of handling the papillary muscles is the ability to reconfigure the correct geometry of the left ventricle that has been compromised by the vector displacement of the PMs .Indeed, the ischemic mitral regurgitation being a pathology that alters the geometry of the MV compromises three main dimensions: the anteroposterior diameter of the annulus, the tenting area, and the interpapillary muscle distance.The objective in using the subvalvular correction procedure in association with RMA not only guarantees correction of the interpapillary muscle distance directly but allows monitoring of overcorrection through the annuloplasty, to develop mitral valve stenosis as complication , 64.The concept of the role of the movement of PMs alongside three directions  has been accepted by the community of cardiologists and cardiac surgeons with the result of directing both the surgical indication and the choice of treatment , 66. The(1) Clinical Use. Initially described by Hvass et al. [s et al. , the raps et al.  considerWe use a 4-0 Goretex suture with pledget the anatomical for PM classified as I, II, and III and a 4-0 Goretex prosthesis for types IV and V –4. Wakas(2) Clinical Evidence. In PMA RCT, we evaluated the effect of PMA on long-term outcomes in 96 patients who had moderate to severe mitral regurgitation. The 48 patients undergoing combined subvalvular repair and RMA had not significantly better 5-year survival rate than those (n = 48) whose IMR was managed with RMA alone , 0.35 to 1.68, P = 0.502). No statistically significant difference in moderate-to-severe MR recurrence was noted between the 2 groups after 2 years (RMA 13.2% vs. PMA 15.0%); However, at 5-year follow-up, we found a statistically significant difference between the proportion of surviving patients with recurrence of severe MR . At 5-year follow-up after surgery in recipients of restrictive mitral annuloplasty plus subvalvular repair, there was an increase in further rehospitalization for heart failure that was lower to those who had received RMA alone . During a follow-up period of 5 years, the incidence of MACCE was significantly reduced in the PMA group in the last year of follow-up  0.02 to 0.49, P = 0.004) [n = 26) or with (n = 34) left ventriculoplasty. During a median follow-up period of 3.4 years, the linearized mortality rate  was comparable in patients with combined surgery versus isolated RMA (P = 0.61 and 0.92). The subvalvular repair without LV reconstruction was used for 26 patients. This surgical strategy was independently associated with a reduced risk of grade ≥ 2+ MR recurrence compared to subvalvular repair plus left ventriculoplasty or RMA alone (P = 0.09)  .P = 0.428). At the final follow-up, the New York Heart Association (NYHA) function class was 1.57 ± 0.62 in the annuloplasty group and 1.45 ± 0.57 in the combination group; there was no significant difference in NYHA function class between the first and final follow-up (P > 0.05)  .P = 0.013 and parameter estimate of -0.104 with standard error of 0.045; P = 0.035). Moreover, the IPMD change was independently associated with a change in LV end-systolic dimension  resulting in a better improvement of IPMD that is linked with the favorable reverse remodeling [Recently, the pivotal role of IPMD has been shown in a report from the Osaka Rosai Hospital . The autmodeling  (Table 5(3) Limitation. Criticisms concerning the use of the PMA procedure are justified when we analyze the results in depth. In fact, at 5-year follow-up, we found 23.8% of patients who had a rehospitalization for heart failure and 27% of patients revealing moderate to severe mitral (preoperative EROA 41.0 ± 5.3 vs. a postoperative EROA 41.1 ± 1.1). The reasons for this adverse result can be partially explained by the fact that the clinical benefit of additional PM approximation is multifactorial. Although surgery of papillary muscles may seem appropriate in patients with dilated left ventricles, with large areas of scar tissue formation, dyskinesia, or a basal aneurysm, prospective trials on the use of subvalvular surgery of mitral valve are currently insufficient to highlight improvements in postoperative tethering among patients with LV lateral wall dysfunction, persistent LV dyskinesis, and severe alteration of LV sphericity as well as predominant lateral displacement of both leaflets due to symmetric tethering [ethering , 56.In recipients with combined restrictive mitral annuloplasty and subvalvular repair who had severe and proportionate mitral regurgitation, the surgery may not directly improve the prognosis. In this 23.8% of patients, the ischemic cardiomyopathy is the leading disease often independent by the degree of mitral regurgitation, showing an adverse global and localized left ventricular reverse remodeling at the five-year follow-up . Finally, despite a few improvements in adverse reverse left ventricular remodeling (mean compared to baseline −6.5 ± 0.7 at 5 years), 2 women (5%) undergoing combined surgery required further surgical intervention between 30 days and 5 years. Women with IMR who have combined subvalvular surgery experienced higher mortality after MV surgery than men despite no significant differences in the degree of reverse LV remodeling between sexes. This result seems to coincide with the subanalysis of the female gender subgroup of the CTSN RCT [(1) Clinical Use. After the initial experimental experience of Liel-Cohen in 2000 [ in 2000 , Kron et in 2000  firstly Briefly, 3-0 Prolene suture is passed through twice through the fibrous portion of the posterior papillary muscle tip and brought down to mitral annulus just posterior to right the fibrous trigone, drawing the PMPM tip closer to the annulus. The final position of the tip of the posterior papillary muscle was considered by determining the point at which the coaptation of the leaflets in the plane of the mitral annulus occurs.Recently, Harmel et al.  used an (2) Clinical Evidence. The pivotal series reported no short-term failures in two months, and the recipients of the relocation did not require the need for a new intervention with the subvalvular option [P = 0.82)). Compared with the RMA, the subvalvular repair has a better 5-year freedom from cardiac-related event rate (83% ± 2.1% and 65.4% ± 1.2% (P < 0.001)). Only 1 RCT studied 101 patients comparing the combined papillary muscle relocation and restrictive mitral annuloplasty with RMA alone. During a maximum follow-up period of 1 year, the 51 patients undergoing subvalvular surgery had a significantly better 1-year survival rate than those whose ischemic mitral regurgitation was managed with isolated RMA (0% vs. 1 0% (P = 0.025)) and a significant tendency to better event-free MR recurrence (98% vs. 86.7% (P = 0.045)) [r option , 71. One 0.045)) , 71 (Tab(3) Limitation. Very few candidates with postero-basal myocardial infarction and asymmetric tethering have contraindications to PM relocation. The technique has a low incidence of severe complications and a good capacity for maintaining the normal three-dimensional relationship between the posterior papillary muscle tip, leaflets, and the annulus. Importantly is that to minimize mitral valve tenting, the relocation of both PMPM is indicated [ndicated , 70. Altndicated , 70, 72 The biomechanical profile of the subvalvular repair has now been extensively studied, and the use of papillary muscle approximation or papillary muscle relocation does not increase perioperative risk. Furthermore, unlike PM approximation, PM relocation could result in potential adverse biomechanical effects. The latter does not address the multidirectional displacement and migration of the PM resulting in increased tension at the level of the posterior trigone and papillary muscle , 72–79. Introduced in mitral valve surgery in the 2000s , the rin2(1) Clinical Use. Restrictive mitral annuloplasty is performed using an undersized ring through the choice of 1 to 2 sizes in relation to the intertrigonal distance. Firstly, a horizontal aortotomy is executed, and a double-armed Teflon