Frailty, periinterventional complications and outcome in patients undergoing percutaneous mitral and tricuspid valve repair.

BACKGROUND: Frailty is common in elderly and multimorbid patients and associated with increased vulnerability to stressors. METHODS: In a single centre study frailty according to Fried criteria was assessed in consecutive patients before transcatheter mitral and tricuspid valve repair. Postprocedural infections, blood transfusion and bleeding and renal failure were retrospectively assessed from records. Median follow-up time for survival was 560 days (IQR: 363 to 730 days). RESULTS: 90% of 626 patients underwent mitral valve repair, 5% tricuspid valve repair, and 5% simultaneous mitral and tricuspid valve repair. 47% were classified as frail. Frailty was associated with a significantly increased frequency of bleeding (16 vs 10%; p = 0.016), blood transfusions (9 vs 3%; p = < 0.001) and infections (18 vs 10%; p = 0.006), but not with acute kidney injury (20 vs 20%; p = 1.00). Bleeding and infections were associated with longer hospital stays, with a more pronounced effect in frail patients (interaction test p < 0.05, additional 3.2 and 4.1 days in frail patients, respectively). Adjustment for the occurrence of complications did not attenuate the increased risk of mortality associated with frailty (HR 2.24 [95% CI 1.62-3.10]; p < 0.001). CONCLUSIONS: Bleeding complications and infections were more frequent in frail patients undergoing transcatheter mitral and tricuspid valve repair and partly explained the longer hospital stay. Albeit some of the complications were associated with higher long-term mortality, this did not explain the strong association between frailty and mortality. Further research is warranted to explore interventions targeting periprocedural complications to improve outcomes in this vulnerable population.

Advanced CT measures of coronary artery disease with intermediate stenosis in patients with severe aortic valve stenosis.

BACKGROUND: Coronary artery disease (CAD) and severe aortic valve stenosis (AS) frequently coexist. While pre-transcatheter aortic valve replacement (TAVR) computed tomography angiography (CTA) allows to rule out obstructive CAD, interpreting hemodynamic significance of intermediate stenoses is challenging. This study investigates the incremental value of CT-derived fractional flow reserve (CT-FFR), quantitative coronary plaque characteristics (e.g., stenosis degree, plaque volume, and composition), and peri-coronary adipose tissue (PCAT) density to detect hemodynamically significant lesions among those with AS and CAD. MATERIALS AND METHODS: We included patients with severe AS and intermediate coronary lesions (20-80% diameter stenosis) who underwent pre-TAVR CTA and invasive coronary angiogram (ICA) with resting full-cycle ratio (RFR) assessment between 08/16 and 04/22. CTA image analysis included assessment of CT-FFR, quantitative coronary plaque analysis, and PCAT density. Coronary lesions with RFR ≤ 0.89 indicated hemodynamic significance as reference standard. RESULTS: Overall, 87 patients (age 77.9 ± 7.4 years, 38% female) with 95 intermediate coronary artery lesions were included. CT-FFR showed good discriminatory capacity (area under receiver operator curve (AUC) = 0.89, 95% confidence interval (CI) 0.81-0.96, p < 0.001) to identify hemodynamically significant lesions, superior to anatomical assessment, plaque morphology, and PCAT density. Plaque composition and PCAT density did not differ between lesions with and without hemodynamic significance. Univariable and multivariable analyses revealed CT-FFR as the only predictor for functionally significant lesions (odds ratio 1.28 (95% CI 1.17-1.43), p < 0.001). Overall, CT-FFR ≤ 0.80 showed diagnostic accuracy, sensitivity, and specificity of 88.4% (95%CI 80.2-94.1), 78.5% (95%CI 63.2-89.7), and 96.2% (95%CI 87.0-99.5), respectively. CONCLUSION: CT-FFR was superior to CT anatomical, plaque morphology, and PCAT assessment to detect functionally significant stenoses in patients with severe AS. CLINICAL RELEVANCE STATEMENT: CT-derived fractional flow reserve in patients with severe aortic valve stenosis may be a useful tool for non-invasive hemodynamic assessment of intermediate coronary lesions, while CT anatomical, plaque morphology, and peri-coronary adipose tissue assessment have no incremental or additional benefit. These findings might help to reduce pre-transcatheter aortic valve replacement invasive coronary angiogram. KEY POINTS: • Interpreting the hemodynamic significance of intermediate coronary stenoses is challenging in pre-transcatheter aortic valve replacement CT. • CT-derived fractional flow reserve (CT-FFR) has a good discriminatory capacity in the identification of hemodynamically significant coronary lesions. • CT-derived anatomical, plaque morphology, and peri-coronary adipose tissue assessment did not improve the diagnostic capability of CT-FFR in the hemodynamic assessment of intermediate coronary stenoses.

