Angiotensin receptor blockers and ß blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials.

BACKGROUND: Angiotensin receptor blockers (ARBs) and ß blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. METHODS: In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus ß blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus ß blocker; and indirectly, ß blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. FINDINGS: We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference -0·07 [95% CI -0·12 to -0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with ß-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with ß blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0·08 [SE 0·03] in ARB groups vs -0·11 [SE 0·02] in ß-blocker groups; absolute difference 0·03 [95% CI -0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between ß blockers and control was -0·09 (95% CI -0·18 to 0·00; p=0·042). INTERPRETATION: In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a ß blocker. The effects of ß blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and ß blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. FUNDING: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial.

BACKGROUND: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. METHODS: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. FINDINGS: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking ß blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. INTERPRETATION: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. FUNDING: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists' Collaboration.

RATIONALE: A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of ß-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. DESIGN: A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus ß-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials).

Exaggerated elastin turnover in young individuals with Marfan syndrome: new insights from the AIMS trial.

Aims: The fragmentation and loss of elastic fibre in the tunica media of the aorta are pathological hallmarks of Marfan syndrome (MFS) but the dynamics of elastin degradation and its relationship to aortic size and physiological growth remain poorly understood. Methods and results: In this post hoc analysis of the AIMS randomized controlled trial, the association of plasma desmosine (pDES)-a specific biomarker of mature elastin degradation-with age and aortic size was analysed in 113 patients with MFS and compared to 109 healthy controls. There was a strong association between age and pDES in both groups, with higher pDES levels in the lower age groups compared to adults. During childhood, pDES increased and peaked during early adolescence, and thereafter decreased to lower adult levels. This trend was exaggerated in young individuals with MFS but in those above 25 years of age, pDES levels were comparable to controls despite the presence of aortic root dilation. In MFS children, increased aortic diameter relative to controls was seen at an early age and although the increase in diameter was less after adolescence, aortic root size continued to increase steadily with age. In MFS participants, there was an indication of a positive association between baseline pDES levels and aortic root dilatation during up to 5 years of follow-up. Conclusion: This study has shown that developmental age has a significant effect on levels of elastin turnover as measured by pDES in MFS individuals as well as healthy controls. This effect is exaggerated in those with MFS with increased levels seen during the period of physiologic development that plateaus towards adulthood. This suggests an early onset of pathophysiology that may present an important opportunity for disease-modifying intervention.

Challenges and opportunities in improving left ventricular remodelling and clinical outcome following surgical and trans-catheter aortic valve replacement.

Over the last half century, surgical aortic valve replacement (SAVR) has evolved to offer a durable and efficient valve haemodynamically, with low procedural complications that allows favourable remodelling of left ventricular (LV) structure and function. The latter has become more challenging among elderly patients, particularly following trans-catheter aortic valve implantation (TAVI). Precise understanding of myocardial adaptation to pressure and volume overloading and its responses to valve surgery requires comprehensive assessments from aortic valve energy loss, valvular-vascular impedance to myocardial activation, force-velocity relationship, and myocardial strain. LV hypertrophy and myocardial fibrosis remains as the structural and morphological focus in this endeavour. Early intervention in asymptomatic aortic stenosis or regurgitation along with individualised management of hypertension and atrial fibrillation is likely to improve patient outcome. Physiological pacing via the His-Purkinje system for conduction abnormalities, further reduction in para-valvular aortic regurgitation along with therapy of angiotensin receptor blockade will improve patient outcome by facilitating hypertrophy regression, LV coordinate contraction, and global vascular function. TAVI leaflet thromboses require anticoagulation while impaired access to coronary ostia risks future TAVI-in-TAVI or coronary interventions. Until comparable long-term durability and the resolution of TAVI related complications become available, SAVR remains the first choice for lower risk younger patients.

Mitigating cardiac dysfunction by TOE-guided cardioplegia and mitral valve repair.