pledgeted 4-0 expanded polytetrafluoroethylene (e-PTFE-Goretex) suture (STRING) is going through the head of the papillary muscle. Secondly, the stitch is passed from the LV cavity through the aorto-mitral continuity below the commissure between the noncoronary and left coronary aortic cusps and then exteriorized. In patients with ischemic MR due to asymmetric tethering, local LV remodeling , the use of a single string for the PMPM is enough. In patients with nonischemic cardiomyopathy or ischemic MR characterized by global LV remodeling, the use of 2 strings, one for each papillary muscle, is more suitable [suitable .The theoretical base for the surgical technique of the edge-to-edge leaflet coaptation was described by Alfieri et al. who showed that the creation of a double orifice mitral valve confers a prompt decrease in the severity of MR . The benThe edge-to-edge operation is considered for patients with MR secondary to ventricular disease, due to nonischemic or ischemic remodeling. Since there are similarities in the pathophysiology of the geometrical alteration between two phenotypes, the procedure is applicable to both conditions considering the grade of coaptation depth or tenting height (TH). The best results the Alfieri procedure yields are related to patient selection. Therefore, during the handling of the mitral valve, the evaluation of the distance from the annular plane of the MV to the leaflet coaptation point should be considered. In fact, this parameter represents the degree of tethering of the mitral leaflet, regardless of the LV function and tethering shape , 82, 83.Patients who are scheduled to receive the edge-to-edge operation should undergo transthoracic echocardiography to assess the mechanism and severity of mitral regurgitation for choosing the site of the approximating stitch. The phenotype identified in symmetric tethering is characterized by a central jet located between A2 and P2 scallops of mitral valve leading for a central edge-to-edge by creating a double-orifice MV configuration. When the regurgitant jet is located at the posterior commissure, as in some cases of ischemic MR, a commissural edge-to-edge suture is applied, resulting in a single orifice MV with a relatively smaller area. The length of the suture is always kept as short as possible to minimize the risk of postoperative MV stenosis: in most patients between a few millimeters and 1 cm. A complete rigid or semirigid prosthetic ring is invariably implanted and is usually 1 or 2 sizes smaller than the anterior leaflet surface , 84–86.n = 26) or ischemic (n = 51) functional mitral regurgitation and with follow-up duration exceeding a mean of 18.4 months. RMA combined with the edge-to-edge procedure was used in 54 recipients (TH > 10 mm) while isolated RMA in 23 (TH < 10 mm). The 54 patients whose mitral regurgitation was managed conservatively using associated edge to edge had a significantly better 2.7-year survival rate than those who underwent isolated RMA . Among patients who had MR recurrence ≥3 + /4+, the rate of 3.7% received a concomitant edge-to-edge repair while 21.7% is undergoing isolated RMA (P = 0.03). Although freedom from repair was 95 ± 3.4% and 77 ± 12.1%, respectively (P = 0.04), however, the absence of the edge-to-edge was the only predictor of repair failure (P = 0.03). In both groups, LV end-diastolic dimensions decreased (67 to 58 mm after RMA and 68 to 62 mm after RMA with edge-to-edge procedure), and NYHA functional class improved after surgery. Of note in patients undergoing concomitant mitral annuloplasty with edge-to-edge repair, larger rings were used to avoid stenosis during the edge-to-edge suture [The survival benefits associated with the use of combined RMA with edge-to-edge procedure over RMA alone were established in a landmark paper from the San Raffaele University Hospital almost 15 years ago. The improved outcome using the edge-to-edge suture is almost certainly due to its superior long-term freedom from MR recurrence. Although several studies have reported substantially disappointing results using an Alfieri stitch, however, these reports are focused on the edge-to-edge procedure without concomitant RMA. Pioneer series evaluated the effect of MV surgery in 77 patients who had moderate to severe idiopathic (e suture .P = 0.5); univariate HR 2.3; 95% CI, 0.9 to 6.1; P = 0.01; multivariate HR 1.8; 95% CI, 0.6–4.8; P = 0.2) [In another report, 54 patients with moderate to severe functional mitral regurgitation (FMR) due to nonischemic idiopathic dilated cardiomyopathy were studied. During a median follow-up period of 4.2 years, the use of the edge-to-edge technique, despite favoring reverse LV remodeling, was not associated with a reduced risk of death (77.7 ± 9.9% associated edge-to-edge technique to RMA and 87.7 ± 5.8% isolated RMA (P = 0.2) .Echocardiography-based follow-up studies have identified that the edge-to-edge procedure may determine a reduction in the area of the MV, leading to mitral valve stenosis which can be clinically relevant. We have used this procedure in patients with ring sizes greater than 36 mm and with a tenting height > 10 mm. Usually, we used a 18 mm Hegar probe number to measure the anterior commissure and 17 mm for the posterior one, respectively . The carAnterior leaflet (AL) enlargement was initially described in the French correction to relieve the restricted leaflets' motion in systole and diastole in patients with mitral valve rheumatic disease (Carpentier type IIIa) . SubsequWe use the autologous pericardium patches in maintaining an optimal quality of life free from long-term anticoagulant treatment in patients with Carpentier type IIIa and IIIb insufficiency –93. We rThe anterior leaflet was measured using a ring sizer, and if the degree of leaflet retraction did not safely allow the downsizing of the annuloplasty ring by two sizes , the anterior leaflet augmentation technique was chosen . To avoiThe technique of anterior leaflet augmentation has been shown to be safe and reproducible, and the enlargement involved not only the anterior leaflet (Carpentier types IIIa and IIIb) but also the commissural areas (Carpentier type IIIa). The procedure may be coupled with cutting secondary chordae to reduce the effect of leaflet tethering cause by the displacement of PMs –99.AL enlargement is effective when the TH does not exceed 8 mm and with LV chambers not very enlarged (LVESD < 50 mm and LVEDD < 60 mm) in which a favorable ventricular remodeling is implemented by optimal CABG operation. In the case of an increased risk of persistent tethering, the procedure is not indicated , 34, 56.The use of cutting secondary chords by performing the “chordal cutting” has been proposed as a surgical handling of mitral valve for decreasing leaflet tethering and mitral regurgitation in patients with ischemic mitral regurgitation –99. The n = 43) compared to those who were managed with the use of conventional restrictive mitral valve repair. In patients who underwent the chordal cutting procedure, authors recorded a greater reduction in tent area than those who received RMA alone . Surely in recipients of chordal-cutting, a greater mobility of the anterior leaflet occurred, leading for a reduction in the distance between the free edge of the anterior mitral valve leaflet and the posterior left ventricular wall .Boger et al.  reportedP = 0.03) and multivariate Cox regression analysis (P = 0.03). In addition, the use of chordal cutting did not adversely affect postoperative left ventricular ejection fraction .The major finding of Boger's study revealed that patients who received RMA alone had more recurrent mitral regurgitation during 2 years of follow-up as demonstrated with univariate  has proven safety and effectiveness in patients with symptomatic moderate to severe secondary MR , 5. ThisIn COAPT  and MITRThe detailed analysis of the results of the RCTs however revealed two distinct phenotypes of patients suggesting the possibility of categorizing proportionate and disproportionate patients thus