Enriquez-Sarano, Maurice

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

Abstract Aims Pulmonary regurgitation (PR) after reparative intervention for congenital heart disease has been studied extensively. However, the burden, distribution of causes, and outcome of PR in adults is unknown. The study aimed to evaluate the prevalence, types, and outcomes of moderate/severe PR in adults in the community setting. Methods and results A total of 398 adult residents of Olmsted County who had clinically indicated echocardiography 2004–2023 at Mayo Clinic, Rochester, and had moderate or severe PR were identified retrospectively. The median age was 77 years, 48% were females, and 61 (51%) had severe PR. The age- and sex-adjusted US prevalence was 0.11% (vs. 0.67% for ≥moderate tricuspid regurgitation). Moderate/severe PR was due to pulmonary hypertension in 77%, congenital/iatrogenic in 11%, primary pulmonary valve disease in 2% (88% due to carcinoid), and idiopathic isolated in 10%. In contrast, severe PR was due to congenital/iatrogenic disease in 52%, pulmonary hypertension in 39%, primary PR in 5%, and isolated idiopathic in 3%. The all-cause mortality rate per 100 person-year was 73 in primary (mostly carcinoid) PR, 16 in pulmonary hypertension–related PR (not different vs. propensity-matched patients without PR), and 6 in isolated idiopathic PR (not different vs. matched patients without PR). Conclusion Moderate or severe PR had a lower prevalence vs. TR. The most frequent cause was pulmonary hypertension for ≥moderate PR and congenital/iatrogenic for severe PR. Mortality in patients with acquired ≥moderate PR appeared to be related to the underlying cause, with no excess mortality compared with matched patients without PR. Whether specifically severe PR confers excess mortality requires future investigation.

Background The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with mortality in patients with DMR. Methods and Results We used data from the MIDA‐Q (Mitral Regurgitation International DAtabase‐Quantitative) registry, which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 2917 (mean age: 66 years, 70.8% male patients, follow‐up: 5.2 [3.3–8.3] years) consecutive patients with severe DMR was included and long‐term mortality was analyzed. RVD, identified in 426 (14.6%) patients, was associated with reduced 8‐year survival (55%±3% versus 77%±1%; P <0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures, and surgery (adjusted hazard ratio, 1.44 [95% CI, 1.17–1.77]; P <0.001). This excess mortality was observed under medical management (adjusted hazard ratio, 1.57 [95% CI, 1.20–2.05]; P =0.001) and after surgical correction of mitral regurgitation (adjusted hazard ratio, 1.45 [95% CI, 1.02–2.05]; P =0.039). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 8‐year survival (73%±4% versus 43%±4%; P <0.001), even after adjustment (adjusted hazard ratio, 0.44 [95% CI, 0.29–0.67]; P <0.001) despite an increase of 1‐month postoperative mortality (7.1% versus 0.5% for patients without RVD; P <0.001). Conclusions RVD is observed in 14.6% of severe DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision‐making process.

Abstract Aims Degenerative mitral stenosis (DMS) is due to degenerative mitral annular calcification (MAC) and valvular calcification. However, DMS impacts on the outcome, and therefore, potential treatment needs are poorly known. We aimed at evaluating survival after DMS diagnosis by Doppler echocardiography in routine practice. Methods and results A cohort of 2937 (75 ± 12 years, 67% women) consecutive patients were diagnosed between 2003 and 2014 with DMS (diastolic mean gradient ≥ 5 mmHg), with analysis of short- and long-term survival. All patients had overt mitral annular/valvular degenerative calcification without rheumatic involvement. Mean gradient was 6.5 ± 2.4 mmHg, and DMS was considered mild in 50%, moderate in 44%, and severe in 6%. DMS was associated with left atrial enlargement (52 ± 23 mL/m2) and elevated pulmonary pressure (49 ± 16 mmHg) despite generally normal ejection fraction (61 ± 13%). DMS was associated with frequent comorbid conditions (74% hypertension, 58% coronary disease, and 52% heart failure) and humoural alterations (haemoglobin 11.3 ± 1.8 g/dL and creatinine 1.5 ± 1.4 mg/dL). One-year mortality was 22%, most strongly related to older age, higher comorbidity, and abnormal haemoglobin/creatinine but only weakly to DMS severity (with anaemia 42% irrespective of DMS severity, P = 0.99; without anaemia 18, 23, and 28% with mild, moderate, and severe DMS, respectively, P &lt; 0.0004). Long-term mortality was high (56% at 5 years) also mostly linked to aging and weakly to DMS severity [with anaemia P = 0.90; without anaemia: adjusted-hazard ratio: 1.30 (1.19–1.42), P &lt; 0.0001, for moderate vs. mild DMS and 1.63 (1.34–1.98), P &lt; 0.0001, for severe vs. mild DMS]. Conclusion DMS is a condition of the elderly potentially resulting in severe mitral obstruction and haemodynamic alterations. However, DMS is frequently associated with severe comorbidities imparting considerable mortality following diagnosis, whereas DMS severity is a weak (albeit independent) determinant of mortality. Hence, patients with DMS should be carefully evaluated and interventional/surgical treatment prudently considered in those with limited comorbidity burden, particularly without anaemia. Keywords: Degenerative Mitral Stenosis; Outcome; Natural history; Ecocardiography; Mitral Stenosis.

