Transcatheter Repair versus Mitral-Valve Surgery for Secondary Mitral Regurgitation.

BACKGROUND: Current treatment recommendations for patients with heart failure and secondary mitral regurgitation include transcatheter edge-to-edge repair and mitral-valve surgery. Data from randomized trials comparing these therapies are lacking in this patient population. METHODS: In this noninferiority trial conducted in Germany, patients with heart failure and secondary mitral regurgitation who continued to have symptoms despite guideline-directed medical therapy were randomly assigned, in a 1:1 ratio, to undergo either transcatheter edge-to-edge repair (intervention group) or surgical mitral-valve repair or replacement (surgery group). The primary efficacy end point was a composite of death, hospitalization for heart failure, mitral-valve reintervention, implantation of an assist device, or stroke within 1 year after the procedure. The primary safety end point was a composite of major adverse events within 30 days after the procedure. RESULTS: A total of 210 patients underwent randomization. The mean (±SD) age of the patients was 70.5±7.9 years, 39.9% were women, and the mean left ventricular ejection fraction was 43.0±11.7%. Within 1 year, at least one of the components of the primary efficacy end point occurred in 16 of the 96 patients with available data (16.7%) in the intervention group and in 20 of the 89 with available data (22.5%) in the surgery group (estimated mean difference, -6 percentage points; 95% confidence interval [CI], -17 to 6; P<0.001 for noninferiority). A primary safety end-point event occurred in 15 of the 101 patients with available data (14.9%) in the intervention group and in 51 of the 93 patients with available data (54.8%) in the surgery group (estimated mean difference, -40 percentage points; 95% CI, -51 to -27; P<0.001). CONCLUSIONS: Among patients with heart failure and secondary mitral regurgitation, transcatheter edge-to-edge repair was noninferior to mitral-valve surgery with respect to a composite of death, rehospitalization for heart failure, stroke, reintervention, or implantation of an assist device in the left ventricle at 1 year. (Funded by Abbott Vascular; MATTERHORN ClinicalTrials.gov number, NCT02371512.).

Timing of Complete Revascularization with Multivessel PCI for Myocardial Infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) with multivessel coronary artery disease, the time at which complete revascularization of nonculprit lesions should be performed remains unknown. METHODS: We performed an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients in a hemodynamically stable condition who had STEMI and multivessel coronary artery disease were randomly assigned to undergo immediate multivessel percutaneous coronary intervention (PCI; immediate group) or PCI of the culprit lesion followed by staged multivessel PCI of nonculprit lesions within 19 to 45 days after the index procedure (staged group). The primary end point was a composite of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year after randomization. The percentages of patients with a primary or secondary end-point event are provided as Kaplan-Meier estimates at 6 months and at 1 year. RESULTS: We assigned 418 patients to undergo immediate multivessel PCI and 422 to undergo staged multivessel PCI. A primary end-point event occurred in 35 patients (8.5%) in the immediate group as compared with 68 patients (16.3%) in the staged group (risk ratio, 0.52; 95% confidence interval, 0.38 to 0.72; P<0.001 for noninferiority and P<0.001 for superiority). Nonfatal myocardial infarction and unplanned ischemia-driven revascularization occurred in 8 patients (2.0%) and 17 patients (4.1%), respectively, in the immediate group and in 22 patients (5.3%) and 39 patients (9.3%), respectively, in the staged group. The risk of death from any cause, the risk of stroke, and the risk of hospitalization for heart failure appeared to be similar in the two groups. A total of 104 patients in the immediate group and 145 patients in the staged group had a serious adverse event. CONCLUSIONS: Among patients in hemodynamically stable condition with STEMI and multivessel coronary artery disease, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year. (Supported by Boston Scientific; MULTISTARS AMI ClinicalTrials.gov number, NCT03135275.).

Cerebral Embolic Protection during Transcatheter Aortic-Valve Replacement.

BACKGROUND: Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke. METHODS: We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR. RESULTS: A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site. CONCLUSIONS: Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).

Kidney disease, diabetes, and diameter stenosis predict Rotablation bailout in modified balloon application for severely calcified coronary lesions.