Early in-hospital discontinuation of aspirin on the first post-procedural day after percutaneous coronary stent implantation in patients on direct oral anticoagulation.

Background: Previous trials investigating antithrombotic therapy with a direct oral anticoagulant (DOAC) and a P2Y12 inhibitor after percutaneous coronary intervention (PCI), termed dual therapy, allowed a short period of triple therapy including a DOAC, a P2Y12 inhibitor, and aspirin. Aims: This study aimed to determine whether discontinuation of aspirin on the first post-procedural day is safe or causes ischemic events. Methods: Ischemic and bleeding events during hospitalization were investigated retrospectively in all patients treated with dual therapy (DOAC + P2Y12 inhibitor, designated as group 1) or triple therapy (DOAC + P2Y12 inhibitor+aspirin, designated as group 2) from day 1 after PCI at our center. Results: Of 4,564 consecutive PCI procedures, 1,059 (23.2%) had an indication for OAC. Of these, 322 met the inclusion criteria for group 1 and 62 for group 2. Baseline characteristics, CHA2DS2-VASc and HAS-BLED scores showed no relevant differences between the two groups, and the main indication for DOAC therapy was atrial fibrillation in both groups. Approximately » of patients were treated for acute coronary syndrome. The mean length of post-procedural hospitalization was 2.1 ± 2.5 and 2.2 ± 3.0 days in group 1 and 2, respectively (p = 0.305). One patient per group suffered a TIA (p = 0.297). There were no other ischemic events and no statistically significant differences in bleeding events. A subgroup analysis of cases hospitalized for ≥2 post-procedural days (group 1: 100 cases, mean 4.4 ± 3.4 days vs. group 2: 25 cases, mean 4.0 ± 4.1 days) confirmed these results. Conclusion: The initiation of dual therapy and thus discontinuation of aspirin on the first postprocedural day appears to be safe with respect to short-term ischemic events in a real-world population. Almost » of patients undergoing PCI have an indication for OAC, highlighting the relevance of this issue.

Alcohol-mediated renal denervation in patients with hypertension in the absence of antihypertensive medications.

BACKGROUND: Ultrasound and radiofrequency renal denervation (RDN) have been shown to safely lower blood pressure (BP) in hypertension. AIMS: The TARGET BP OFF-MED trial investigated the efficacy and safety of alcohol-mediated renal denervation (RDN) in the absence of antihypertensive medications. METHODS: This randomised, blinded, sham-controlled trial was conducted in 25 centres in Europe and the USA. Patients with a 24-hour systolic BP of 135-170 mmHg, an office systolic BP 140-180 mmHg and diastolic BP ≥90 mmHg on 0-2 antihypertensive medications were enrolled. The primary efficacy endpoint was the change in mean 24-hour systolic BP at 8 weeks. Safety endpoints included major adverse events up to 30 days. RESULTS: A total of 106 patients were randomised; the baseline mean office BP following medication washout was 159.4/100.4±10.9/7.0 mmHg (RDN) and 160.1/98.3±11.0/6.1 mmHg (sham), respectively. At 8 weeks post-procedure, the mean (±standard deviation) 24-hour systolic BP change was â2.9±7.4 mmHg (p=0.009) versus â1.4±8.6 mmHg (p=0.25) in the RDN and sham groups, respectively (mean between-group difference: 1.5 mmHg; p=0.27). There were no differences in safety events between groups. After 12 months of blinded follow-up, with medication escalation, patients achieved similar office systolic BP (RDN: 147.9±18.5 mmHg; sham: 147.8±15.1 mmHg; p=0.68) with a significantly lower medication burden in the RDN group (mean daily defined dose: 1.5±1.5 vs 2.3±1.7; p=0.017). CONCLUSIONS: In this trial, alcohol-mediated RDN was delivered safely but was not associated with significant BP differences between groups. Medication burden was lower in the RDN group up to 12 months.

