Purpose: Our study aimed to determine whether 4D cardiac computed tomography (4DCCT) based quantitative myocardial analysis may improve risk stratification and can predict reverse remodeling (RRM) and mortality after transcatheter aortic valve implantation (TAVI). Methods: Consecutive patients undergoing clinically indicated 4DCCT prior to TAVI were prospectively enrolled. 4DCCT-derived left- (LV) and right ventricular (RV), and left atrial (LA) dimensions, mass, ejection fraction (EF) and myocardial strain were evaluated to predict RRM and survival. RRM was defined by either relative increase in LVEF by 5% or relative decline in LV end diastolic diameter (LVEDD) by 5% assessed by transthoracic echocardiography prior TAVI, at discharge, and at 12-month follow-up compared to baseline prior to TAVI. Results: Among 608 patients included in this study (55 % males, age 81 +/- 6.6 years), RRM was observed in 279 (54 %) of 519 patients at discharge and in 218 (48 %) of 453 patients at 12-month echocardiography. While no CCT based measurements predicted RRM at discharge, CCT based LV mass index and LVEF independently predicted RRM at 12-month (ORadj = 1.012; 95 %CI:1.001-1.024; p = 0.046 and ORadj = 0.969; 95 % CI:0.943-0.996; p = 0.024, respectively). The most pronounced changes in LVEF and LVEDD were observed in patients with impaired LV function at baseline. In multivariable analysis age (HRadj = 1.037; 95 % CI:1.005-1.070; p = 0.022) and CCT-based LVEF (HRadj = 0.972; 95 %CI:0.945-0.999; p = 0.048) and LAEF (HRadj = 0.982; 95 %CI:0.968-0.996; p = 0.011) independently predicted survival. Conclusion: Comprehensive myocardial functional information derived from routine 4DCCT in patients with severe aortic stenosis undergoing TAVI could predict reverse remodeling and clinical outcomes at 12-month following TAVI.

Background: Conduction system disease, atrial and ventricular arrhythmias may require pacemaker or ICD implantation in transthyretin amyloid cardiomyopathy (ATTR-CM). The optimal pacing mode in ATTR-CM patients remains unknown. Objective: To assess how availability of cardiac resynchronization and conduction system pacing influenced pacemaker indications and to compare early electrical performance of conventional, resynchronisation and conduction system pacing in ATTR-CM. Methods and Results: 67 of 250 (26.8%) patients presenting with ATTR-CM between June 2019 and February 2023 received a pacemaker [HA1] and were included in this retrospective analysis. Pacemaker implantation occurred in 25 patients (37.3%) prior to, and in 42 (62.7%) after ATTR-CM diagnosis. Implantation of conventional single- (VVI) or dual-chamber (DDD) pacemakers was more common (n=17/25, 68%) in undiagnosed ATTR-CM, while physiological pacing systems (CRT/ CSP) were preferably implanted in patients (n=24/42; 57.1%) after diagnosis. Sick sinus syndrome (11/35; 31.4% vs. 6/32; 18.8%) and higher degree AV-block (20/35; 57.1% vs. 9/32; 28.1%) were more common indications for VVI/DDD compared to CRT/CSP pacemakers, with pursuit of a pace/ablate strategy (12/32; 37.5%) and heart failure (5/32; 15.6%) contributing significantly to implantation of CRT/CSP. QRS width was significantly lower with CSP [122ms (IQR: 120-139)], compared to CRT [155ms (IQR: 141-160); p=0.005] or VVI/DDD [160ms (IQR: 144-180)], with the latter resulting in a significant increase in QRS width compared to intrinsic QRS [from 138 (IQR: 123-150) (p<0.001)]. LV/LBBAP pacing capture thresholds (0.4ms pulse width) were significantly lower after CSP [0.75V (IQR: 0.5-1.2)] compared to CRT [1.3V (IQR: 1.0-1.6); p=0.049]. RA and RV lead performance were comparable between all pacing systems (p>0.05). Conclusions: Pacing indications are changing with earlier diagnosis of ATTR-CM. CSP may offer improved electrical performance and resynchronization, the effect of conduction system pacing on clinical outcomes should be further explored.

Amyloid transthyretin (ATTR) amyloidosis is a protein-misfolding disease characterized by fibril accumulation in the extracellular space that can result in local tissue disruption and organ dysfunction. Cardiac involvement drives morbidity and mortality, and the heart is the major organ affected by ATTR amyloidosis. Multimodality cardiac imaging (ie, echocardiography, scintigraphy, and cardiac magnetic resonance) allows accurate diagnosis of ATTR cardiomyopathy (ATTR-CM), and this is of particular importance because ATTR-targeting therapies have become available and probably exert their greatest benefit at earlier disease stages. Apart from establishing the diagnosis, multimodality cardiac imaging may help to better understand pathogenesis, predict prognosis, and monitor treatment response. The aim of this review is to give an update on contemporary and evolving cardiac imaging methods and their role in diagnosing and managing ATTR-CM. Further, an outlook is presented on how artificial intelligence in cardiac imaging may improve future clinical decision making and patient management in the setting of ATTR-CM.