Based on current guidelines, 15% to 20% of patients undergoing mitral valve repair for regurgitation develop left ventricular dysfunction (ejection fraction < 50%-55%) despite a normal baseline. Two schools of thought have been debated: preexisting myocardial disease or suboptimal intraoperative myocardial protection. In our view, they could be reconciled. It is well recognized that left ventricular ejection fraction with a standard cut off at 50%-55% has limited sensitivity in detecting early systolic impairment in mitral regurgitation patients. Mitral regurgitation also leads to mitochondrial oxidative stress, thus rendering the myocardium more susceptible to ischemia-reperfusion injury and precipitating postoperative cardiac dysfunction. The fall in left ventricular ejection fraction early after mitral valve repair was shown to be caused by the reduction in both myocardial contractility and left ventricular stroke volume. To mitigate the risk to myocardial reperfusion injury, appropriate cardioplegia volume and distribution and well-defined surgical repair processes are equally important. We use transesophageal echocardiography-guided cardioplegia delivery, imaging the intramyocardial flow and ensuring adequate protection of the subendocardium during mitral valve repair. Mild aortic regurgitation on a beating heart often leads to left ventricular dilatation with diminished cardioplegia flow in the myocardium, thus requiring direct ostia cardioplegia. Systematic transesophageal echocardiography assessment before surgery is essential for establishing the mitral regurgitation mechanisms and translating them into precise surgical repair strategies. The benefits of transesophageal echocardiography-guided cardioplegia delivery warrant further clinical trials in order to evolve into part of a high surgical standard.

Surgical Complexity and Outcome of Patients Undergoing Re-do Aortic Valve Surgery.

Objectives: Re-do aortic valve surgery carries a higher mortality and morbidity compared with first time aortic valve replacement (AVR) and often requires concomitant complex procedures. Transcatheter aortic valve replacement (TAVR) is an option for selective patients. The aim of this study is to present our experience with re-do aortic valve procedures and give an insight into the characteristics of these patients and their outcomes. Methods: Retrospective review of 80 consecutive re-do aortic valve procedures. Results: Mean patients' age was 51.80±18.73 years. Aortic regurgitation (AR) was present in 51 (65.4%) patients and aortic stenosis (AS) in 38 (48.7%). Indications for reoperation were: infective endocarditis (IE) (23.8%), bioprosthetic degeneration (12.5%), mechanical valve dysfunction (5%), paravalvular leak (6.2%), patient-prosthesis mismatch (3.8%), native valve disease (25%), aortic aneurysm, pseudoaneurysm and dissection (35%), aortic root/homograft degeneration (27.5%). Forty-one (51.2%) patients underwent re-do AVR, 39 (48.8%) re-do complex aortic valve surgery (28 root, 23 ascending aorta and 6 hemiarch procedures) and 37.5% concomitant procedures. A bioprosthesis was implanted in 43.8%, a mechanical valve in 37.5%, a composite graft in 2.5%, a Biovalsalva graft in 6.2% and a homograft in 10% of patients. In-hospital mortality was 3.8% and incidence of major complications was low. Conclusions: A significant proportion of patients were young (61%<60 y), required complex aortic procedures (49%) or presented with contraindications for TAVR (mechanical valve, AR, IE, proximal aortic disease, need for concomitant surgery). Re-do aortic surgery remains the only treatment for such challenging cases and can be performed with acceptable mortality and morbidity in a specialised aortic centre.

Coronary Injury in Mitral and Aortic Valve Surgery: A Case Series Using Optical Coherence Tomography.

Coronary occlusion is a rare but well-described complication of heart valve surgery. The left circumflex coronary artery, especially when it is dominant, is particularly at risk owing to the proximity of the mitral valve annulus. We report three cases of acute coronary complications of different valvular surgical procedures diagnosed and treated in the cardiac catheterization laboratory. Intracoronary optical coherence tomography was used to identify the cause of coronary flow impairment and provided important insights into the mechanism of intraoperative vascular damage.

Aortic valve repair techniques: an early UK experience.

Objectives: Retrospective review of early results with aortic valve repair (AVr) techniques. Methods: 61 consecutive patients underwent AVr surgery at our institutions between 2008 and 2018. 14 patients had a bicuspid aortic valve and 16 had a connective tissue disorder. In 48 patients, aortic regurgitation (AR) was secondary to an aortic root and/or ascending aneurysms, while in 13 it was due to primary cusp pathologies. 13 patients underwent isolated cusp repair, 19 sinotubular junction remodelling, 25 valve-sparing root replacement (VSRR) and 4 hemiroot replacement. Cusp repair techniques included: 18 free margin plication, 18 commissural re-suspensions, 3 raphe resections and 1 free-edge reinforcement. Subcommissural annuloplasty was performed in 25 patients (42%) with a dilated annulus (>28 mm). Results: 50 patients (82%) left the operating theatre with no AR, 8 with mild central and 3 with mild eccentric AR. In-hospital survival was 100%. Clinical follow-up was complete at 5.08±2.29 years and all patients were alive. Transthoracic echocardiographic follow-up was complete at 2.35±1.92 years and showed the presence of a moderate AR in 10 patients (18%) and severe AR in 2 patients (4%). One of these required re-do aortic valve replacement 6 years after VSRR. Freedom from re-operation at 8 years was 88.15%±1.51%. Conclusion: Good early results are achievable following AVr with acceptable medium-term outcomes. AVr surgery continues to evolve, and concentrating the experience in specialist centres in the UK is recommended.