Disentangling Heart Failure and Physical Frailty: Prospective Study of Patients Undergoing Percutaneous Mitral Valve Repair.

BACKGROUND: Frailty and heart failure share pathophysiology and clinical characteristics. OBJECTIVES: The aim of this study was to analyze the contribution of heart failure to the physical frailty phenotype by examining patients with heart failure before and after percutaneous mitral valve repair (PMVR). METHODS: Frailty according to the Fried criteria (weight loss, weakness, exhaustion, slowness, and low activity) was assessed in consecutive patients before and 6 weeks after PMVR. RESULTS: A total of 118 of 258 patients (45.7%) (mean age: 78 ± 9 years, 42% female, 55% with secondary mitral regurgitation) were frail at baseline, which significantly decreased to 74 patients (28.7 %) at follow-up (P < 0.001). The frequency of frailty domains slowness, exhaustion, and inactivity significantly decreased, whereas weakness remained unchanged. Baseline frailty was significantly associated with comorbidities, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and functional capacity, whereas frailty after PMVR was not associated with NT-proBNP levels. Predictors of postprocedural reversibility of frailty were NYHA functional class 

Prognostic impact of resting full-cycle ratio and diastolic non-hyperemic pressure ratios in patients with deferred revascularization.

BACKGROUND: Non-hyperemic pressure ratios (NHPRs) like resting full-cycle ratio (RFR), diastolic pressure ratio during entire diastole (dPR[entire]) and diastolic pressure ratio during wave-free period (dPR[WFP]) are increasingly used to guide revascularization. The effect of NHPRs on mid-term prognosis has not been well established. OBJECTIVE: We investigated the prognostic implications of NHRPs in patients whose revascularization was deferred based on fractional flow reserve (FFR) in a single-centre population. METHODS: NHPRs and FFR were calculated offline from pressure tracings by an independent core laboratory. Follow-up data were acquired through records of hospital visits or telephone interviews. The primary outcome was a vessel-oriented composite outcome (VOCO) (a composite of cardiac death, vessel-related myocardial infarction, and ischemia-driven revascularization) in deferred vessels at 2 years. RESULTS: 316 patients with 377 deferred lesions were analysed. Discordance of NHPRs and FFR was found in 13.0-18.3% of lesions. The correlation coefficient between NHPRs was 0.99 (95% confidence interval 0.99-1.00). At 2 years, VOCO occurred in 19 lesions (5.0%). Estimated glomerular filtration rate < 30 mL/min/1.73 m2 [hazard ratio (HR) 5.7, p = 0.002], previous myocardial infarction (HR 3.3, p = 0.018), diabetes (HR 2.7, p = 0.042), RFR ≤ 0.89 (HR 2.7, p = 0.041) and dPR[WFP] ≤ 0.89 (HR 2.7, p = 0.049) were associated with higher incidence of VOCO at 2 years in the univariable analysis. A non-significant trend was found for dPR[entire] (HR 1.9, p = 0.26). CONCLUSION: A positive RFR or dPR[WFP] were associated with a worse prognosis in deferred lesions, suggesting that the use of NHPRs in addition to FFR may improve risk estimation.

Comparison of vessel fractional flow reserve with invasive resting full-cycle ratio in patients with intermediate coronary lesions.