Quantitative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]Tc-DPD) SPECT may be used for risk-stratifying patients with amyloid transthyretin-related cardiomyopathy (ATTR-CM). We aimed to analyze the predictive value of quantitative [99mTc]Tc-DPD SPECT/CT in suspected and confirmed ATTR-CM according to different disease stages. Methods: The study enrolled consecutive patients with suspected ATTR-CM who were referred to a single tertiary center and underwent quantitative [99mTc]Tc-DPD SPECT/CT allowing SUVmax and SUVpeak analysis. Patients were divided into 2 groups according to left ventricular ejection fraction (LVEF) at baseline (i.e., ≥50% and <50%). Clinical, laboratory, and echocardiographic parameters and major adverse cardiac events (i.e., all-cause death, sustained ventricular tachyarrhythmia, hospitalization for heart failure, implantation of a cardioverter defibrillator) were investigated for any correlation with quantitative uptake values. Results: In total, 144 patients with suspected ATTR-CM were included in the study (98 with LVEF ≥ 50% and 46 with LVEF < 50%), of whom 99 were diagnosed with ATTR-CM (68.8%; 69 with LVEF ≥ 50% and 30 with LVEF < 50%). A myocardial SUVmax of at least 7 was predictive of major adverse cardiac events at 21.9 ± 13.0 mo of follow-up (hazard ratio, 2.875; 95% CI, 1.23-6.71; P = 0.015) in patients with suspected or confirmed ATTR-CM (global χ2 = 6.892, P = 0.02) and an LVEF of at least 50%. SUVmax was not predictive in patients with an LVEF of less than 50% and suspected or confirmed ATTR-CM. Conclusion: In patients with suspected or confirmed ATTR-CM and preserved LVEF, representing an early disease stage, quantitative [99mTc]Tc-DPD SPECT should be considered to improve early-stage risk stratification.

AbstractAimsTafamidis improves clinical outcomes in transthyretin amyloid cardiomyopathy (ATTR‐CM), yet how tafamidis affects cardiac structure and function remains poorly described. This study prospectively analysed the effect of tafamidis on 12‐month longitudinal changes in cardiac structure and function by cardiac magnetic resonance (CMR) compared with the natural course of disease in an untreated historic control cohort.Methods and resultsATTR‐CM patients underwent CMR at tafamidis initiation and at 12 months. Untreated patients with serial CMRs served as reference to compare biventricular function, global longitudinal strain (GLS), LV mass and extracellular volume fraction (ECV). Thirty‐six tafamidis‐treated (n = 35; 97.1% male) and 15 untreated patients (n = 14; 93.3% male) with a mean age of 78.3 ± 6.5 and 76.9 ± 6.5, respectively, and comparable baseline characteristics were included. Tafamidis was associated with preserving biventricular function (LVEF (%): 50.5 ± 12 to 50.7 ± 11.5, P = 0.87; RVEF (%): 48.2 ± 10.4 to 48.2 ± 9.4, P = 0.99) and LV‐GLS (−9.6 ± 3.2 to −9.9 ± 2.4%; P = 0.595) at 12 months, while a significantly reduced RV‐function (50.8 ± 7.3 to 44.2 ± 11.6%, P = 0.028; P (change over time between groups) = 0.032) and numerically worsening LVGLS (−10.9 ± 3.3 to −9.1 ± 2.9%, P = 0.097; P (change over time between groups) = 0.048) was observed without treatment. LV mass significantly declined with tafamidis (184.7 ± 47.7 to 176.5 ± 44.3 g; P = 0.011), yet remained unchanged in untreated patients (163.8 ± 47.5 to 171.2 ± 39.7 g P = 0.356, P (change over time between groups) = 0.027). Irrespective of tafamidis, ECV and native T1‐mapping did not change significantly from baseline to 12‐month follow‐up (P > 0.05).ConclusionsCompared with untreated ATTR‐CM patients, initiation of tafamidis preserved CMR‐measured biventricular function and reduced LV mass at 12 months. ECV and native T1‐mapping did not change significantly comparable to baseline in both groups.

Background and Aims Randomized clinical trials (RCTs) assessing semaglutide reported reductions of systolic blood pressure (SBP) in trial populations with baseline blood pressure in the normotensive range. This study aimed to determine whether this SBP reduction is greater in hypertensive groups. Methods Individual patient data (IPD) from three RCTs examining the effect of semaglutide 2.4 mg on body weight over 68 weeks were included. Trial participants were categorized according to a hypertension diagnosis, treatment or baseline measurement (HTN), baseline SBP > 130 mmHg (HTN130) or >140 mmHg (HTN140), and those with apparent resistant hypertension (RH). The primary analysis compared the in-trial change in SBP in the semaglutide and placebo arms. Alterations of anti-hypertensive medications were quantified by treatment intensity score and compared between arms. These analyses were performed using analysis of covariance. Results Overall, 3136 participants were included. The difference in SBP change between the treatment (n = 2109) and placebo (n = 1027) groups was -4.95 mmHg [95% confidence interval (CI) -5.86 to -4.05] overall. This difference was -4.78 mmHg (95% CI -5.97 to -3.59) for HTN, -4.93 mmHg (95% CI -6.75 to -3.11) for HTN130, -4.09 mmHg (95% CI -7.12 to -1.06) for HTN140, and -3.16 mmHg (95% CI -8.69-2.37) for RH. Reduction in SBP was mediated substantially by weight loss. The anti-hypertensive treatment intensity score decreased for those on semaglutide compared to placebo (-0.51; 95% CI -0.71 to -0.32). Conclusions This IPD analysis of three large RCTs found blood pressure reductions with semaglutide in participants with hypertension that were similar to those seen in all trial participants. This finding may in part be due to concurrent reductions to anti-hypertensive medications. These results suggest that semaglutide is a useful adjunctive treatment for patients with hypertension and obesity.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a frequent concomitant condition in patients with severe aortic stenosis (AS), yet it often remains undetected. This study aims to comprehensively evaluate artificial intelligence-based models developed based on preprocedural and routinely collected data to detect ATTR-CM in patients with severe AS planned for transcatheter aortic valve implantation (TAVI). In this prospective, single-center study, consecutive patients with AS were screened with [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]-DPD) for the presence of ATTR-CM. Clinical, laboratory, electrocardiogram, echocardiography, invasive measurements, 4-dimensional cardiac CT (4D-CCT) strain data, and CT-radiomic features were used for machine learning modeling of ATTR-CM detection and for outcome prediction. Feature selection and classifier algorithms were applied in single- and multi-modality classification scenarios. We split the dataset into training (70