highlighting an inhomogeneous response after transcatheter mitral valve repair , 101.The proportionate phenotype , 101 in The unevenness of the results suggests great caution in extending THVT to categories of patients indicated as intermediate and low risk –104.Existing evidence has shown that secondary IMR is a serious disease, and patients with worsening left ventricular dysfunction may not respond to medical therapy and conventional mechanical intervention procedures, thus showing a very poor prognosis.Patients who have worse left ventricular remodeling that can lead to further deterioration of LV function and recurrence of MR have an unfavorable pathological substrate. For these patients, the use of the transcatheter approach, while maintaining the advantage of avoiding the perioperative risks of the standard intervention, may sometimes not be decisive , 5.The results of the two recent randomized studies MITRA-FR  and COAPProcedures for using LVAD have improved over the past decade, and the survival of patients benefiting from the LVAD implant has steadily improved in parallel with the technological advances of the armamentarium platform that supports the LVAD implant procedure. The work of the multidisciplinary Heart Team has improved patient selection, perioperative management, and outpatient treatment.Patients with severe end-stage heart failure who were managed with the use of ventricular assist devices demonstrated better outcomes than those who received a GDMT, as evidenced by the dramatic improvement in life expectancy , 106.Today, the results after LVAD implantation show survival that reaches approximately 75% at 1 year . SometimPatients with secondary IMR who have received LVAD are at risk of developing thromboembolic events related to anticoagulation, bleeding, and infection. LVAD implantation should be considered prior to deterioration of right ventricular function .The unanimous and shared strategy for the optimal treatment of patients with secondary IMR has not yet been achieved. The first-rate management for these patients remains drug therapy and combined resynchronization with device implantation as recommended by the guidelines –104. PatThe management of patients with secondary mitral regurgitation must be entrusted to a multidisciplinary Heart Team, whose work is carried out by specialists in different fields: heart failure, interventional cardiology, cardiology of arrhythmias, cardiac surgery, and treatment of heart failure. The coordinated work of the team is committed to orienting the patient towards the best possible treatment option –104 Fig.Patients with disease progression and life expectancy < 1 year and with severe comorbidities should be directed to palliative therapy –104.The clinical presentation of the patient may be variable and not limited solely to FMR surgery. So, a concomitant procedure such as CABG operation, treatment of severe tricuspid regurgitation, and direct mechanical intervention to cure cardiac arrhythmia may be necessary.Mitral valve repair has long been considered the primary option for clinical benefits supported primarily by retrospective cohort studies. A veil of uncertainty about the use of MV repair has been lifted by the evidence reported in the RCTs , 2, 47 oThe MV repair option is not indicated for the subgroup of patients who are at high risk for reverse left ventricular remodeling and/or recurrent MR. For patients with a low degree of geometric distortion , RMA with or without anterior leaflet augmentation is indicated if combined with complete revascularization of the ischemic myocardium in the presence of nonextensive postscarring infarct. Generally, the extension of the infarct zone into the lateral territory, perfused by the circumflex artery, leaves more extensive scars thus responsible for an accentuated apical tethering. In these patients, the TH exceeds 8 mm, reducing the chance of RMA success. A combined RMA procedure with subvalvular repair is recommended in patients with greater geometric distortion of the LV chambers . In this circumstance, the other procedures that can be considered in addition to the RMA are the edge-to-edge procedure and RING + STRING. Although these techniques may improve outcomes in terms of no recurrence of IMR and reverse LV remodeling, however, they have not been widely used leading to scarce evidence as reported in long-term follow-up.For patients with moderate S-MVR, the use of an RMA associated with CABG operation is indicated in case of extensive postinfarct scars also in combination with a subvalvular repair if the geometric distortion of the ventricle is accentuated as in the apical tethering of the leaflets , 24, 110The use of the MitraClip procedure is recommended in patients with disproportionate secondary mitral regurgitation in which severe MR is coupled with nonseverely dilated left ventricular chambers , 96. AltThe use of subvalvular repair associated with RMA is the new procedural key to achieve efficacy in the treatment of secondary mitral regurgitation in both patients with asymmetrical tethering and in those with symmetrical tethering. Restrictive mitral annuloplasty associated with cutting chordal procedure and/or to anterior mitral leaflet enlargement may be suitable for patients with moderate geometrical abnormalities of mitral valve and with nonsevere left ventricular dilatation.


Meerman et al. carefully examined the issue of radiation exposure related to long-distance space travel, with a particular focus on its cardiovascular effects. The pathogenic mechanisms that can lead to radiation-induced cardiovascular disease (RI-CVD), including myocardial remodeling and fibrosis, atherosclerosis, and microvascular damage, are elucidated. In addition, potential countermeasures and protection methods are reported, from physical shielding to pharmacological means.More than 50 years after Neil Armstrong first set foot on the moon, space travel is gaining new popularity. However futuristic this topic may seem, humankind will probably undertake space travel on a broader scale in the upcoming centuries or even decades. This means that people will need to learn how to cope with challenges related to microgravity, hypoxia, disrupted circadian rhythms, and radiation exposure. The evidence raised from radiation exposure for curative aims and nuclear disasters has led the scientific community to recognize and understand its multiple pathogenic effects on the human body's various systems, including cardiovascular one. Accardi et al. showed that BIS-measured extracellular fluid was higher in patients with heart failure compared to healthy individuals and that this result was consistent with the echocardiographic parameters of fluid status, such as inferior vena cava size. It was suggested that this tool may contribute to the risk stratification of patients with heart failure and facilitate clinical decision-making both in the clinic and potentially at home. Another tool of increasing study is seismocardiography (SCG), which allows the non-invasive estimation of stroke volume, cardiac output, and myocardial contractility through cardiac and blood-induced motions transmitted to the chest surface as vibratory phenomena. In an original research article, Morra et al. show that SCG can quantify cardiac kinetic energy and continuously track its changes during an acute myocardial infarction and subsequent reperfusion. As it has already happened for atrial fibrillation with smartwatches, thanks to its ease of use SCG could potentially help in the follow-up of heart failure patients monitoring their myocardial mechanical activity.The future is entering our lives not only by enhanced horizons but also with new technologies. Bioimpedance spectroscopy (BIS) is a non-invasive method that relies on the different electrical impedance of biological tissues to assess fluid volume status. A clinical trial by Fahmy et al. used machine learning for predicting heart failure progression in a huge cohort of patients affected by hypertrophic cardiomyopathy (HCM). Heart failure progression was defined as worsening in NYHA class, a drop in left ventricular ejection fraction, need for septal reduction procedure, and/or indication for heart transplantation. A set of 17 clinical and imaging variables, also confirmed by an independent validation dataset, were identified as the most important predictors of progressive heart failure in HCM patients.Above all the technological advances that are presented to us nowadays, the one that is playing an increasingly prominent role is with no doubt machine learning. Machine learning is a branch of artificial intelligence that uses statistical methods to enhance the performance of an algorithm to identify patterns in data. Mo et al. The predictive value of big ET-1 was comparable to NT-proBNP; moreover, the combined use of the two molecules increased the predictivity of the primary outcome, defined as a composite of in-hospital death, cardiac arrest, and utilization of mechanical circulatory support. Many articles also take into account chronic heart failure and much interest addresses the more ambiguous categories, namely heart failure with mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). Regarding the latter, Abramov and Parwani criticized the tendency to gather all patients with preserved ejection fraction under a unique definition, since this group of patients is very heterogeneous. These authors suggest not focusing on the cutoffs identified by the recently introduced diagnostic score algorithms (HFA-PEFF and H2FPEF) but instead trying to understand the underlying pathophysiology to come to better management decisions. The other equivocal category is HFmrEF. Patients can fall into this subgroup even though they may have different backgrounds. The diction “mildly reduced” implies that the ejection fraction used to be normal before. However, since ejection fraction is a dynamic state, an improvement is also possible, which underlies the emerging concept of recovered/improved ejection fraction. Therefore, HFmrEF could be “mildly reduced” as much as “mildly recovered” ejection fraction. Zhang et al. demonstrated that HFmrEF patients with previously preserved ejection fraction have worse outcomes compared to those with a previously reduced ejection fraction. Definitions of heart failure are continuously evolving as well as therapeutic options. Pascual-Figal et al. have undertaken a comprehensive review on Sacubitril-Valsartan, a game-changer drug not only in the field of HFrEF.Besides new technologies, an important branch of research remains the one whose aim is to identify biological molecules with a potential clinical application for diagnostic and prognostic purposes. This is the case with Big Endothelin-1, the prepropeptide of endothelin-1 (ET-1), the most potent endogenous vasoconstrictor, which has been recently recognized as an independent predictor of short-term adverse events in acute decompensated heart failure by Huang et al. undertook an interesting systematic review on the effects of Tai Chi exercise among adults with chronic heart failure, which shows potential as a cardiac rehabilitation discipline thanks to its low-intensity, making it suitable for people with poor exercise tolerance. Finally, diametrically opposite to rehabilitation and of equal importance, there is prevention for people with cardiovascular risk factors. It is a common opinion that prevention and rehabilitation will cover more and more space in the following decades to ensure a better quality of life and at the same time improve health care sustainability. Among the most common cardiovascular risk factors, there is diabetes, with more than 500 million people affected worldwide. Chadalavada et al. analyzed an enormous UK dataset and found that mortality and heart failure risk were almost doubled in people with diabetes compared to those without it, this being more evident for female patients.Drugs are not the only way of managing heart failure. We get better and better at identifying risk factors for diseases' development and progression, at predicting their course, and deploying increasingly effective therapies at the right time. For the whole spectrum of time frames in heart failure course, we know what to do in order to either prevent it or improve the prognosis and quality of life of our patients. Research continuously casts light on previously unsolved dilemmas in clinical management.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


While the prognostic impact of QRS axis deviation has been assessed, it has never been investigated in patients without conduction block. Thus, we evaluated the prognostic impact of QRS-axis deviation in patients without conduction block. We retrospectively analyzed 3353 patients who had undergone both scheduled transthoracic echocardiography and electrocardiography in 2013 in a hospital-based population, after excluding patients with a QRS duration of ≥ 110 ms, pacemaker placement, and an QRS-axis − 90° to − 180° (northwest axis). The study population was categorized into three groups depending on the mean frontal plane QRS axis as follows: patients with left axis deviation (N = 171), those with right axis deviation (N = 94), and those with normal axis (N = 3088). The primary outcome was a composite of all-cause death and major adverse cardiovascular events. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the left axis deviation group . After adjusting for confounders, the excess risk of primary outcome measure remained significant in the left axis deviation group , while the excess risk of primary outcome measure was not significant in the right axis deviation group . Left axis deviation was associated with a higher risk of a composite of all-cause death and major adverse cardiovascular events in hospital-based patients without conduction block in Japan. Right axis deviation is usually seen in children and young adults under physiological conditions9. However, most causes of pathological conditions in right axis deviation are right ventricular hypertrophy10, lateral myocardial infarction11, altered conduction pathways5, and changes in the position of the heart in the chest12.QRS axis deviation can be easily determined in electrocardiograms (ECGs). Although left axis deviation is often an age-related physiological change15, it has never been investigated in patients without conduction block in Asian population. Thus, the present study investigated the prognostic impact of QRS axis deviation with QRS duration less than 110 ms and performed multivariable adjustment to assess the adjusted risk of QRS axis deviation.While the prognostic impact of QRS axis deviation in patients including a wide QRS complex has been assessed from the 1980s in Western countries16.We retrospectively analyzed 4444 patients who had undergone simultaneous scheduled transthoracic echocardiography and electrocardiography at outpatient visits or stable in-hospital conditions at Kitano Hospital in 2013, which were ordered at the physician’s discretion. A flowchart of the study population is shown in Fig. 17. A flowchart of the study population using QRS ≥ 100 ms as exclusion criteria is shown in Supplementary Fig. As a supplementary analysis, we also adopted Japanese recommendation of ≥ 100 ms QRS duration as a wide QRS complex definition19. The requirement of informed consent was waived because of the retrospective study design. We disclosed the details of the present study to the public as an opt-out method and the notice clearly informed patients of their right to refuse enrollment. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s Human Research Committee. Patient records and information were anonymized and deidentified before analysis.The research protocol was approved by the Institutional Review Board of Kitano Hospital 18. Using the transthoracic echocardiography database, we extracted data regarding wall thickness, left ventricular (LV) diastolic dimensions, LV systolic dimensions, left atrial dimension, left atrial volume index, LV ejection fraction, transmitral flow, tissue Doppler imaging, and body mass index (BMI)24. Based on the transthoracic echocardiography data along with the catheter suite database, we identified patients with previous myocardial infarction or structural heart disease. LV mass index and relative wall thickness were calculated using the formula recommended by the American Society of Echocardiography25. A high LV mass index was defined as LV mass index > 115 g/m2 for men and > 95 g/m2 for women. The LV ejection fraction was measured using the Teichholz or modified Simpson’s rule methods. All transthoracic echocardiography measurements were performed using the average of at least three cardiac cycles. We also extracted patient information from their electronic medical records at our institution, including age, sex, and type of disease 19. Follow-up data from serial clinic visits until June 2017 were also collected retrospectively from electronic medical records.Using the ECG database, we extracted data regarding QRS duration and the mean frontal plane QRS axisThe primary outcome measure was a composite of all-cause death and major adverse cardiovascular events (MACE) defined as acute heart failure, acute myocardial infarction, unstable angina pectoris, cerebral infarction, cerebral hemorrhage, and emerging aorta and peripheral vascular disease, including treatment for aortic aneurysm, all of which required unplanned hospitalization. The secondary outcome measures were all-cause death and MACE, separately.2, diabetes, hypertension, dyslipidemia, ischemic heart disease, chronic kidney disease, LV ejection fraction < 50%, and high LV mass index. In a supplementary analysis, we used the Japanese criteria which define wide QRS complex as a QRS duration of ≥ 100 ms17 and excluded patients with QRS ≥ 100 ms from the analysis. The results are expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical analyses were performed by physicians (YS and TK) using JMP 15. All reported P values are two-tailed and the level of statistical significance was set at P < 0.05.Categorical variables are presented as numbers with percentages and were compared using the chi square test or Fisher’s exact tests. Continuous variables are expressed as means with standard deviations and were compared using one-way analysis of variance (ANOVA) tests. We compared the patient characteristics and 3-year clinical outcomes among the three groups with (1) left axis deviation, (2) right axis deviation, and (3) normal axis. The cumulative incidences of clinical events were estimated using the Kaplan Meier method, and intergroup differences were assessed using the log-rank tests. Multivariable Cox proportional hazards models were used to estimate the risk of primary and secondary outcomes associated with the three groups. The model also included the following nine clinically relevant covariates: age > 70 years, BMI > 25 kg/mThis study included 171 patients (5.1%) with left axis deviation, 94 patients (2.8%) with right axis deviation, and 3088 patients (92.1%) with normal axis  days, with a 80.4% follow-up rate at 1 year. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the left axis deviation group   patients with left axis deviation with narrow QRS complex had worse clinical outcomes in hospital-based population in Japan after adjusting for confounders; (2) the outcomes in patients with right axis deviation and narrow QRS complex were not different compared to those in patients with normal QRS axis; and (3) the results were essentially same both using the AHA/ACCF/HRS recommendation of ≥ 110 ms QRS duration and the Japanese recommendation of ≥ 100 ms QRS duration of wide QRS complex definition. These are the novel findings of the present study.14. This does not appear to be consistent with our results; however, the target populations differed between the two studies. O’Neal et al. reported that, while the patients had no apparent cardiovascular disease in the US, a substantial proportion of them showed the wide QRS complex (20%) and were having anti-hypertensive drugs (36%), statins (15%), and aspirin (24%), but without adjustment for the comorbid diseases. Our study comprised outpatient with cardiovascular risk factors or diseases in Japan. Moreover, we excluded the patients with wide QRS complex and performed the adjustment for comorbid diseases, LV ejection fraction, and LV mass index. Our data suggested that left axis deviation was an independent factor associated with worse outcomes in a hospital-based population with narrow QRS complex in Japan. Right axis deviation itself showed no apparent increased risk for outcomes in the present study. While there may be a serious condition that causes right axis deviation11, its risk in a hospital-based outpatient was comparable to that of the normal axis in the present study. This may be because a substantial proportion of the right axis deviation may be a normal variant considering the younger patients included.O’Neal et al. reported that left and right axis deviations were independent risk factors related to heart failure with reduced LV ejection fraction in patients without cardiovascular disease7. Hypertension along with LV hypertrophy causes elevated pressure in the LV cavity and affects the conduction system; it also results in a more horizontal heart position4. Due to the accumulation of abdominal organ fat, the obesity may be related to the more horizontal heart position through diaphragm elevation8. However, high BMI was more common in patients with normal QRS axis than in patients with left axis deviation in our study. This may be due to the result that patients with normal axis were significantly younger than those with left axis deviation. Older age may cause stiffening of the aorta, leading to the LV hypertrophy and changes in heart position2. All these factors have prognostic influences on the outcome. However, after adjusting for these factors, left axis deviation remained at risk for adverse outcomes. These results suggested two possible mechanisms why the left axis deviation was linked to worse clinical outcomes. First, left axis deviation reflect the horizontal heart position due to other unadjusted causes such as congenital heart disease or pulmonary disease7. Second, mild but unacknowledged multiple pathological conditions caused left axis deviation. In either case, we should try to look for comorbidities and unacknowledged conditions that can cause left axis deviation, if they exist, by systematic evaluation to prevent their worse clinical outcome. Because ECG is a simple and easy modality, the left axis deviation should signal the need for careful observation of given patients.Left axis deviation may be caused by various physiological and pathological conditionsThis study has several limitations. First, our data shows a significant difference in the primary outcome but fails to show a difference in the secondary outcomes. Although the trend of the secondary outcomes was consistent across the groups, the reason why there was no significant difference in the secondary outcomes may be due to the low incidence rate of events in stable patients who underwent scheduled tests. Second, ECG and transthoracic echocardiograms were ordered at the discretion of the treating physician, with no standardized indications. Third, patient data were extracted from their electronic medical records, which resulted in a low follow-up rate, especially at 3 years. In addition, information on the symptoms was not included. Thus, we had no data regarding the proportion of patients with symptomatic heart failure. Fourth, this was a single-center study performed in Japan; thus, selection bias cannot be excluded despite the large sample size. Finally, there remain unmeasured confounders affecting long-term prognosis. Nevertheless, we conducted extensive statistical adjustment for the measured confounders.Left axis deviation was associated with a higher risk of a composite of all-cause death and MACE in patients without conduction block.Supplementary Information.