BACKGROUND: Modified balloon (MB) treatment in severely calcified coronary artery lesions is an established technique. However, some lesions require Rotablation (RA) as bailout strategy. AIMS: This study aimed to assess predictors of switch from MB to RA and its impact on procedural and midterm outcomes. METHODS: Four hundred and eighty-three consecutive patients were included undergoing MB treatment (n = 204) with a scoring or cutting balloon, or upfront RA treatment (n = 279) serving as control cohort. Strategy switch from MB to RA was performed in 19 of 204 patients. Procedural success was defined as successful stent implantation and TIMI III flow. RESULTS: In the MB cohort, median age was 72 [63-78] years, 75.5% were male and 42.1% had acute coronary syndrome. Procedure success was achieved in 89.4% of the switch group versus 98.4% of the MB only group (p < 0.001) and in 96.4% of the RA cohort. In the switch group, periprocedural complications (31.6% vs. 8.1% vs. 11.8%, p = 0.007), radiation dose (149 [126-252] vs. 59 [30-97] vs. 102 [59-156] Gcm2; p < 0.001) and contrast volume (250 [190-250] vs. 190 [150-250] vs. 195 [190--250] mL; p < 0.001) were significantly higher. Diabetes (OR 3.8, 95% CI 1.1-13.9, p = 0.042), chronic kidney disease stage 4 or 5 (OR 19.0, 95% CI 3.3-108.6, p < 0.001) and pronounced calcification resulting in higher angiographic diameter stenosis (OR 1.13, 95% CI 1.1-1.2, p = 0.001) independently predicted strategy switch. Midterm results were not affected by strategy switch regarding 1-year target lesion revascularization rates (86% vs. 89% vs. 89%; log-rank p = 0.95). CONCLUSION: Primary RA strategy might be considered in patients with severely calcified coronary artery lesions with high angiographic diameter stenosis, diabetes or impaired renal function due to increased periprocedural complication rates, radiation dose, and contrast volume following strategy switch.

Histone deacetylase 1 controls cardiomyocyte proliferation during embryonic heart development and cardiac regeneration in zebrafish.

In contrast to mammals, the zebrafish maintains its cardiomyocyte proliferation capacity throughout adulthood. However, neither the molecular mechanisms that orchestrate the proliferation of cardiomyocytes during developmental heart growth nor in the context of regeneration in the adult are sufficiently defined yet. We identified in a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen the recessive, embryonic-lethal zebrafish mutant baldrian (bal), which shows severely impaired developmental heart growth due to diminished cardiomyocyte proliferation. By positional cloning, we identified a missense mutation in the zebrafish histone deacetylase 1 (hdac1) gene leading to severe protein instability and the loss of Hdac1 function in vivo. Hdac1 inhibition significantly reduces cardiomyocyte proliferation, indicating a role of Hdac1 during developmental heart growth in zebrafish. To evaluate whether developmental and regenerative Hdac1-associated mechanisms of cardiomyocyte proliferation are conserved, we analyzed regenerative cardiomyocyte proliferation after Hdac1 inhibition at the wound border zone in cryoinjured adult zebrafish hearts and we found that Hdac1 is also essential to orchestrate regenerative cardiomyocyte proliferation in the adult vertebrate heart. In summary, our findings suggest an important and conserved role of Histone deacetylase 1 (Hdac1) in developmental and adult regenerative cardiomyocyte proliferation in the vertebrate heart.

Hdac1-deficiency affects the cell cycle axis Cdc25-Cdk1 causing impaired G2/M phase progression and reduced cardiomyocyte proliferation in zebrafish.