BACKGROUND: Vessel fractional flow reserve (vFFR) is a novel angiography-derived index for the assessment of myocardial ischemia without the need for pressure wires and hyperemic agents. vFFR has demonstrated very good diagnostic performance compared with the hyperemic index fractional flow reserve (FFR). The aim of this study was to compare vFFR to the non-hyperemic pressure ratio resting full-cycle ratio (RFR). METHODS: This was a retrospective, observational, single-center study of an all-comer cohort undergoing RFR assessment. Invasive coronary angiography was obtained without a dedicated vFFR acquisition protocol, and vFFR calculation was attempted in all vessels interrogated by RFR (1483 lesions of 1030 patients). RESULTS: vFFR could be analyzed in 986 lesions from 705 patients. Median diameter stenosis was 37% (interquartile range (IQR): 30.0-44.0%), vFFR 0.86 (IQR: 0.81-0.91) and RFR 0.94 (IQR: (0.90-0.97). The correlation between vFFR and RFR was strong (r = 0.70, 95% confidence interval (CI): 0.66-0.74, p < 0.001). Using RFR ≤0.89 as reference, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for vFFR were 77%, 93%, 77%, and 92% and 89%. vFFR yielded a high area under the curve (AUC) of 0.92 (95% CI: 0.90-0.94). The good diagnostic performance of vFFR was confirmed among subgroups of patients with diabetes, severe aortic stenosis, female gender and lesions located in the left anterior descending artery. CONCLUSION: vFFR has a high diagnostic performance taking RFR as the reference standard for evaluating the functional significance of coronary stenoses.

Contemporary treatment of mitral valve disease with transcatheter mitral valve implantation.

BACKGROUND: Transcatheter mitral valve implantation (TMVI) with self-expanding (SAV) or balloon-expandable (BAV) valves are rising as promising treatment options for high-risk patients with symptomatic mitral valve (MVD) disease unsuitable for alternative treatment options. AIMS: The aim of this study was to examine the clinical, procedural and outcome parameters of patients undergoing SAV or BAV for MVD. METHODS: In this observational and single-center case series, fifteen consecutive patients treated with the Tendyne Mitral Valve System (SAV) and thirty-one patients treated with SAPIEN prosthesis (BAV) were included. RESULTS: The patients (aged 78 years [interquartile range (IQR): 65.5 to 83.1 years], 41% women, EuroSCORE II 10.3% [IQR: 5.5 to 17.0%] were similar regarding baseline characteristics, despite a higher rate of prior heart valve surgery and prevalence of MV stenosis in the SAV-group. At discharge, the SAV-group had a mean transvalvular gradient of 4.2 mmHg, whereas the BAV-group had a mean transvalvular gradient of 6.2 mmHg. None or trace paravalvular leakage (PVL) was assessed in 85% in SAV-group and 80% in the BAV-group. 320 day all-cause and cardiac mortality rates were comparable in both groups (SAV: 26.7% vs BAV: 20%, p = 0.60). Four deaths occurred early in the SAV-group until 32 days of follow-up. CONCLUSIONS: In high-risk patients with MVD, TMVI presents a promising treatment option with encouraging mid-term outcomes and good valve durability. TMVI either with BAV or SAV may be developed to an established treatment option.

Cardiopulmonary function during exercise in heart failure with reduced ejection fraction following baroreflex activation therapy.

PURPOSE: Baroreflex activation therapy has favorable effects in heart failure patients. We report the results of a single-center study of baroreflex activation therapy in heart failure with reduced ejection fraction including cardiopulmonary exercise testing for the first time to show the effect on exercise capacity. METHODS: A total of 17 patients were treated with baroreflex activation therapy. Eligibility criteria were the New York Heart Association class ⩾III and ejection fraction ⩽35% on guideline-directed medical and device therapy. The New York Heart Association class, quality of life, and 6-min hall walk distance were assessed in all patients. Twelve patients underwent cardiopulmonary exercise testing before and 8.9 ± 6.4 months after initiation of baroreflex activation therapy. RESULTS: The New York Heart Association class and 6-min hall walk distance improved after baroreflex activation therapy, while quality of life remained stable. Weight-adapted peak oxygen uptake increased significantly from 10.1 (8.2-12.9) ml/min/kg to 12.1 (10.4-14.6) ml/min/kg (p = 0.041). Maximal heart rate was stable. Maximal oxygen pulse increased from 9.7 (5.5-11.3) to 9.9 (7.1-12.1) ml/heartbeat (p = 0.047) in 10 patients with low maximal oxygen pulse at baseline (<16.5 ml/heartbeat). There was no significant change in maximal oxygen pulse in the whole cohort. Ventilatory efficiency remained stable. CONCLUSION: Weight-adapted peak oxygen uptake improved after baroreflex activation therapy, pointing to an enhanced exercise capacity. Ventilatory efficiency and heart rate did not change, while oxygen pulse increased in patients with low oxygen pulse at baseline, indicating an improvement in circulatory efficiency, that is, a beneficial effect on stroke volume and peripheral oxygen extraction.