Preterm birth affects about 10% of live births worldwide and is associated with cardiac alterations. Animal models of preterm birth suggest that left ventricular functional impairment may be due to an up-regulation of myocardial fibrosis.The aim of this study was to determine whether diffuse left ventricular fibrosis is evident in young adults born preterm.One hundred one normotensive young adults born preterm  and term (n = 54) were included from YACHT . Left ventricular structure and function were quantified by cardiovascular magnetic resonance and echocardiography. Intravenous administration of a gadolinium-based contrast agent during cardiovascular magnetic resonance was used to quantify focal myocardial fibrosis on the basis of late gadolinium enhancement and, in combination with T1 mapping, to quantify diffuse myocardial fibrosis on the basis of assessment of myocardial extracellular volume fraction.P < 0.001). In addition, longitudinal peak systolic strain and diastolic strain rate by both cardiovascular magnetic resonance and echocardiography, and E/A ratio measured by echocardiography, were lower in preterm-born compared to term-born adults (P < 0.05). Extracellular volume fraction was greater in preterm-born compared with term-born adults  and was a significant mediator in the relationship between gestational age and both longitudinal peak diastolic strain rate and E/A ratio.Adults born preterm had smaller left ventricular end-diastolic and stroke volumes, with greater left ventricular mass and wall thickness (Preterm-born young adults have greater extracellular volume fraction in the left ventricle that is inversely related with gestational age and may underlie their diastolic functional impairments.  Preterm birth  affects >10% of live births worldwide  and longIn line with an increased cardiovascular risk, left ventricular (LV) morphologic and functional changes in people born preterm are first observed in the neonatal period and continue into infancy, childhood, and young adulthood . These pTo date, there have been no human studies investigating myocardial fibrosis in adults born preterm and how this relates to changes in systolic and diastolic function. Cardiovascular magnetic resonance (CMR) imaging offers the opportunity to assess focal myocardial fibrosis with late gadolinium enhancement (LGE) and diffuse myocardial fibrosis by pre- and postcontrast T1 mapping to measure myocardial extracellular volume fraction (ECV), without requiring direct access to tissue ,16. We hNCT02103231), a cross-sectional, case-control study of preterm-born  and term-born  young adults  to ensure anonymity and blinded analysis. YACHT was granted ethical approval by the South Central Berkshire Research Ethics Committee (14/SC/0275) in the United Kingdom.Subjects were recruited into YACHT . Image acquisition was made in the left lateral decubitus position per standard guidelines to include diastolic function measures . LV apicCMR was performed using a 3.0-T magnetic resonance imaging scanner . Horizontal and vertical long-axis and LV outflow tract retrospective electrocardiographically gated steady-state free precession cine images were acquired, followed by short-axis steady-state free precession cine images . Data weEchocardiographic analysis of LV E/A and E/e′ ratios was completed using Philips IntelliSpace Cardiovascular 2.1  in accordance with standard guidelines . The E aLV CMR analysis was done using analytical software . To evaluate LV volumes, mass, and dimensions, both the epicardial and endocardial borders were manually contoured on short-axis cine images for each slice at end-diastole and endocardial borders at end-systole. The end-diastolic and end-systolic cardiac phases, as well as the basal and apical LV slices, were visually determined as previously described ,24. LV wQuantitative analysis of LGE and T1 maps was done using commercially available software (CVI42). For LGE analysis, the endocardial and epicardial myocardial borders at end-diastole were contoured for all short-axis slices. To quantify LGE mass, a signal intensity threshold of 5 SDs above the mean intensity of a reference region of interest was placed in a remote area of myocardium with no visual evidence of enhancement. The relative LGE mass was calculated as the percentage of total LV myocardial mass (LGE mass/LV mass × 100%). For T1 mapping analysis, myocardial contours were drawn on native T1 images and postcontrast T1 images. Blinded and experienced analysts undertook all analyses. Native and postcontrast average myocardial T1 values were generated for each participant. R2 maps of shortened modified Look-Locker inversion recovery fit were used to verify the quality of T1 maps. To allow the calculation of ECV, a measure of diffuse myocardial fibrosis , native t-tests for normally distributed data and Mann-Whitney and Kruskal-Wallis tests for skewed data. Group comparisons between the preterm-born and term-born adults were adjusted for sex to account for differing sex distributions between groups using multivariable linear regression, with adjusted mean differences and 95% confidence intervals (CIs) reported for the variables of interest. Bivariate and multivariable linear regression modeling were completed using forced entry with missing data excluded pairwise. For each analysis, unstandardized coefficients (B) with 95% CI, standardized coefficients (β), and P values are reported. Mediation analyses were performed to determine potential mediating pathways among gestational age, ECV, and diastolic function parameters after first performing bivariate regressions among these parameters . Shapiro-Wilk testing and visual inspection were used to assess normality of variables. Comparisons between preterm-born and term-born adults were performed using independent-samples Student’s rameters . To deteP = 0.05. There were no differences in age and body mass index between preterm-born and term-born groups (P > 0.05). The percentage of men was lower in the group of young adults born preterm compared with the term-born group, and as such, group comparisons throughout were adjusted for sex. All biochemistry measures, except for high-density lipoprotein and C-reactive protein, differed between groups (P < 0.05). There were no differences in average awake ambulatory systolic  and diastolic blood pressure between groups  . Of the 101 normotensive young adult participants included in this analysis, 54 were born at term , and 47 were born preterm . The cohort size allowed us to detect a 0.65-SD difference between groups powered at 90% and = 0.058) .Table 1C2 vs 88.21 ± 11.49 mL/m2; adjusted mean difference −14.56 mL/m2; P < 0.001), end-systolic volume , and stroke volume . Preterm-born adults also had greater LV average wall thickness , mass , mass index , and mass/end-diastolic volume ratio  compared with term-born adults  or midventricular peak systolic circumferential strain (P = 0.893) and strain rate (P = 0.953), though both longitudinal peak systolic strain  and strain rate  were lower in those born preterm. Although midventricular peak diastolic strain rate did not differ between preterm-born and term-born adults (P = 0.203), longitudinal peak diastolic strain rate was lower in the preterm group . On echocardiography, there was no difference in E/e′ ratio (P = 0.768), but E/A ratio was lower in preterm-born adults compared with term-born adults .There were no differences between preterm-born and term-born adults for LV ejection fraction (P = 0.908), ECV was higher in the preterm-born adults compared with term-born adults  with 4 of 47 adults born preterm (9%) having ECV >3 SDs (∼30%) above the mean defined by our term-born adult group (P = 0.222). LGE mass and relative LGE mass did not differ between groups .Although native T1 mapping did not differ between groups  and E/A ratio  were the only parameters inversely related to ECV. In bivariate regression analysis within the preterm group, gestational age was inversely related with ECV, with a 0.289% lower ECV (P = 0.001) per 1-week greater gestational age. Gestational age was also positively related with E/A ratio and longitudinal peak diastolic strain rate, with a 0.041-unit higher E/A ratio (P = 0.020), 0.075-s−1 higher CMR-derived longitudinal peak diastolic strain rate (P = 0.016), and 0.083-s−1 higher echocardiography-derived longitudinal peak diastolic strain rate (P = 0.018) per 1-week greater gestational age.LV cardiac structure and function parameters that differed in those born preterm compared with term were selected for bivariate regressions with ECV . LongituP = 0.021), but gestational age was no longer a significant predictor of E/A ratio  (P = 0.013), but gestational age was no longer a significant predictor of CMR-derived longitudinal peak diastolic strain rate  (P = 0.044), but gestational age was no longer a significant predictor of echocardiography-derived longitudinal peak diastolic strain rate . The indirect effect of gestational age on E/A ratio via ECV was significant , as was the indirect effect of gestational age on CMR-derived longitudinal peak diastolic strain rate via ECV  and echocardiography-derived longitudinal peak diastolic strain rate via ECV .Mediation analyses