Zebrafish have the ability to fully regenerate their hearts after injury since cardiomyocytes subsequently dedifferentiate, re-enter cell cycle, and proliferate to replace damaged myocardial tissue. Recent research identified the reactivation of dormant developmental pathways during cardiac regeneration in adult zebrafish, suggesting pro-proliferative pathways important for developmental heart growth to be also critical for regenerative heart growth after injury. Histone deacetylase 1 (Hdac1) was recently shown to control both, embryonic as well as adult regenerative cardiomyocyte proliferation in the zebrafish model. Nevertheless, regulatory pathways controlled by Hdac1 are not defined yet. By analyzing RNA-seq-derived transcriptional profiles of the Hdac1-deficient zebrafish mutant baldrian, we here identified DNA damage response (DDR) pathways activated in baldrian mutant embryos. Surprisingly, although the DDR signaling pathway was transcriptionally activated, we found the complete loss of protein expression of the known DDR effector and cell cycle inhibitor p21. Consequently, we observed an upregulation of the p21-downstream target Cdk2, implying elevated G1/S phase transition in Hdac1-deficient zebrafish hearts. Remarkably, Cdk1, another p21-but also Cdc25-downstream target was downregulated. Here, we found the significant downregulation of Cdc25 protein expression, explaining reduced Cdk1 levels and suggesting impaired G2/M phase progression in Hdac1-deficient zebrafish embryos. To finally prove defective cell cycle progression due to Hdac1 loss, we conducted Cytometer-based cell cycle analyses in HDAC1-deficient murine HL-1 cardiomyocytes and indeed found impaired G2/M phase transition resulting in defective cardiomyocyte proliferation. In conclusion, our results suggest a critical role of Hdac1 in maintaining both, regular G1/S and G2/M phase transition in cardiomyocytes by controlling the expression of essential cell cycle regulators such as p21 and Cdc25.

Impact of concomitant tricuspid regurgitation on outcome after edge-to-edge mitral valve repair.

AIMS: To evaluate the impact of tricuspid regurgitation (TR) on echocardiographic and functional outcome after mitral valve transcatheter edge-to-edge-repair (M-TEER). METHODS AND RESULTS: A total of 740 patients underwent M-TEER at our center from 2010 to 2021. Patients were analyzed according to severity of concomitant TR at the time of M-TEER procedure: low-grade TR (grade ≤I [trace-mild], 279 patients [37.7%]), moderate TR (grade II, 170 patients [23.0%]) and high-grade TR (grade III-V [severe-torrential], 291 patients [39.3%]). Patients with moderate to high-grade TR had higher morbidity. Procedural success of M-TEER was achieved similarly in all groups (98.2% vs. 97.6% vs. 95.9%, p = 0.22). TR severity decreased rapidly and consistently after M-TEER to only 48.0% of high-grade TR patients after 3 months (p < 0.001) and to 46.8% after 12 months (p = 0.99). High-grade TR patients had significantly higher mortality (21.5% vs. 18.2% vs. 11.1%, p = 0.003) up to 12 months after M-TEER. However, high-grade TR did not independently predict mortality (HR 1.302, 95% CI 0.937-1.810; p = 0.116). Echocardiographic and functional outcome was similar in both secondary and primary MR patients. CONCLUSIONS: High-grade concomitant TR did not independently predict adverse outcome following M-TEER. A wait-and-observe approach for these patients is reasonable.

Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency.

Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3-/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3-/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3-/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3+/+ or bag3+/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1, an essential NMD factor, caused severe heart and skeletal muscle defects in bag3-/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo.

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes.

BACKGROUND: The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. METHODS: In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding. RESULTS: A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46). CONCLUSIONS: Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.).

Elevated platelet-leukocyte complexes are associated with, but dispensable for myocardial ischemia-reperfusion injury.

AIMS: P-selectin is an activatable adhesion molecule on platelets promoting platelet aggregation, and platelet-leukocyte complex (PLC) formation. Increased numbers of PLC are circulating in the blood of patients shortly after acute myocardial infarction and predict adverse outcomes. These correlations led to speculations about whether PLC may represent novel therapeutic targets. We therefore set out to elucidate the pathomechanistic relevance of PLC in myocardial ischemia and reperfusion injury. METHODS AND RESULTS: By generating P-selectin deficient bone marrow chimeric mice, the post-myocardial infarction surge in PLC numbers in blood was prevented. Yet, intravital microscopy, flow cytometry and immunohistochemical staining, echocardiography, and gene expression profiling showed unequivocally that leukocyte adhesion to the vessel wall, leukocyte infiltration, and myocardial damage post-infarction were not altered in response to the lack in PLC. CONCLUSION: We conclude that myocardial infarction associated sterile inflammation triggers PLC formation, reminiscent of conserved immunothrombotic responses, but without PLC influencing myocardial ischemia and reperfusion injury in return. Our experimental data do not support a therapeutic concept of selectively targeting PLC formation in myocardial infarction.

Coronary Stent Fracture Causing Myocardial Infarction: Case Report and Review of Literature.