An Option for Concomitant Management of Moderate Marfan Root Aneurysm at the Time of Mitral Valve Repair: A Role for Personalized External Aortic Root Support.

Two patients had mitral valve repair for severe regurgitation in the presence of a Marfan aortic root aneurysm. Concomitant personalized external aortic root support was used at the same operation to halt aneurysm progression and to correct mild aortic regurgitation.

Incremental value of contrast echocardiography in the diagnosis of left ventricular noncompaction.

Contrast echocardiography with left ventricular opacification (LVO) improves the definition of endocardium in two-dimensional echocardiography (2DE). This study was aimed to determine whether LVO offered added diagnostic value in noncompaction of left ventricular myocardium (NCVM). A total of 85 patients (40 ± 20 years, 54 males) with suspected NCVM were subjected to transthoracic 2DE and LVO, and 40 healthy volunteers were examined with 2DE and assigned as control subjects. The location of NCVM, the thickness ratio of noncompacted to compacted myocardium (NCR), and the cavity size and ejection fraction of LV were quantified. Results revealed that NCVM was mainly located in the LV medium (53.2%), apical (46.2%) segments, and lateral wall (39.8%). The NCR obtained through LVO was greater than that detected through 2DE (4.2 ± 1.3 vs. 3.3 ±1.2, P < 0.001), and higher inter-correlations and less intra- and inter-observer variabilities were determined in the former than in the latter. The NCVM detection rates were also increased from 63.5% via 2DE to 83.5% via LVO and 89.4% via 2DE combined with LVO (2DE + LVO) (P = 0.0004). The LV cavity size was greater and the LVejection fraction (LVEF) was lower in the NCVM patients than in the control group (P < 0.01). In the NCVM group, the LV cavity size was higher and the LVEF was lower in LVO than in 2DE (P < 0.01). In conclusion, contrast echocardiography contributes significant sensitivity and reproducibility to routine transthoracic echocardiography in NCVM diagnosis. Therefore, this technique should be clinically performed to diagnose suspected NCVM.

Elucidation of cardiac physiology in aortic valve replacement: what should we know?

Over the past 50 years, aortic valve surgery has achieved enormous progress towards restoring durable and physiological performance of aortic valve prostheses, physiological coronary circulation, and thus the normal structure and function of the left ventricle. Throughout the entire history of aortic valve surgery, it has been clear that interactions between surgeons and physicians have not only led to improvements in operative techniques and results, but have also facilitated a better understanding of left ventricupathophysiology underlying the surgery. Embracing genetic technology with classical cardiac physiology will create a new platform to yield a more in-depth understanding of the nature of myocardial adaptation to pressure and volume changes associated with valve disease, and myocardial responses to heart valve surgery. Ultimately, this new knowledge will have a significant impact on heart valve surgery and cardiac medicine.

The evolution of surgical and medical treatment of aortic root aneurysm.

Since first report of aortic root replacement in 1968, the surgical risk and long term outcome of patients with aortic root aneurysm have been continuously improving. In the last 30 years, the surgical approach is also evolving towards more valve conservation with prophylactical intervention at an earlier clinical stage. Translational research has also led to emerging surgical innovation and new drug therapy. Their efficacies are currently under vigorous clinical trials and evaluations.

PAK1 is a novel cardiac protective signaling molecule.

We review here the novel cardiac protective effects of the multifunctional enzyme, p21-activated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAK1 signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates.We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca(2+) homeostasis and electrophysiological stability under physiological, ß-adrenergic and hypertrophic stress conditions.

A prospective, randomized, placebo-controlled, double-blind, multicenter study of the effects of irbesartan on aortic dilatation in Marfan syndrome (AIMS trial): study protocol.