Diagnostic performance of quantitative flow ratio versus fractional flow reserve and resting full-cycle ratio in intermediate coronary lesions.

BACKGROUND: Quantitative flow ratio (QFR) is a novel angiography-derived index aimed to assess the functional relevance of coronary stenoses without pressure wires and adenosine. Good diagnostic yield with the hyperemic fractional flow reserve (FFR) have been reported, while data on the comparison of QFR to non-hyperemic pressure ratios (NHPR) are scarce. METHODS: In this retrospective, observational and single-center study with a large population representative of the real practice, we assessed and compared the diagnostic performance of contrast flow (cQFR) and fixed flow (fQFR) QFR against the NHPR resting full-cyle ratio (RFR) using FFR as reference standard. RESULTS: A total of 626 lesions from 544 patients were investigated. Mean diameter stenosis, FFR, cQFR, fQFR and RFR were 44.8%, 0.842, 0.847, 0.857 and 0.912, respectively. The correlation between cQFR and FFR was stronger (r = 0.830, P < 0.001) compared to that between FFR and RFR (r = 0.777, P < 0.001) and between cQFR and RFR (r = 0.687, P < 0.001). Using FFR ≤0.80 as reference, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for cQFR were 82%, 95%, 87%, 92%, and 91%, respectively. cQFR displayed a higher area under the curve (AUC) than fQFR and RFR (0.938 vs. 0.891 vs. 0.869, P < 0.01). The good diagnostic yield of cQFR appeared to be maintained in different clinical subsets including female gender, aortic valve stenosis and atrial fibrillation, and in different anatomical subsets including focal and non-focal lesions. CONCLUSION: cQFR has a high and better diagnostic performance than the NHPR RFR in predicting FFR-based functional significance of coronary stenoses.

Prevalence of left ventricular thrombus formation after mitral valve edge-to-edge repair.

The prevalence of left ventricular (LV) thrombus formation following percutaneous mitral valve edge-to-edge repair (TMVR) with the MitraClip system is unclear. Decreased total stroke volume and perfusion of the LV apex after mitral valve repair may facilitate thrombus formation especially in the context of reduced LV function. LV thrombus may cause disabling stroke or other thromboembolic events in this elderly and multimorbid patient cohort. Analyses of the prevalence of and risk factors for left ventricular thrombus formation in patients treated with the MitraClip system due to severe mitral valve regurgitation. All discharge and follow-up transthoracic echocardiographic examinations up to 6 months of 453 consecutive patients treated with the MitraClip system were screened for the presence of LV thrombus. Prevalence of LV thrombus formation was 1.1% (5/453). Importantly, LV thrombi were exclusively found in patients with severely depressed left ventricular systolic function (LV-EF < 30%), comprising a prevalence of 4.4% in this subgroup (5/113). Importantly, two of these patients were under active DOAC therapy with Rivaroxaban and Apixaban, respectively. Apart from LV-EF, we did not identify other factors that might have facilitated LV thrombus formation. LV thrombus formation following percutaneous mitral valve repair occurred exclusively in patients with severely depressed LV-EF. As two patients developed LV thrombus despite of DOAC therapy, anticoagulation with a Vitamin K antagonist should be considered in patients with an indication for oral anticoagulation following TMVR.