Background: Despite being the most commonly performed valvular intervention, risk prediction for aortic valve replacement in patients with severe aortic stenosis by currently used risk scores remains challenging. The study aim was to develop a biomarker-based risk score by means of a neuronal network. Methods: In this multicenter study, 3595 patients were divided into test and validation cohorts (70% to 30%) by random allocation. Input variables to develop the ABC-AS score were age, the cardiac biomarker high-sensitivity troponin T, and a patient history of cardiac decompensation. The validation cohort was used to verify the scores’ value and for comparison with the Society of Thoracic Surgery Predictive Risk of Operative Mortality score. Results: Receiver operating curves demonstrated an improvement in prediction by using the ABC-AS score compared to the Society of Thoracic Surgery Predictive Risk of Operative Mortality (STS prom) score. Although the difference in predicting cardiovascular mortality was most notable at 30-day follow-up (area under the curve of 0.922 versus 0.678), ABC-AS also performed better in overall follow-up (0.839 versus 0.699). Furthermore, univariate analysis of ABC-AS tertiles yielded highly significant differences for all-cause (p < 0.0001) and cardiovascular mortality (p < 0.0001). Head-to-head comparison between both risk scores in a multivariable cox regression model underlined the potential of the ABC-AS score (HR per z-unit 2.633 (95% CI 2.156–3.216), p < 0.0001), while the STS prom score failed to reach statistical significance (p = 0.226). Conclusions: The newly developed ABC-AS score is an improved risk stratification tool to predict cardiovascular outcomes for patients undergoing aortic valve intervention.

Background: Tafamidis reduces cardiovascular morbidity and mortality in transthyretin amyloid cardiomyopathy (ATTR-CM), yet availability and access to therapy vary. Objective: To determine how availability and access to tafamidis impact time-to-diagnosis, time-to-therapy, and cardiovascular outcomes in ATTR-CM. Methods: Ninety-one consecutive ATTR-CM (~97% wt-TTR) patients diagnosed between June 2019 and June 2021 were evaluated for tafamidis. Access to therapy was regulated by compassionate use [n(CU) = 42] prior to, and insurance [n(IA) = 49] after regulatory approval. Results: Tafamidis was started in 37/42 (88.1%), and 39/49 (79.6%) patients, respectively. At diagnosis, ATTR-CM disease stage (≤stage 2: 88.2% vs. 90.9%, p = 0.92) was similar between groups. Timely access (after tafamidis approval) reduced the median time from first presentation to diagnosis from 6.2 (IQR: 1.3–28.9) to 2.4 (0.7–21.7) months, and from first presentation to therapy from 24.4 (10.7–46.8) to 11.8 (6.4–32.4) months. While RV function significantly worsened between diagnosis and therapy initiation in CU patients diagnosed before tafamidis approval (S’-velocity 10.0 ± 2.2 to 9.2 ± 2.2 cm/s; p = 0.018; TAPSE 17.3 ± 4.7 to 15.7 ± 3.9 mm, p = 0.008), it remained unchanged in IA patients (S’-velocity 9.6 ± 2.6 to 9.4 ± 2.3 cm/s; p = 0.83; TAPSE 15.6 ± 4.2 to 16.3 ± 3.1 mm, p = 0.45). After a median follow-up of 42.3 and 24.9 months in CU and IA patients, respectively, timely availability was associated with a reduction in annual heart failure hospitalizations (0.40 vs. 0.16 per patient, p < 0.001) and improved MACE-free survival (HR = 0.51; 95%CI: 0.26–1.00; p = 0.051). Timely diagnosis (<12-months) prolonged MACE-free survival (HR = 0.424; 95%CI: 0.22–0.81; p = 0.004), and reduced HFH (HR = 0.40; 95%CI: 0.19–0.81); p = 0.011) and all-cause mortality (HR = 0.29; 95%CI: 0.11–0.74); p = 0.009). Conclusions: Availability of tafamidis improves diagnostic efficacy in ATTR-CM patients. Timely diagnosis and initiation of therapy reduces adverse cardiovascular events.