Abstract Background and Aims Severe tricuspid regurgitation is associated with increased mortality rates, but benefit of its correction and ideal timing are not clearly determined. This study aimed to identify patient subsets who might benefit from the surgery. Methods In TRIGISTRY, an international cohort study of consecutive patients with severe isolated functional tricuspid regurgitation (33 centres, 10 countries), survival rates up to 10 years were compared between patients who underwent isolated tricuspid valve surgery (repair or replacement) and those conservatively managed, overall and according to TRI-SCORE category (low: ≤3, intermediate: 4–5, and high: ≥6). Results One thousand and two hundred seventeen were managed conservatively, and 551 underwent isolated tricuspid valve surgery (200 repairs and 351 replacements). TRI-SCORE distribution was 33% low, 32% intermediate, and 35% high. At 10 years, survival rates were similar between surgical and conservative management [41% vs. 36%; hazard ratio (HR) .97; 95% confidence interval (CI) .88–1.08, P = .57]. Surgery improved survival compared with conservative management in the low TRI-SCORE category (72% vs. 44%; HR .27; 95% CI .20–.37, P &lt; .0001), but not in the intermediate (36% vs. 37%; HR 1.17; 95%CI .98–1.40, P = .09) or high categories (20% vs. 24%; HR 1.06; 95% CI .91–1.25, P = .45). Both repair and replacement improved survival in the low TRI-SCORE category (84% and 61% vs. 44%; HR .11; 95% CI .06–.19, P &lt; .0001, and HR .65; 95% CI .47–.90, P = .009). Repair showed benefit in the intermediate category (59% vs. 37%; HR .49; 95% CI .35–.68, P &lt; .0001) while replacement was possibly harmful (25% vs. 37%; HR 1.43; 95% CI 1.18–1.72, P = .0002). Conclusions Higher survival rates were observed with repair than replacement and benefit of intervention declined as TRI-SCORE increased with no benefit of any type of surgery in the high TRI-SCORE category. These results emphasize the importance of timely intervention and patient selection to achieve the best outcomes and the need for randomized controlled trials.