Coronary stent fracture (SF) is a potential cause of stent failure increasing the risk for in-stent restenosis, stent thrombosis, target lesion revascularization and major adverse cardiac events. Overall incidence of SF ranges from < 1.0% up to 18.6% and SF can be found in up to 60% of failed devices. Advanced imaging techniques have improved the detection of SF. However, defining the optimal therapeutic approach towards these complex lesions is challenging. This review summarizes the most important publications on the topic of SF and discusses current insights into pathophysiology, diagnostic tools, classification and therapeutic management. Furthermore, two illustrative cases of SF leading to myocardial infarction are presented, which demonstrate typical SF risk factors such as vessel angulation and hinge motion, stenting in the right coronary artery, use of long stents and multiple stent layers.

CRISPR/Cas9-Mediated Constitutive Loss of VCP (Valosin-Containing Protein) Impairs Proteostasis and Leads to Defective Striated Muscle Structure and Function In Vivo.

Valosin-containing protein (VCP) acts as a key regulator of cellular protein homeostasis by coordinating protein turnover and quality control. Mutations in VCP lead to (cardio-)myopathy and neurodegenerative diseases such as inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) or amyotrophic lateral sclerosis (ALS). To date, due to embryonic lethality, no constitutive VCP knockout animal model exists. Here, we generated a constitutive CRISPR/Cas9-induced vcp knockout zebrafish model. Similar to the phenotype of vcp morphant knockdown zebrafish embryos, we found that vcp-null embryos displayed significantly impaired cardiac and skeletal muscle function. By ultrastructural analysis of skeletal muscle cells and cardiomyocytes, we observed severely disrupted myofibrillar organization and accumulation of inclusion bodies as well as mitochondrial degeneration. vcp knockout was associated with a significant accumulation of ubiquitinated proteins, suggesting impaired proteasomal function. Additionally, markers of unfolded protein response (UPR)/ER-stress and autophagy-related mTOR signaling were elevated in vcp-deficient embryos, demonstrating impaired proteostasis in VCP-null zebrafish. In conclusion, our findings demonstrate the successful generation of a stable constitutive vcp knockout zebrafish line that will enable characterization of the detailed mechanistic underpinnings of vcp loss, particularly the impact of disturbed protein homeostasis on organ development and function in vivo.

Spen deficiency interferes with Connexin 43 expression and leads to heart failure in zebrafish.

Genome-wide association studies identified Spen as a putative modifier of cardiac function, however, the precise function of Spen in the cardiovascular system is not known yet. Here, we analyzed for the first time the in vivo role of Spen in zebrafish and found that targeted Spen inactivation led to progressive impairment of cardiac function in the zebrafish embryo. In addition to diminished cardiac contractile force, Spen-deficient zebrafish embryos developed bradycardia, atrioventricular block and heart chamber fibrillation. Assessment of cardiac-specific transcriptional profiles identified Connexin 43 (Cx43), a cardiac gap junction protein and crucial regulator of cardiomyocyte-to-cardiomyocyte communication, to be significantly diminished in Spen-deficient zebrafish embryos. Similar to the situation in Spen-deficient embryos, Morpholino-mediated knockdown of cx43 in zebrafish resulted in cardiac contractile dysfunction, bradycardia, atrioventricular block and fibrillation of the cardiac chambers. Furthermore, ectopic overexpression of cx43 in Spen deficient embryos led to the reconstitution of cardiac contractile function and suppression of cardiac arrhythmia. Additionally, sensitizing experiments by simultaneously injecting sub-phenotypic concentrations of spen- and cx43-Morpholinos into zebrafish embryos resulted in pathological supra-additive effects. In summary, our findings highlight a crucial role of Spen in controlling cx43 expression and demonstrate the Spen-Cx43 axis to be a vital regulatory cascade that is indispensable for proper heart function in vivo.

Extracorporeal life support in patients with acute myocardial infarction complicated by cardiogenic shock - Design and rationale of the ECLS-SHOCK trial.