BACKGROUND: Cardiovascular complications are the leading cause of mortality and morbidity in Marfan syndrome (MFS), a dominantly inherited disorder caused by mutations in the gene that encodes fibrillin-1. There are approximately 18,000 patients in the UK with MFS. Current treatment includes careful follow-up, beta blockers, and prophylactic surgical intervention; however, there is no known treatment which effectively prevents the rate of aortic dilatation in MFS. Preclinical, neonatal, and pediatric studies have indicated that angiotensin receptor blockers (ARBs) may reduce the rate of aortic dilatation. This trial will investigate the effects of irbesartan on aortic dilatation in Marfan syndrome. METHODS/DESIGN: The Aortic Irbesartan Marfan Study (AIMS) is an investigator-led, prospective, randomized, placebo-controlled, double-blind, phase III, multicenter trial. Currently, 26 centers in the UK will recruit 490 clinically confirmed MFS patients (aged ≥6 to ≤40 years) using the revised Ghent diagnostic criteria. Patients will be randomized to irbesartan or placebo. Aortic root dilatation will be measured by transthoracic echocardiography at baseline and annually thereafter. The primary outcome is the absolute change in aortic root diameter per year measured by echocardiography. The follow-up period will be a minimum of 36 months with an expected mean follow-up period of 48 months. DISCUSSION: This is the first clinical trial to evaluate the ARB irbesartan versus placebo in reducing the rate of aortic root dilatation in MFS. Not only will this provide useful information on the safety and efficacy of ARBs in MFS, it will also provide a rationale basis for potentially lifesaving therapy for MFS patients. TRIAL REGISTRATION: ISRCTN, 90011794.

Local suture annuloplasty for posterior mitral valve repair: 18-year experience.

We retrospectively reviewed 128 consecutive patients who underwent quadrangular resection of a prolapsed posterior mitral leaflet and local suture annuloplasty. The median age was 68.1 ± 10.0 years (range, 30-84 years) and 63.3% were male. Mean left ventricular ejection fraction was 63.8% ± 10.2% (range, 25%-80%). The etiology of mitral regurgitation was fibroelastic degeneration in 94 (73.4%) patients, myxomatous degeneration in 26 (20.3%), myxomatous infective endocarditis in 7 (5.5%), and post-infarction papillary rupture in one. There was 1 (0.8%) hospital death. The median follow-up was 4.7 ± 4.7 years (range, 0.01-18.29 years). The freedom from reoperation was 98%, 94%, 87%, and 79% at 1, 5, 10, and 15 years, respectively, improving for the most recent 107 patients, subsequent to technical modification, to: 100%, 96%, 94%, and 90% at 1, 5, 10, and 14 years, respectively. Ten- and 15-year freedom from severe mitral regurgitation was 91%, and 88%, respectively. The overall actuarial 1-, 5-, 10-, and 15-year survival rates were 98%, 90%, 70%, and 52%, respectively, similar to that of the age- and sex-matched United Kingdom population. The long-term results of this technique in selected patients with prolapsed posterior leaflet were considered acceptable.

3f prosthesis aortic cusp replacement: implantation technique and early results.

Stentless aortic bioprostheses have been successfully used for over a decade. The 3f bioprosthesis is a new equine pericardial stentless valve, unique in its tubular design, preserving the native aortic sinuses post-implant. Forty-six consecutive aortic valve replacements with the 3f bioprosthesis were performed between June 2003 and January 2005. The patients were prospectively assessed and echocardiography was performed at 6 months, 12 months, and annually thereafter. The median follow-up was 2.1 + or - 0.9 years. There was one early and 4 late deaths; none were valve-related. The 2-year mean transvalvular gradient was 8.8 + or - 3.8 mm Hg, the mean echocardiographic aortic regurgitation grade was 0.4 + or - 0.7 (grade 1 being trivial). Echocardiographic sizing of the aortic annulus before surgery accurately predicted prosthesis size. The 3f bioprosthesis is easy to implant. Early clinical results are favorable, with hemodynamic profiles consistent with those of other stentless prostheses. Longer follow-up is required to confirm its durability.

Prosthetic valve endocarditis.

Prosthetic valve endocarditis is a catastrophic complication of cardiac valve replacement, associated with high mortality rates. Medical treatment is effective in a few instances of endocarditis involving the leaflets alone in bioprostheses. However, accurate diagnosis, better myocardial protection, and improved surgical strategies have led to better survival in patients undergoing surgery after failed conservative therapy. This comprehensive review addresses various issues involved in the management of this complication.