Abstract Aims In patients with degenerative mitral regurgitation (DMR), left ventricular (LV) dysfunction is associated with increased risk of heart failure and excess mortality. LV end‐systolic diameter (LVESD) is an established trigger for intervention, yet recommended LVESD thresholds apply poorly to patients with small body size. Whether LV normalization to body surface area (BSA) may be used as a trigger for DMR correction is unknown. We examined the link between LVESD index (LVESDi) and outcome in DMR to identify appropriate thresholds for excess mortality. Methods and results This study focuses on 2753 consecutive patients with DMR due to flail leaflets diagnosed in tertiary centres from Europe and the United States, with prospective echocardiographic measurement of LVESD and BSA and long‐term follow‐up. The primary endpoint was mortality after diagnosis under conservative management. Secondary endpoints were mortality under conservative and surgical management and postoperative mortality of patients who underwent surgery. The optimal LVESDi cut‐off for mortality prediction was 20 mm/m 2 . Irrespective of management type, 10‐year survival was lower with LVESDi ≥20 mm/m 2 than with LVESDi <20 mm/m 2 (both p < 0.001). After covariate adjustment, LVESDi ≥20 mm/m 2 was independently predictive of mortality under conservative management (adjusted hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.15–1.75), and with conservative and surgical management (adjusted HR 1.34, 95% CI 1.17–1.54). LVESDi remained associated with poorer postoperative outcome in patients who underwent intervention. LVESDi showed higher incremental predictive value over the baseline model compared to LVESD. The association between LVESDi ≥20 mm/m 2 and outcome was consistent in subgroups of patients with DMR. Conclusions In severe DMR due to flail leaflets, LVESDi is a marker of risk additive and incremental to LVESD. Its use in clinical practice should lead to earlier referral to mitral valve surgery and improved long‐term outcome.

Abstract Aims Operating on patients with severe degenerative mitral regurgitation (DMR) is based on ACC/AHA or ESC/EACTS guidelines. Doubts persist on best surgical indications and their potential association with postoperative survival loss. We sought to investigate whether guideline-based indications lead to late postoperative survival loss in DMR patients. Methods and results We analysed outcome of 2833 patients from the Mitral Regurgitation International Database registry undergoing surgical correction of DMR. Patients were stratified by surgical indications: Class I trigger (symptoms, left ventricular end-systolic diameter ≥ 40 mm, or left ventricular ejection fraction &lt; 60%, n = 1677), isolated Class IIa trigger [atrial fibrillation (AF), pulmonary hypertension (PH), or left atrial diameter ≥ 55 mm, n = 568], or no trigger (n = 588). Postoperative survival was compared after matching for clinical differences. Restricted mean survival time (RMST) was analysed. During a median 8.5-year follow-up, 603 deaths occurred. Long-term postoperative survival was lower with Class I trigger than in Class IIa trigger and no trigger (71.4 ± 1.9, 84.3 ± 2.3, and 88.9 ± 1.9% at 10 years, P &lt; 0.001). Having at least one Class I criterion led to excess mortality (P &lt; 0.001), while several Class I criteria conferred additional death risk [hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.42–1.66]. Isolated Class IIa triggers conferred an excess mortality risk vs. those without (HR: 1.46, 95% CI: 1.00–2.13, P = 0.05). Among these patients, isolated PH led to decreased postoperative survival vs. those without (83.7 ± 2.8% vs. 89.3 ± 1.6%, P = 0.011), with the same pattern observed for AF (81.8 ± 5.0% vs. 88.3 ± 1.5%, P = 0.023). According to RMST analysis, compare to those operated on without triggers, operating on Class I trigger patients led to 9.4-month survival loss (P &lt; 0.001) and operating on isolated Class IIa trigger patients displayed 4.9-month survival loss (P = 0.001) after 10 years. Conclusion Waiting for the onset of Class I or isolated Class IIa triggers before operating on DMR patients is associated with postoperative survival loss. These data encourage an early surgical strategy.

Abstract Aims Aortic valve calcification (AVC) is prognostic in patients with aortic stenosis (AS). We assessed the AVC prognostic value in non-severe AS patients. Methods and results We conducted a retrospective study of 395 patients with non-severe AS, LVEF ≥ 50%. The Agatston method was used for CT AVC assessment. The log-rank test determined the best AVC cut-offs for survival under medical surveillance: 1185 arbitrary unit (AU) in men and 850 AU in women, lower than the established cut-offs for severe AS (2064 AU in men and 1274 AU in women). Patients were divided into 3 AVC groups based on these cut-offs: low (&lt;1185 AU in men and &lt;850 AU in women), sub-severe (1185–2064 AU in men and 850–1274 AU in women), and severe (&gt;2064 AU in men and &gt;1274 AU in women). Of 395 patients (mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30 cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention (AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1 (0.7–4.9) years. Compared with the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score (all P ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups (all P ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC (all P ≤ 0.01), but not in the low AVC groups. Conclusion Sub-severe AVC is a robust risk stratification parameter in patients with non-severe AS and may inform AVI timing.