Abstract Background Randomised clinical trials of patients with obesity treated with semaglutide (STEP trials) reported clinically significant reductions in blood pressure (BP). The mean baseline BP of trial participants was in the normal range. The effect of semaglutide on patients with hypertension has yet to be elucidated. Purpose To determine the blood pressure effect of semaglutide in patients with uncontrolled BP at randomization (baseline BP). Methods Individual participant data from three randomised placebo-controlled trials examining the effect of semaglutide 2.4mg on body weight (STEP 1, 3 and 4) over 68 weeks were included (the Cohort). Participants with systolic BP (SBP) >140mmHg at baseline were identified (HTN140 group). The effect of semaglutide on SBP estimated by ANCOVA with baseline SBP as a covariate. Adjustments of antihypertensive treatment (escalated if treatment started or dose increased; de-escalated if treatment stopped or dose decreased) were assessed using logistic regression analysis adjusted for baseline SBP. Results 3136 participants were included in the pooled analysis. 397 (13%) had a baseline SBP >140mmHg (semaglutide arm, n=257; placebo arm, n=140). The baseline BP and body weight of the HTN140 group were comparable between treatment arms [Table 1]. The effect of semaglutide on SBP was estimated as -4.09mmHg (95% CI -7.12 to -1.06, p<0.05). This effect was comparable to that for the Cohort (-4.95mmHg; 95% CI -5.86 to -4.05, p<0.05). The observed SBP reduction was 17.41mmHg for those in the semaglutide arm and 12.57mmHg in the placebo arm (Figure 1). This large in-trial effect was partly due to the escalation of anti-hypertensive treatment in 11.3% and 14.3% of participants randomized to semaglutide and placebo respectively (OR 0.76; 95% CI 0.39 to 1.49, p=0.42). Conclusions The effect of semaglutide on SBP was not greater in patients with uncontrolled SBP at randomization compared to the Cohort of all patients in STEP 1, 3, 4. The adjustment of anti-hypertensive medications contributed to a large observed reduction in SBP for both trial arms. This demonstrates the Hawthorne effect during these trials. Effect on SBP

Left ventricular assist devices (LVADs) improve symptoms and outcomes in patients with advanced heart failure. We report the case of a patient with a freshly implanted HeartMate 3 LVAD, suffering abruptly on postoperative day 55 from pejoration of his heart failure with multiple episodes of low-flow alarm. Outflow graft obstruction (OGO) due to local aortic dissection was diagnosed with multimodality imaging. After a multidisciplinary discussion, a surgical approach was decided, and the patient benefited from a revision of his outflow graft.

Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard‐of‐care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in‐depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype‐first screening of asymptomatic individuals for Mendelian CVD. This approach could transform health care by diagnostic refinement and facilitating prevention or therapeutic interventions. Yet, potential benefits must be weighed against the potential risks, which include evolving variant pathogenicity assertion or identification of variants with low disease penetrance; costly, stressful, and inappropriate diagnostic evaluations; negative psychological impact; disqualification for employment or of competitive sports; and denial of insurance. Furthermore, the natural history of Mendelian CVD is often unpredictable, making identification of those who will benefit from preventive measures a priority. Currently, there is insufficient evidence that population‐based genetic screening for Mendelian CVD can reduce adverse outcomes at a reasonable cost to an extent that outweighs the harms of true‐positive and false‐positive results. Besides technical, clinical, and financial burdens, ethical and legal aspects pose unprecedented challenges. This review highlights key developments in the field of genotype‐first approaches to Mendelian CVD and summarizes challenges with potential solutions that can pave the way for implementing this approach for clinical care.

Click to increase image sizeClick to decrease image size AcknowledgmentsWe thank Laura Morf, Lukas Lüthi and Sakthivel Subramaniam from the research study team for their excellent technical and administrative support.Disclosure statementThe authors declare no conflict of interest.Data availability statementThe data underlying this article will be shared on reasonable request to the corresponding author.Additional informationFundingDr. Dobner received a research grant for the Bern amyloidosis registry (B-CARE) (NCT04776824) on behalf of the institution (Inselspital Bern) from Pfizer. Dr. Bernhard reports a career development grant from the Swiss National Science Foundation. Y. Safarkhanlo received research funding from the Centre for Artificial Intelligence in Medicine Research Project Fund University Bern, outside of the submitted work. Dr. Gräni received research funding from the GAMBIT foundation for the current study. Further Dr. Gräni received funding from the Swiss National Science Foundation, Innosuisse and from the Centre for Artificial Intelligence in Medicine Research Project Fund University Bern, outside of the submitted work. All other authors report no conflicts.