Feasibility and Comparison of Resting Full-Cycle Ratio and Computed Tomography Fractional Flow Reserve in Patients with Severe Aortic Valve Stenosis.

Background: Computed tomography derived Fractional Flow Reserve (CT-FFR) has been shown to decrease the referral rate for invasive coronary angiography (ICA). The purpose of the study was to evaluate the diagnostic performance of CT-FFR compared to hyperemia-free index Resting Full-cycle Ratio (RFR) in patients with relevant aortic stenosis (AS) and intermediate coronary stenosis. Methods: 41 patients with 46 coronary lesions underwent ICA with quantitative coronary angiography (QCA), pressure wire assessment and routine pre-transcatheter aortic valve replacement (TAVR) computed tomography (CT). CT-FFR analysis was performed using prototype on-site software. Results: RFR showed a significant correlation with CT-FFR (Pearson's correlation, r = 0.632, p < 0.001). On a per-lesion basis, diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CT-FFR were 82.6% (95% CI 68.6−92.2), 69.6% (95% CI 47.1−86.8), 95.7% (95% CI 78.1−99.9), 94.1% (95% CI 69.8−99.1), and 75.9% (95% CI 62.7−85.4), respectively. The optimal cutoff value of the CT-FFR for RFR ≤ 0.89 prediction was 0.815. The area under the receiver curve showed a larger area under the curve for CT-FFR (0.87; 95% CI 0.75−0.98) compared with CTA stenosis of ≥50% (0.54, 95% CI 0.38−0.71), CTA ≥ 70% (0.72, 95% CI 0.57−0.87) and QCA ≥ 50% (0.67, 95% CI 0.52−0.83). Conclusions: CT-FFR assessed by routine pre-TAVR CT is safe and feasible and shows a significant correlation with RFR in patients with AS. CT-FFR is superior to QCA ≥ 50%, CT ≥ 50% and CT ≥ 70% in assessing the hemodynamic relevance of intermediate coronary lesions. Thus, CT-FFR has the potential to guide revascularization in patients with AS.

The Hypertension Paradox: Survival Benefit After ST-Elevation Myocardial Infarction in Patients With History of Hypertension. A Prospective Cohort- and Risk-Analysis.

Background: Mortality after ST-elevation myocardial infarction (STEMI) is dependent from best-medical treatment after initial event. Objectives: Determining the impact of prescription of guideline-recommended therapy after STEMI in two cohorts, patients with and without history of arterial hypertension, on survival. Methods: 1,025 patients of the Cologne Infarction Model registry with invasively adjudicated STEMI were dichotomized according to their history of arterial hypertension. We recorded prescription rates and dosing of RAS-inhibitors, ß-blockers and statins in all patients. The primary outcome was all-cause death. Mean follow-up was 2.5 years. Results: Mean age was 64 ± 13 years, 246 (25%) were women. 749 (76%) patients had a history of hypertension. All-cause mortality was 24.2%, 30-day and 1-year mortality was 11.3% and 16.6%, respectively. History of hypertension correlated with lower mortality (hazard ratio [HR], @30 days: 0.41 [0.27-0.62], @1 year: 0.37 [0.26-0.53]). After adjusting for age, sex, Killip-class, diabetes mellitus, body-mass index, kidney function and statin prescription at discharge 1-year mortality HR was 0.24 (0.12-0.48). At discharge, prescription rates for RAS-inhibitors, ß-blockers and statins, as well as individual dosing and long-term persistence of RAS-inhibitors were higher in patients with history of hypertension. On the same lines, prescription rates for RAS-inhibitors, ß-blockers and statins at discharge correlated significantly with lower mortality regardless of history of hypertension. Conclusion: Patients with history of hypertension show higher penetration of guideline recommended drug therapy after STEMI, which may contribute to better survival. Better tolerance of ß-blockers and RAS-inhibitors in patients with history of hypertension, not hypertension itself, likely explains these differences in prescription and dosing.

Persistence of intramyocardially transplanted murine induced pluripotent stem cell-derived cardiomyocytes from different developmental stages.