Abstract Background and Aims Presentation, outcome, and management of females with degenerative mitral regurgitation (DMR) are undefined. We analysed sex-specific baseline clinical and echocardiographic characteristics at referral for DMR due to flail leaflets and subsequent management and outcomes. Methods In the Mitral Regurgitation International Database (MIDA) international registry, females were compared with males regarding presentation at referral, management, and outcome (survival/heart failure), under medical treatment, post-operatively, and encompassing all follow-up. Results At referral, females (n = 650) vs. males (n = 1660) were older with more severe symptoms and higher MIDA score. Smaller cavity diameters belied higher cardiac dimension indexed to body surface area. Under conservative management, excess mortality vs. expected was observed in males [standardized mortality ratio (SMR) 1.45 (1.27–1.65), P &lt; .001] but was higher in females [SMR 2.00 (1.67–2.38), P &lt; .001]. Female sex was independently associated with mortality [adjusted hazard ratio (HR) 1.29 (1.04–1.61), P = .02], cardiovascular mortality [adjusted HR 1.58 (1.14–2.18), P = .007], and heart failure [adjusted HR 1.36 (1.02–1.81), P = .04] under medical management. Females vs. males were less offered surgical correction (72% vs. 80%, P &lt; .001); however, surgical outcome, adjusted for more severe presentation in females, was similar (P ≥ .09). Ultimately, overall outcome throughout follow-up was worse in females who displayed persistent excess mortality vs. expected [SMR 1.31 (1.16–1.47), P &lt; .001], whereas males enjoyed normal life expectancy restoration [SMR 0.92 (0.85–0.99), P = .036]. Conclusions Females with severe DMR were referred to tertiary centers at a more advanced stage, incurred higher mortality and morbidity under conservative management, and were offered surgery less and later after referral. Ultimately, these sex-related differences yielded persistent excess mortality despite surgery in females with DMR, while males enjoyed restoration of life expectancy, warranting imperative re-evaluation of sex-specific DMR management.

Abstract Background and Aims Severe aortic stenosis (AS) is the guideline-based indication for aortic valve replacement (AVR), which has markedly increased with transcatheter approaches, suggesting possible increasing AS incidence. However, reported secular trends of AS incidence remain contradictory and lack quantitative Doppler echocardiographic ascertainment. Methods All adults residents in Olmsted County (MN, USA) diagnosed over 20 years (1997–2016) with incident severe AS (first diagnosis) based on quantitatively defined measures (aortic valve area ≤ 1 cm2, aortic valve area index ≤ 0.6 cm2/m2, mean gradient ≥ 40 mmHg, peak velocity ≥ 4 m/s, Doppler velocity index ≤ 0.25) were counted to define trends in incidence, presentation, treatment, and outcome. Results Incident severe AS was diagnosed in 1069 community residents. The incidence rate was 52.5 [49.4–55.8] per 100 000 patient-year, slightly higher in males vs. females and was almost unchanged after age and sex adjustment for the US population 53.8 [50.6–57.0] per 100 000 residents/year. Over 20 years, severe AS incidence remained stable (P = .2) but absolute burden of incident cases markedly increased (P = .0004) due to population growth. Incidence trend differed by sex, stable in men (incidence rate ratio 0.99, P = .7) but declining in women (incidence rate ratio 0.93, P = .02). Over the study, AS clinical characteristics remained remarkably stable and AVR performance grew and was more prompt (from 1.3 [0.1–3.3] years in 1997–2000 to 0.5 [0.2–2.1] years in 2013–16, P = .001) but undertreatment remained prominent (&gt;40%). Early AVR was associated with survival benefit (adjusted hazard ratio 0.55 [0.42–0.71], P &lt; .0001). Despite these improvements, overall mortality (3-month 8% and 3-year 36%), was swift, considerable and unabated (all P ≥ .4) throughout the study. Conclusions Over 20 years, the population incidence of severe AS remained stable with increased absolute case burden related to population growth. Despite stable severe AS presentation, AVR performance grew notably, but while declining, undertreatment remained substantial and disease lethality did not yet decline. These population-based findings have important implications for improving AS management pathways.