were performed to determine whether the relationships between the degree of prematurity and impaired diastolic function were mediated by diffuse myocardial fibrosis (ECV). Controlling for gestational age did not alter the association between ECV and E/A ratio  . Control= 0.502) . SimilarThis study demonstrates for the first time that young adults born preterm have evidence of greater diffuse myocardial fibrosis in the LV that relates to the degree of prematurity . PretermECV has emerged as a sensitive surrogate marker for interstitial myocardial fibrosis . Unlike The sustained alterations in cardiac morphology and performance exhibited by people born preterm  may be dAdditional stimuli, including inflammation and oxidative stress, are also likely to be involved in the pathogenesis of extracellular matrix fibrosis in people born preterm . In humaAn important negative finding within the preterm-born adults was the lack of an association between higher LV mass and wall thickness with greater ECV. This supports the hypothesis that the higher myocardial mass following preterm birth is driven by cardiomyocyte hypertrophic growth through other mechanisms, such as the adaptation to early hemodynamic changes faced by the immature myocardium ,11. HoweFirst, despite the associations among gestational age, ECV, and diastolic function, further work is needed to explore this relationship across gestational age ranges, given the small number of individuals in the very and extreme preterm group  in our cohort.Second, given the cross-sectional nature of the study, we cannot confirm causality and whether changes in ECV occurred around the time of birth or have emerged over time. Nevertheless, our analyses showing that ECV is a mediator in the relationship between the degree of prematurity and diastolic functional impairments, which are first seen during infancy , suggestThird, our measure of ECV is based on a single, midventricular short-axis slice. However, slice position was standardized on the basis of the presence of papillary muscles, and our methodology is consistent with other studies that have shown ECV is a biopsy-validated surrogate measure of interstitial fibrosis ,29. FurtFinally, previous studies have demonstrated that the right ventricle has greater functional impairments than the left ventricle in young adults born preterm , indepenPerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Preterm birth is associated with an increased risk for cardiovascular diseases and diastolic ventricular dysfunction in young adulthood, possibly mediated by myocardial fibrosis.TRANSLATIONAL OUTLOOK: Further research is needed to determine whether myocardial fibrosis in young adults born preterm worsens with aging and acquisition of conventional cardiovascular risk factors.We have demonstrated that preterm-born young adults have alterations in LV morphology and function, including greater diffuse myocardial fibrosis that mediates the relationship between the degree of prematurity and impaired diastolic function . GreaterThis study was funded by a British Heart Foundation project grant (PG/13/58/30397). Dr Lewandowski is funded by a British Heart Foundation Intermediate Research Fellowship (FS/18/3/33292). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Pulmonary arterial hypertension (PAH) is a disease resulting in increased right ventricular (RV) afterload and RV remodeling. PAH results in altered RV structure and function at different scales from organ-level hemodynamics to tissue-level biomechanical properties, fiber-level architecture, and cardiomyocyte-level contractility. Biomechanical analysis of RV pathophysiology has drawn significant attention over the past years and recent work has found a close link between RV biomechanics and physiological function. Building upon previously developed techniques, biomechanical studies have employed multi-scale analysis frameworks to investigate the underlying mechanisms of RV remodeling in PAH and effects of potential therapeutic interventions on these mechanisms. In this review, we discuss the current understanding of RV structure and function in PAH, highlighting the findings from recent studies on the biomechanics of RV remodeling at organ, tissue, fiber, and cellular levels. Recent progress in understanding the underlying mechanisms of RV remodeling in PAH, and effects of potential therapeutics, will be highlighted from a biomechanical perspective. The clinical relevance of RV biomechanics in PAH will be discussed, followed by addressing the current knowledge gaps and providing suggested directions for future research. Clinically, pulmonary hypertension (PH) is defined as a condition with resting mean pulmonary artery pressures (mPAP) >20 mmHg . PH resuPulmonary arterial hypertension has been shown to result in RV remodeling at different scales, from changes in organ-level hemodynamics to tissue stiffening, fiber reorientation, and altered myocyte contractility and mitochondrial energetics . Mechaniin silico studies for multi-scale evaluation of adaptive vs. maladaptive PAH-induced remodeling events. Common techniques for biomechanical characterization of the RV at different scales will be summarized, followed by a discussion on recent progress in understanding the biomechanical effects of potential therapeutic interventions.In this review, we discuss the recent progress in understanding the multi-scale biomechanics of the RV in PAH across different scales from organ-level function to tissue, fiber, and cellular-level mechanics. This will be followed by highlighting the potential of computational/Clinical work has been focused on studying RV mechanics in human patients using invasive hemodynamics, cardiac magnetic resonance imaging (cMRI) and echocardiography. On the other hand, pre-clinical studies have employed animal models of PAH for mechanistic investigation of different RV remodeling events and the role of mechanical stimuli in these processes. The most commonly used animal models of PAH include: (1) PAH induced via vascular endothelial growth factor (VEGF) receptor blocker Sugen-5416 followed by exposure to hypoxia (SuHx), (2) Monocrotaline (MCT)-induced PAH, and (3) PAH induced via pulmonary artery banding (PAB) . The SuHDifferent species have been used as PAH models, including mouse, rat, chicken, dog, sheep, pig, cow, monkey. Rat and mouse models of PAH have been the most commonly studied. Hypoxia induces similar pulmonary vascular changes across species, with increasing pulmonary vascular smooth muscle cell hypertrophy and perivascular inflammation in larger animals . Differemax and min).Due to the multi-scale structure of the RV, with specific features and function at different levels , differeRight ventricular function is the most critical determinant of survival in PAH . Recent es) to PA elastance (Ea), which conceptually is RV contractility per hydraulic load. In animal models, Ees (the load-independent measure of organ-level RV contractility) is assessed by preload reduction of the RV, via vena caval occlusion, which exposes the RV to a wide range of operational pressures and forms multiple P-V loops   over stroke volume  may be calculated by calculating the individual components, Ees and Ea. However, alternatively, Ees/ Ea may be estimated using the ratio of stroke volume/end-systolic volume which may be obtained from noninvasive imaging such as magnetic resonance imaging (The dynamic supply demand mechanics of the RV and the pulmonary artery (PA) is another determinant of organ-level RV function (RV-PA coupling). A commonly used metric for evaluation of RV-PA coupling efficiency is the ratio of RV end-systolic elastance (E-V loops . Ees is  (ESPVR) . While r (ESPVR)  has char setting . The sinaveforms . Ees is e volume . Ea, on l models , using tl models . The rat imaging  or 3D ec imaging . Other n imaging . Many ofRight ventricular-PA coupling efficiency is a major determinant of outcomes in PH . Along wed) and the end-diastolic pressure-volume relationship (EDPVR), also obtained by measurement of RV P-V patterns at different loads via preload reduction (0 (ed) may be used for biomechanical analysis of RV diastolic function  thefunction , by evaled) was observed in response to increased pressures via PAB, in a rat model of PAH (ed was found to be positively correlated with β (ed and β were found to be significantly higher in patients with severe vs. mild PAH (max), which was accompanied by increased RV elastance , which was correlated with metrics of disease severity such as RV stroke volume, 6-min walking distance and RA pressures . A signil of PAH . Moreoved with β . Both Eemild PAH . In a lalastance . While nlastance . Taken tlastance . A struclastance .ed) and PA elastance (Ea). In another clinical study, Attard et al. demonstrated that RV wall stress could be an independent predictor of all-cause mortality in a population of patients with PH of different etiologies (32% with PAH)  .in vivo contractile deformations can be characterized by placement of radiopaque markers on the RVFW, combined with biplane fluoroscopy  by 106% and 48%, respectively. RVFW contractile deformations, however, demonstrated heterogenous regional variations. While RVFW