BACKGROUND: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are regarded as promising cell type for cardiac cell replacement therapy, but it is not known whether the developmental stage influences their persistence and functional integration in the host tissue, which are crucial for a long-term therapeutic benefit. To investigate this, we first tested the cell adhesion capability of murine iPSC-CM in vitro at three different time points during the differentiation process and then examined cell persistence and quality of electrical integration in the infarcted myocardium in vivo. METHODS: To test cell adhesion capabilities in vitro, iPSC-CM were seeded on fibronectin-coated cell culture dishes and decellularized ventricular extracellular matrix (ECM) scaffolds. After fixed periods of time, stably attached cells were quantified. For in vivo experiments, murine iPSC-CM expressing enhanced green fluorescent protein was injected into infarcted hearts of adult mice. After 6-7 days, viable ventricular tissue slices were prepared to enable action potential (AP) recordings in transplanted iPSC-CM and surrounding host cardiomyocytes. Afterwards, slices were lysed, and genomic DNA was prepared, which was then used for quantitative real-time PCR to evaluate grafted iPSC-CM count. RESULTS: The in vitro results indicated differences in cell adhesion capabilities between day 14, day 16, and day 18 iPSC-CM with day 14 iPSC-CM showing the largest number of attached cells on ECM scaffolds. After intramyocardial injection, day 14 iPSC-CM showed a significant higher cell count compared to day 16 iPSC-CM. AP measurements revealed no significant difference in the quality of electrical integration and only minor differences in AP properties between d14 and d16 iPSC-CM. CONCLUSION: The results of the present study demonstrate that the developmental stage at the time of transplantation is crucial for the persistence of transplanted iPSC-CM. iPSC-CM at day 14 of differentiation showed the highest persistence after transplantation in vivo, which may be explained by a higher capability to adhere to the extracellular matrix.

Comparison of Resting Full-Cycle Ratio and Fractional Flow Reserve in a German Real-World Cohort.

Objective: The aim of this study was to evaluate non-hyperemic resting pressure ratios (NHPRs), especially the novel "resting full-cycle ratio" (RFR; lowest pressure distal to the stenosis/aortic pressure during the entire cardiac cycle), compared to the gold standard fractional flow reserve (FFR) in a "real-world" setting. Methods: The study included patients undergoing coronary pressure wire studies at one German University Hospital. No patients were excluded based on any baseline or procedural characteristics, except for insufficient quality of traces. The diagnostic performance of four NHPRs vs. FFR ≤ 0.80 was tested. Morphological characteristics of stenoses were analyzed by quantitative coronary angiography. Results: 617 patients with 712 coronary lesions were included. RFR showed a significant correlation with FFR (r = 0.766, p < 0.01). Diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of RFR were 78% (95% confidence interval = 75; 81), 72% (65; 78), 81% (77; 84), 63% (57; 69), and 86% (83; 89). Relevant predictors for discordance of RFR ≤ 0.89/FFR > 0.8 were LAD lesions, peripheral artery disease, age, female sex and non-focal stenoses. Predictors for discordance of RFR > 0.89/FFR ≤ 0.8 included non-LCX lesions, percent diameter stenosis and previous percutaneous coronary intervention in the target vessel. RFR and all other NHPRs were highly correlated with each other. Conclusion: All NHPRs have a similar correlation with the gold standard FFR and may facilitate the acceptance and implementation of physiological assessments of lesion severity. However, we found ~20% discordant results between NHPRs and FFR in our "all-comers" German cohort.

Baroreflex activation therapy reduces frequency and duration of hypertension-related hospitalizations in patients with resistant hypertension.