Background The prevalence of calcific aortic stenosis and amyloid transthyretin cardiomyopathy (ATTR‐CM) increase with age, and they often coexist. The objective was to determine the prevalence of ATTR‐CM in patients with severe aortic stenosis and evaluate differences in presentations and outcomes of patients with concomitant ATTR‐CM undergoing transcatheter aortic valve implantation. Methods and Results Prospective screening for ATTR‐CM with Technetium99‐3,3‐diphosphono‐1,2‐propanodicarboxylic acid bone scintigraphy was performed in 315 patients referred with severe aortic stenosis between August 2019 and August 2021. Myocardial Technetium99‐3,3‐diphosphono‐1,2‐propanodicarboxylic acid tracer uptake was detected in 34 patients (10.8%), leading to a diagnosis of ATTR‐CM in 30 patients (Perugini ≥2: 9.5%). Age (85.7±4.9 versus 82.8±4.5; P=0.001), male sex (82.4% versus 57.7%; P=0.005), and prior carpal tunnel surgery (17.6% versus 4.3%; P=0.007) were associated with coexisting ATTR‐CM, as were ECG (discordant QRS voltage to left ventricular wall thickness [42% versus 12%; P<0.001]), echocardiographic (left ventricular ejection fraction 48.8±12.8 versus 58.4±10.8; P<0.001; left ventricular mass index, 144.4±45.8 versus 117.2±34.4g/m2; P<0.001), and hemodynamic parameters (mean aortic valve gradient, 23.4±12.6 versus 35.5±16.6; P<0.001; mean pulmonary artery pressure, 29.5±9.7 versus 25.8±9.5; P=0.037). Periprocedural (cardiovascular death: hazard ratio [HR], 0.71 [95% CI, 0.04–12.53]; stroke: HR, 0.46 [95% CI, 0.03–7.77]; pacemaker implantation: HR, 1.54 [95% CI, 0.69–3.43]) and 1‐year clinical outcomes (cardiovascular death: HR, 1.04 [95% CI, 0.37–2.96]; stroke: HR, 0.34 [95% CI, 0.02–5.63]; pacemaker implantation: HR, 1.50 [95% CI, 0.67–3.34]) were similar between groups. Conclusions Coexisting ATTR‐CM was observed in every 10th elderly patient with severe aortic stenosis referred for therapy. While patients with coexisting pathologies differ in clinical presentation and echocardiographic and hemodynamic parameters, peri‐interventional risk and early clinical outcomes were comparable up to 1 year after transcatheter aortic valve implantation. REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT04061213.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) often coexists with severe aortic stenosis (AS). Although strain analysis from cardiac MRI and echocardiography was demonstrated to predict coexisting ATTR-CM, comparable data from four-dimensional (4D) cardiac CT are lacking despite wide availability. Purpose: To evaluate the diagnostic performance of 4D cardiac CT-derived parameters in identifying ATTR-CM in older adults considered for transcatheter aortic valve implantation (TAVI). Materials and Methods: This prospective single-center screening study for ATTR-CM included consecutive patients with severe AS considered for TAVI who underwent 4D cardiac CT between August 2019 and August 2021 approximately 1 day before technetium 99m (Tc-99m) 3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) scintigraphy. The diagnostic performance of CT-based left ventricular (LV), right ventricular, and left atrial dimensions, ejection fraction (EF), and myocardial strain were evaluated against Tc-99m-DPD scintigraphy as the reference standard to identify ATTR-CM. Predictors and an unweighted cardiac CT score were validated with internal bootstrapping. The assignment of variables to the score was based on cutoff values achieving the highest Youden index J. Results: Among 263 participants (mean age, 83 years +/- 4.6 [SD]; 149 male and 114 female participants), Tc-99m-DPD scintigraphy (Perugini grade 2 or 3) confirmed coexisting ATTR-CM in 27 (10.3%). CT-derived LV mass index, LV and LA global longitudinal strain (GLS), and relative apical longitudinal strain each predicted the presence of ATTR-CM with an area under the curve (AUC) of at least 0.70. Implementing these parameters with cutoff values of 81 g/m(2) or higher, -14.9% or higher, less than 11.5%, and 1.7 or higher in the CT score, respectively, yielded high diagnostic performance (AUC = 0.89; 95% CI: 0.81, 0.94; P < .001) robust to internal bootstrapping validation (AUC = 0.88; 95% CI: 0.82, 0.94). If two criteria were fulfilled, the sensitivity and specificity in the detection of ATTR-CM were 96.3% (95% CI: 81.0, 99.9) and 58.9% (95% CI: 52.3, 65.2), respectively. Conclusion: When compared against Tc-99m-DPD scintigraphy as the reference standard, routine 4D cardiac CT in older adults considered for TAVI provided high diagnostic performance in the detection of concomitant ATTR-CM by assessing LV and left atrial GLS, relative apical longitudinal strain, and LV mass index.

Abstract Aims Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in heart failure patients with reduced and preserved left ventricular ejection fraction (LVEF), but have not yet been investigated in transthyretin amyloid cardiomyopathy (ATTR‐CM). This study aimed to evaluate tolerability, clinical outcomes, and changes in NT‐proBNP levels and glomerular filtration rate (GFR) in ATTR‐CM patients treated with dapagliflozin. Methods and results Patients with stable, tafamidis‐treated ATTR‐CM were retrospectively evaluated at the initiation of dapagliflozin and 3 months thereafter. Tafamidis‐treated ATTR‐CM patients without SGLT2i served as a reference cohort. Overall, SLGT2i therapy was initiated in 34 patients. Seventeen patients with stable disease on tafamidis, who were subsequently started on dapagliflozin, were included in the analysis. Patients selected for SGLT2i presented with signs of advanced disease, evidenced by higher Gillmore disease stage (stage ≥2: 53% vs. 27.5%; P = 0.041), baseline median NT‐proBNP [median (IQR) 2668 pg/mL (1314–3451) vs. 1424 (810–2059); P = 0.038] and loop diuretic demand (76.5% vs. 45% of patients; P = 0.044), and lower LVEF (46.6 ± 12.9 vs. 53.7 ± 8.7%; P = 0.019) and GFR (51.8 ± 16.5 vs. 68.5 ± 18.6 mL/min; P = 0.037) compared with the reference cohort. At 3‐month follow‐up, a numerical decrease in NT‐proBNP levels was observed in 13/17 (76.5%) patients in the dapagliflozin (−190 pg/mL, IQR: −1,028–71, P = 0.557) and 27/40 (67.5%) of patients in the control cohort (−115 pg/mL, IQR: −357–105, P = 0.551). Other disease parameters remained stable and no adverse events occurred. Conclusions In tafamidis‐treated ATTR‐CM patients, initiation of dapagliflozin was well tolerated. The efficacy of SGLT2i therapy in patients with ATTR‐CM needs to be studied in randomized controlled trials.

Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered.

IntroductionPrevious analyses have reported the outcomes of transcatheter aortic valve replacement (TAVR) for patients with low-flow, low-gradient (LFLG) aortic stenosis (AS), without stratifying according to the route of access. Differences in mortality rates among access routes have been established for high-gradient (HG) patients and hypothesized to be even more pronounced in LFLG AS patients. This study aims to compare the outcomes of patients with LFLG or HG AS following transfemoral (TF) or transapical (TA) TAVR.MethodsA total of 910 patients, who underwent either TF or TA TAVR with a median follow-up of 2.22 (IQR: 1.22–4.03) years, were included in this multicenter cohort study. In total, 146 patients (16.04%) suffered from LFLG AS. The patients with HG and LFLG AS were stratified according to the route of access and compared statistically.ResultsThe operative mortality rates of patients with HG and LFLG were found to be comparable following TF access. The operative mortality rate was significantly increased for patients who underwent TA access [odds ratio (OR): 2.91 (1.54–5.48), p = 0.001] and patients with LFLG AS [OR: 2.27 (1.13–4.56), p = 0.02], which could be corroborated in a propensity score-matched subanalysis. The observed increase in the risk of operative mortality demonstrated an additive effect [OR for TA LFLG: 5.45 (2.35–12.62), p < 0.001]. LFLG patients who underwent TA access had significantly higher operative mortality rates (17.78%) compared with TF LFLG (3.96%, p = 0.016) and TA HG patients (6.36%, p = 0.024).ConclusionsHG patients experienced a twofold increase in operative mortality rates following TA compared with TF access, while LFLG patients had a fivefold increase in operative mortality rates. TA TAVR appears suboptimal for patients with LFLG AS. Prospective studies should be conducted to evaluate alternative options in cases where TF is not possible.