contractility at the inflow and midventricular regions did not show any significant changes in response to acute pressure rise, the outflow region demonstrated decreased fractional area reduction by 22%  results in decreased RVFW contractility and minimum principal strains  at the basal level, within 10 weeks . Alterations in RVFW contractile strains manifest early in the progression of PAH . In animoroscopy . Marker  regions . Acute Pn by 22% . The obsn by 22% . Echocarfunction . PAH wasfunction . PAH patfunction . Reducedfunction . Despitefunction . Additiofunction . cMRI is10 weeks . Moderat10 weeks .2) has been investigated in animal models of PAH (es) and RV-PA coupling efficiency in female patients (a), median RV-PA coupling efficiency was higher than the 0.805 threshold  based on provocative pilot data  in a PAB model of PAH  mainly consists of fibrillar collagen networks (type I and III), basement membrane type IV collagen, elastin, proteoglycans, fibronectin, and laminin . HealthyThe RVFW is formed by a transmural stack of myofibers and collagen with different orientations throughout the tissue thickness. Gradient-based image analysis techniques have been employed to analyze the transmural orientations of RV fibers from histological sections . In addi2+ dependent) forces generated by RV trabeculae are then measured at different lengths, over a range of different Ca2+ concentrations. Passive mechanical properties of RV fibers can also be estimated from equibiaxial tissue-level responses of the RVFW  trabeculae, to facilitate characterization of myocyte properties in the absence of mechanical contributions from the ECM. Mechanical characterizations are performed by attachment of ends of isolated trabeculae to force transducers and servo motors, while sarcomere length is monitored under a microscope. Passive and active . Myocytactivity . Transmiactivity .α and β-adrenergic receptors (α-AR and β-AR) on cardiomyocytes play a crucial role in regulating myocardial morphology and contractility. β-AR stimulation is primarily responsible for increased cardiac performance under pressure overload, while α-ARs contribute to myocardial hypertrophy . RVFW biIn addition to alterations in active myocyte contractile properties, pressure overload in PAH results in a progressive increase in passive stiffness of myofibers by ≈2 folds , most ofDespite recent developments of several therapeutics for management of PH, so far, lung transplantation remains the only curative treatment. While multiple clinical and preclinical studies have investigated the effects of potential therapeutics on RV function in PAH, only a few have analyzed the effects of these interventions on the biomechanics of the RV.The renin-angiotensin-aldosterone system (RAAS) plays a major role in regulating RV remodeling in response to pressure overload . In respmax and min, and RV-PA coupling efficiency  is an enzyme upregulated in PA vascular smooth muscle cells in PAH, resulting in PA remodeling and proliferation. ILK inhibition was shown to result in reduced PA and RV hypertrophy, decreased RV systolic and end-diastolic pressures, and improved contractility in male, but not female rats in a SuHx model . This waficiency . ReducedIn silico modeling of RV biomechanics in PAH has gained significant traction in recent years. Computational models can provide valuable insights into the underlying mechanisms of RV remodeling in PAH and can help better understanding the time-course of different remodeling events. In silico modelling facilitates parametric analysis of the relative contribution of isolated remodeling events to RV dysfunction; something that would be otherwise time-consuming or impractical to measure experimentally. The multi-scale in silico models used to study RV function range from lumped parameter hemodynamic models of the pulmonary vasculature Long-term longitudinal biomechanical studies looking at the time-course of different multi-scale remodeling events in PAH.(2)Biomechanical evaluation of the underlying mechanisms of fiber reorientation in PAH, elucidating the effects of fiber realignment on organ-level function.(3)Biomechanical analysis of the adaptiveness of different RV remodeling events in relation to function, and characterization of the transition points from adaptation to maladaptation.(4)Identification of a biomechanical metric for characterization of the “point of no return” in PAH progression, beyond which the RV progresses into failure(5)Biomechanical analysis of RV function in other phenotypes of PH, including PH-LHD.DS drafted the manuscript and generated the figures. KK drafted the manuscript. MS drafted the manuscript and provided clinical perspective on the review topic. All authors reviewed the final manuscript.DK is employed by Align Technology, Inc. MS was on the consultation/scientific advisory board for Bial, Acceleron, Altavant; and executed hemodynamic core lab work for Aadi. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Elevated resting heart rate (HR) is a recognized cardiovascular risk factor in populations with or without cardiovascular affliction , 2. HighConsumer-grade wearable devices capable of monitoring health represent an ever-growing market that is expected to reach 27.5 billion USD by 2026. Wrist-worn devices, including smartwatches and fitness trackers, account for more than half of all wearable devices being used . VariousInterestingly, wrist-worn devices were shown to accurately and reliably determine short-term and 24-hour (24-h) heart rate variability (HRV) by extrapolation from PPG-derived waveforms . Time- avia algorithms and data analytics. Such sources of noise can be primarily divided into three categories: (i) individual variation, e.g., skin tone, obesity, age, and gender; (ii) physiology, e.g., respiratory rate, venous pulsation, and local body temperature; and (iii) external factors, e.g., motion artifacts, ambient light, and pressure applied to the skin  and 2 in 3 healthcare professionals surveyed intend to use wearable devices for remote patient monitoring .Here, we suggest that monitoring non-dipping HR by consumer-grade wrist-worn devices may be of help in cardiovascular risk assessment in hypertension . Our sugNon-dipping HR is an independent, yet somewhat neglected, cardiovascular risk factor , 2, 5.Consumer-grade wrist-worn devices are able to continuously or almost continuously (HR measurements are taken every few minutes) monitor HR during a 24-h period (or even longer), encompassing daytime activities and night-time sleep. Moreover, the HR readings are reliable and accurate, with at least 90% agreement with 24-h ECG .Simultaneously with HR monitoring, wearable devices can track physical activity and sleep –38, thusCompared to conventional continuous cardiac monitors, 98% of surveyed patients deemed wrist-worn devices more convenient and 91% acknowledged they were likely to use a wrist-worn device to determine cardiac rhythm during symptoms . Indeed,Data collected by wearable devices can be automatically transmitted to smartphones for patient notification and stored in remote servers (cloud) or electronic health records to be accessed remotely by a healthcare professional. This ensures timely data collection and the avoidance of errors by subjective data reporting or secondary data entry, which may contribute to increased patient convenience, satisfaction and compliance, as well as reduced in-office visits, administrative burden and healthcare costs , 41, 42.via telemedicine. The proper management of chronic illnesses is also imperative under these circumstances (The COVID-19 pandemic brought about new challenges in delivering health care to patients with chronic illnesses, including hypertension and diabetes mellitus . With somstances . MonitorImportantly, HR monitoring with wearable devices could play a pivotal role in clinical research pertaining to sleep-time HR or non-dipping HR in various cardiovascular pathologies. Indeed, wearable devices can continuously and during any time interval collect data from large populations encompassing thousands of healthy subjects or subjects with hypertension or diabetes mellitus and associated cardiovascular affliction, such as ischemic heart disease, heart failure or stroke. In fact, large populations can be stratified into specific subpopulations by age, gender, demographics, and other factors, thus allowing for larger and denser datasets and advanced analyses . PopulatConsidering the above remarks, monitoring non-dipping HR by consumer-grade wrist-worn devices can be construed as an emerging avenue for cardiovascular risk assessment in hypertension, particularly in the realm of primary care. As primary care often struggles with high healthcare costs and a shortage of physicians or cutting-edge diagnostic tools, the suggested cost-effective approach to cardiovascular risk assessment using wearable devices may be advantageous. Moreover, early identification and management of high-risk patients in primary care can curb long-term healthcare expenditures , 47.TB conceived and drafted the manuscript. FS revised the manuscript. All authors participated in data analysis, interpretation, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.