PURPOSE: Baroreflex activation therapy (BAT) has been shown to lower blood pressure in patients with resistant hypertension. The purpose of this study was to analyze whether this translates into a reduction of more relevant clinical endpoints. METHODS: Patients with resistant hypertension were treated with the second-generation BAT system. Records on hospitalization (dates of admission and discharge, main diagnosis) were obtained from medical insurance companies. RESULTS: Records on hospitalization were available for a period of 1 year before BAT in two patients and 2 years in 22 patients. The total number of hospitalizations per patient was 3.3 ± 3.5/year before BAT and 2.2 ± 2.7/year after BAT (p = 0.03). Hospitalizations related to hypertension were significantly decreased from 1.5 ± 1.6/year before BAT to 0.5 ± 0.9/year after BAT (p < 0.01). The cumulative duration of hypertension-related hospital stays was significantly reduced from 8.0 ± 8.7 days/year before BAT to 1.8 ± 4.8 days/year after BAT (p < 0.01). Office cuff blood pressure was 183 ± 27 mmHg over 102 ± 17 mmHg under 6.6 ± 2.0 antihypertensive drugs before BAT and 157 ± 32 mmHg over 91 ± 20 mmHg (both p < 0.01) under 5.9 ± 1.9 antihypertensive drugs (p = 0.09 for number of drugs) at latest follow-up. Daytime ambulatory blood pressure was 164 ± 21 mmHg over 91 ± 14 mmHg before BAT and 153 ± 21 mmHg (p = 0.03) over 89 ± 15 mmHg (p = 0.56) at latest follow-up. Heart rate was 75 ± 16 bpm before BAT and 72 ± 12 bpm at latest follow-up (p = 0.35). CONCLUSIONS: Rate and duration of hypertension-related hospitalizations in patients with severe resistant hypertension were lowered after BAT. Whether the response is mediated through improvements in blood pressure control requires further studies.

Efficacy of Electrical Baroreflex Activation Is Independent of Peripheral Chemoreceptor Modulation.

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67±8 years, body mass index: 31.6±5.2 kg/m2, 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end-tidal O2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO2 and O2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164±27 to 151±25 mm Hg (mean±SD, P<0.001), heart rate from 64±13 to 61±13 bpm (P=0.002), and muscle sympathetic nerve activity from 42±12 to 36±12 bursts/min (P=0.004). Hypoxia increased systolic blood pressure 8±12 mm Hg (P=0.057), heart rate 10±6 bpm (P<0.001), muscle sympathetic nerve activity 7±7 bursts/min (P=0.031), and ventilation 10±7 L/min (P=0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: -15±7 versus -14±8 mm Hg (P=0.938), heart rate: -2±3 versus -2±2 bpm (P=0.701), and muscle sympathetic nerve activity: -6±4 versus -4±3 bursts/min (P=0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise.

In Vitro Grown Micro-Tissues for Cardiac Cell Replacement Therapy in Vivo.

BACKGROUND/AIMS: Different approaches have been considered to improve heart reconstructive medicine and direct delivery of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) appears to be highly promising in this context. However, low cell persistence post-transplantation remains a bottleneck hindering the approach. Here, we present a novel strategy to overcome the low engraftment of PSC-CMs during the early post-transplantation phase into the myocardium of both healthy and cryoinjured syngeneic mice. METHODS: Adult murine bone marrow mesenchymal stem cells (MSCs) and PSC-CMs were co-cultured on thermo-responsive polymers and later detached through temperature reduction, resulting in the protease-free generation of cell clusters (micro-tissues) composed of both cells types. Micro-tissues were transplanted into healthy and cryo-injured murine hearts. Short term cell retention was quantified by real-time-PCR. Longitudinal cell tracking was performed by bioluminescence imaging for four weeks. Transplanted cells were further detected by immunofluorescence staining of tissue sections. RESULTS: We demonstrated that in vitro grown micro-tissues consisting of PSC-CMs and MSCs can increase cardiomyocyte retention by >10fold one day post-transplantation, but could not fully rescue a further cell loss between day 1 and day 2. Neutrophil infiltration into the transplanted area was detected in healthy hearts and could be attributed to the cellular implantation rather than tissue damage exerted by the transplantation cannula. Injected PSC-CMs were tracked and successfully detected for up to four weeks by bioluminescence imaging. CONCLUSION: This approach demonstrated that in vitro grown micro-tissues might contribute to the development of cardiac cell replacement therapies.