HomeJournal of the American Heart AssociationVol. 11, No. 17Paroxetine‐Mediated G‐Protein Receptor Kinase 2 Inhibition in Patients With Acute Anterior Myocardial Infarction: Final 1‐Year Outcomes of the Randomized CARE‐AMI Trial Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBParoxetine‐Mediated G‐Protein Receptor Kinase 2 Inhibition in Patients With Acute Anterior Myocardial Infarction: Final 1‐Year Outcomes of the Randomized CARE‐AMI Trial Thomas Pilgrim, MD, MSc, Benedikt Bernhard, MD, Monika Fürholz, MD, René Vollenbroich, MD, MPP, Flora Babongo Bosombo, PhD, Sylvain Losdat, PhD, Nicole Reusser, RN, Stephan Windecker, MD, Stefan Stortecky, MD, MPH, George C. M. Siontis, MD, PhD, Lukas Hunziker, MD, Jonas Lanz, MD, MSc and Stephan Dobner, MD, PhD Thomas PilgrimThomas Pilgrim * Correspondence to: Thomas Pilgrim, MD, MSc, Department of Cardiology, Inselspital Bern University Hospital, CH‐3010 Bern, Switzerland. Email: E-mail Address: [email protected] https://orcid.org/0000-0001-8721-4068 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Benedikt BernhardBenedikt Bernhard https://orcid.org/0000-0002-0996-9681 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Monika FürholzMonika Fürholz , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , René VollenbroichRené Vollenbroich , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Flora Babongo BosomboFlora Babongo Bosombo , Clinical Trials Unit, , University of Bern, , Switzerland, , Sylvain LosdatSylvain Losdat , Clinical Trials Unit, , University of Bern, , Switzerland, , Nicole ReusserNicole Reusser , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Stephan WindeckerStephan Windecker https://orcid.org/0000-0003-2653-6762 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Stefan StorteckyStefan Stortecky https://orcid.org/0000-0002-5076-0177 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , George C. M. SiontisGeorge C. M. Siontis https://orcid.org/0000-0003-2128-9205 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Lukas HunzikerLukas Hunziker https://orcid.org/0000-0003-0081-8518 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, , Jonas LanzJonas Lanz https://orcid.org/0000-0002-5035-6625 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, and Stephan DobnerStephan Dobner https://orcid.org/0000-0003-2220-9799 , Department of Cardiology, Inselspital, Bern University Hospital, , University of Bern, , Switzerland, Originally published24 Aug 2022https://doi.org/10.1161/JAHA.122.026362Journal of the American Heart Association. 2022;11:e026362Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 24, 2022: Ahead of Print Left ventricular (LV) remodeling after ischemic injury is catalyzed by dysregulation of G‐protein–coupled receptor kinases (GRKs).1 Preclinical studies suggest that competitive inhibition of GRK2 mitigates the extent of myocardial fibrosis and improves LV function.2 Paroxetine, a selective serotonin reuptake inhibitor, selectively inhibits GRK2 and has been shown to attenuate maladaptive remodeling in a mouse model.3 The CARE‐AMI (Paroxetine‐Mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction) trial was an investigator‐initiated, double‐blind, randomized controlled trial investigating the potential of paroxetine‐mediated GRK2 inhibition compared with placebo to reduce adverse LV remodeling in patients with acute anterior ST‐segment–elevation myocardial infarction (STEMI) with a LV ejection fraction (LVEF) ≤45% (ClinicalTrials.gov identifier: NCT03274752). The study protocol was approved by the local ethics committee, and all participants provided written informed consent before randomization. Anonymized data and materials have been made publicly available at the Bern Open Repository and Information System and can be accessed at https://boris.unibe.ch. Eligibility criteria, end point definitions, and details of randomization, masking, and study conduct have been described elsewhere.4 The primary end point results were assessed by means of cardiac magnetic resonance imaging at 12 weeks after STEMI and have been reported previously.4 Herein, we report the final clinical and echocardiographic outcomes at 1 year. LV volume and ejection fraction were measured with the use of the biplane Simpson method. LV global longitudinal strain was assessed by speckle‐tracking echocardiography. Outcome assessors were blinded to treatment allocation. P values for differences in categorical variables were computed using χ2 or Fisher exact test. We used the Wilcoxon rank sum tests to compare patient‐level changes from baseline to follow‐up within each treatment group and between the experimental and the control group. Only patients with available serial echocardiographic data were considered for the primary analysis. A total of 50 patients with anterior STEMI were randomly assigned to the experimental or the control group between October 26, 2017, and September 21, 2020. At 1 year, clinical and echocardiographic follow‐up was complete in 100% and 80% of patients, respectively. The mean age of the patients was 61.8±12.6 years, and 41 (82%) were men. Demographic and clinical baseline characteristics have been reported previously.4 At 1 year, there were no significant differences between the experimental and the control groups with regard to antiplatelet or antithrombotic treatment, nor with regard to treatment with β blockers (81% versus 82%; P>0.999), renin‐angiotensin system inhibitors (71% versus 82%; P=0.49), or angiotensin receptor–neprilysin inhibitors (14% versus 5%; P=0.35). Between baseline and follow‐up at 1 year, mean LVEF and global longitudinal strain improved in both the experimental group and the control group, with no significant difference between the 2 treatment arms (Table). There were no differences in the change in LV dimensions and volumes between the 2 treatment groups, nor were there any differences in parameters of diastolic dysfunction between the 2 treatment arms. At 1 year, all study participants were alive and in New York Heart Association functional class I or II. One patient in each group had a hospitalization for heart failure. Two patients in the placebo group underwent transcatheter edge‐to‐edge mitral repair. One patient in the experimental arm underwent modified endoventricular circular plasty (Dor procedure). Four patients in the experimental group and 6 patients in the control group underwent implantation of an internal cardioverter‐defibrillator. In this double‐blind, placebo‐controlled, randomized clinical trial, the extent of LVEF recovery and improvement of global longitudinal strain 1 year after anterior STEMI was comparable in patients treated with a 3‐month course of paroxetine or placebo. A greater reduction in late gadolinium enhancement in patients in the experimental compared with the control group documented at 12 weeks by means of cardiac magnetic resonance imaging did not translate into differences in echocardiographic or clinical outcomes at 1 year. Both early revascularization and installation of guideline‐directed heart failure treatment may have attenuated a potential effect of GRK2 inhibition as an add‐on therapy. The reliability of the reported findings is limited by the modest sample size. In addition, reduction of LVEF at baseline was only moderate, thus attenuating the potential effect of paroxetine on LVEF recovery. In contrast to the assessment at 12 weeks, LV function at 1 year was assessed by use of echocardiocardiography and not by magnetic resonance imaging. Moreover, both LVEF and global longitudinal strain provide an aggregate estimate of LV function, but may not be sensitive enough to assess differences in LV remodeling at a more granular level. Furthermore, GRK2 signaling levels were not measured in this study. The CARE‐AMI study documented no effect of paroxetine on LVEF recovery at 1 year in patients with STEMI.Table 1. LV Dimension and LV Function Between Baseline and 12 Months, as Assessed by Transthoracic EchocardiographyVariableParoxetinePlaceboParoxetine vs placeboBaseline12 moChangeP valueBaseline12 moChangeP valueP valueLV functionEF (Simpson, biplane), %41.0(37.0 to 44.3)50.0(43.5 to 56.5)8.0(3.0 to 15.0)0.00543.0(36.0 to 50.0)54.0(41.9 to 63.5)7.1(0.0 to 13.4)0.0080.86GLS, %12.4(10.2 to 13.8)15.2(12.8 to 17.4)3.2(1.2 to 3.9)<0.00111.8(10.7 to 13.5)14.7(14.1 to 17.6)2.1(1.0 to 4.2)<0.0010.92LV dimensionsEnd‐diastolic diameter, mm51.0(47.0 to 54.0)53.0(47.5 to 55.5)3.0(−2.0 to 6.0)0.03851.0(45.8 to 53.2)49.0(45.5 to 56.5)3.0(−5.0 to 4.0)0.5530.42End‐diastolic volume, mL142.0(114.8 to 153.8)119.1(105.5 to 148.0)−2.7(−29.7 to 15.9)0.551114.5(102.0 to 128.0)112.0(89.9 to 137.2)−16.5(−18.9 to 9.5)0.1260.97Data are presented as stratified by allocated study drug according to the intention‐to‐treat principle. Data are expressed as median (25%–75%). EF indicates ejection fraction; GLS, global longitudinal strain; and LV, left ventricular.Sources of FundingThe trial was an investigator‐initiated study supported by dedicated grants from the Clinical Trial Unit, University of Bern, and the Gottfried und Julia Bangerter‐Rhyner‐Stiftung. The funding sources had no role in the design of the study, data collection, data monitoring, data analysis, data interpretation, writing of the report, and the decision to submit. The first and last authors (Drs Pilgrim and Dobner), as well as the trial statistician (Dr Babongo Bosombo), had full access to all the data in the study and assume final responsibility for the decision to submit for publication.DisclosuresRelationships with industry: Dr Pilgrim reports research grants to the institution from Edwards Lifesciences, Boston Scientifc, and Biotronik; personal fees from Biotronik, Boston Scientific, HighLife SAS, Abbott, and Medtronic outside of the submitted work. Dr Windecker reports research and educational grants to the institution from Abbott, Amgen, BMS, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Johnson&Johnson, Medtronic, Querbet, Polares, Sanofi, Terumo, and Sinomed. Dr Windecker serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V‐Wave, and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/excecutive committee group of several investigated‐initiated trials that receive funding by industry without impact on his personal remuneration. Dr Windecker is an unpaid member of the Pfizer Research Award selection committee in Switzerland. All other authors have no potential conflicts of interest to disclose. S Stortecky reports research grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, Abbott and Guerbet AG as well as consulting fees from BTG/Boston Scientific and Teleflex outside the submitted work.Footnotes* Correspondence to: Thomas Pilgrim, MD, MSc, Department of Cardiology, Inselspital Bern University Hospital, CH‐3010 Bern, Switzerland. Email: thomas.[email protected]chRegistration: URL: https://clinicaltrials.gov; Unique identifier: NCT03274752.For Sources of Funding and Disclosures, see page 3.References1 Pfleger J, Gresham K, Koch WJ. G protein‐coupled receptor kinases as therapeutic targets in the heart. Nat Rev Cardiol. 2019; 16:612–622. doi: 10.1038/s41569-019-0220-3CrossrefMedlineGoogle Scholar2 Woodall MC, Woodall BP, Gao E, Yuan A, Koch WJ. Cardiac fibroblast GRK2 deletion enhances contractility and remodeling following ischemia/reperfusion injury. Circ Res. 2016; 119:1116–1127. doi: 10.1161/CIRCRESAHA.116.309538LinkGoogle Scholar3 Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJG, Koch WJ. Paroxetine‐mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015; 7:277ra31. doi: 10.1126/scitranslmed.aaa0154CrossrefMedlineGoogle Scholar4 Pilgrim T, Vollenbroich R, Deckarm S, Gräni S, Dobner S, Stark AW, Erne SA, Babonog Bosombo F, Fischer K, Stortecky S, et al. Effect of paroxetine‐mediated G‐protein receptor kinase 2 inhibition vs placebo in patients with anterior myocardial infarction: a randomized clinical trial. JAMA Cardiol. 2021; 6:1171–1176. doi: 10.1001/jamacardio.2021.2247CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 6, 2022Vol 11, Issue 17Article InformationMetrics Copyright © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.https://doi.org/10.1161/JAHA.122.026362PMID: 36000427 Manuscript receivedApril 5, 2022Manuscript acceptedJune 21, 2022Originally publishedAugust 24, 2022 Keywordshumansmyocardial infarctionparoxetineGTP‐binding proteinsPDF download SubjectsMyocardial Infarction

BACKGROUND:Increased left ventricular afterload resulting from severe aortic stenosis (AS) leads to progressive cardiac remodeling. Left atrial enlargement (LAE) is an early manifestation in a series of maladaptive changes and may affect clinical outcomes after valvular replacement therapy. The aim of this study is to determine the impact of LAE on clinical outcomes in symptomatic patients with severe AS undergoing transcatheter aortic valve implantation (TAVI).METHODS:In a prospective single-center TAVI registry, we analyzed LA dimensions measured by echocardiography before intervention. Patients with atrial fibrillation or concomitant mitral valve disease were excluded. LAE was defined as indexed LA volume >34 ml/m2 . The primary endpoint was cardiovascular death (CVD) at 1 year.RESULTS:Among 1663 patients undergoing TAVI between August 2007 and December 2016, 768 (46.2%) were eligible for the present analysis and 486 patients had LAE. The prevalence of LAE was higher in males (68.3%) as compared to females (58.8%). Patients with LAE were older (82.3 ± 6.7 years vs. 80.0 ± 6.4 years) and had a higher STS-PROM score (6.1 ± 4.7% vs. 4.7 ± 2.9%). After adjustment, patients with LAE had an increased risk of CVD at 1-year compared to patients with normal LA dimensions (49 [10.4%] vs. 8 [2.9%]; HRadj , 3.52; 95% CI, 1.66-7.44)]. In multivariable analysis, LAE was independently associated with an increased risk of CVD at 1-year (HRadj , 3.52; 95% CI, 1.66-7.44).CONCLUSIONS:LAE secondary to AS was documented in a significant proportion of patients undergoing TAVI and was associated with a more than threefold increased risk of CVD at 1-year.