BACKGROUND: In acute myocardial infarction complicated by cardiogenic shock the use of mechanical circulatory support devices remains controversial and data from randomized clinical trials are very limited. Extracorporeal life support (ECLS) - venoarterial extracorporeal membrane oxygenation - provides the strongest hemodynamic support in addition to oxygenation. However, despite increasing use it has not yet been properly investigated in randomized trials. Therefore, a prospective randomized adequately powered clinical trial is warranted. STUDY DESIGN: The ECLS-SHOCK trial is a 420-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare whether treatment with ECLS in addition to early revascularization with percutaneous coronary intervention or alternatively coronary artery bypass grafting and optimal medical treatment is beneficial in comparison to no-ECLS in patients with severe infarct-related cardiogenic shock. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of ECLS-SHOCK is 30-day mortality. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, a longer follow-up at 6 and 12 months will be performed including quality of life assessment. Safety endpoints include peripheral ischemic vascular complications, bleeding and stroke. CONCLUSIONS: The ECLS-SHOCK trial will address essential questions of efficacy and safety of ECLS in addition to early revascularization in acute myocardial infarction complicated by cardiogenic shock.

Catheter ablation for atrial fibrillation in HFpEF patients-A propensity-score-matched analysis.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are both common conditions associated with high morbidity and mortality, especially if they coexist. Catheter ablation (CA) for AF has been shown recently to induce reverse remodeling and improve symptoms in HFpEF patients. The aim of this study was to compare outcomes of AF patients with HFpEF, who either underwent CA for AF or received medical therapy only. METHODS AND RESULTS: We included all AF patients with HFpEF according to current guidelines treated at our hospital between 2013 and 2018. Out of 6614 AF patients, we identified 127 with confirmed HFpEF. After applying propensity score matching to balance patient groups, 43 patients treated by CA and 43 patients receiving medical treatment were compared. Patients in the CA group underwent a mean of 1.5 ± 0.8 ablation procedures. Arrhythmia recurrence occurred significantly less frequently in the CA group (hazard ratio [HR]: 0.47; 95% CI: 0.25-0.87; p = .016). The primary endpoint, a composite of heart failure hospitalization and death, was reduced significantly by CA compared to medical therapy (HR: 0.30; 95% CI: 0.13-0.67; p = .003). This was driven by a decrease in heart failure hospitalization. Clinical and echocardiographic parameters of HFpEF improved significantly only after CA. Remarkably, reassessment of diagnostic HFpEF criteria at the end of follow-up demonstrated HFpEF resolution in 15 out of 43 patients (35%) treated by CA and only 4 out of 43 patients (9%) treated medically (p = .008). CONCLUSION: Catheter ablation for AF in HFpEF patients in comparison to medical therapy decreases heart failure hospitalization, heart failure symptoms, and improves diastolic function. AF ablation should be considered in patients with HFpEF and concomitant AF.

Tiny golden angle ultrashort echo-time lung imaging in mice.

Imaging the lung parenchyma with MRI is particularly difficult in small animals due to the high respiratory and heart rates, and ultrashort T2* at high magnetic field strength caused by the high susceptibilities induced by the air-tissue interfaces. In this study, a 2D ultrashort echo-time (UTE) technique was combined with tiny golden angle (tyGA) ordering. Data were acquired continuously at 11.7 T and retrospective center-of-k-space gating was applied to reconstruct respiratory multistage images. Lung (proton) density (fP ), T2*, signal-to-noise ratio (SNR), fractional ventilation (FV) and perfusion (f) were quantified, and the application to dynamic contrast agent (CA)-enhanced (DCE) qualitative perfusion assessment tested. The interobserver and intraobserver and interstudy reproducibility of the quantitative parameters were investigated. High-quality images of the lung parenchyma could be acquired in all animals. Over all lung regions a mean T2* of 0.20 ± 0.05 ms was observed. FV resulted as 0.31 ± 0.13, and a trend towards lower SNR values during inspiration (EX: SNR = 12.48 ± 6.68, IN: SNR = 11.79 ± 5.86) and a significant (P < 0.001) decrease in lung density (EX: fP  = 0.69 ± 0.13, IN: fP  = 0.62 ± 0.13) were observed. Quantitative perfusion results as 34.63 ± 9.05 mL/cm3 /min (systole) and 32.77 ± 8.55 mL/cm3 /min (diastole) on average. The CA dynamics could be assessed and, because of the continuous nature of the data acquisition, reconstructed at different temporal resolutions. Where a good to excellent interobserver reproducibility and an excellent intraobserver reproducibility resulted, the interstudy reproducibility was only fair to good. In conclusion, the combination of tiny golden angles with UTE (2D tyGA UTE) resulted in a reliable imaging technique for lung morphology and function in mice, providing uniform k-space coverage and thus low-artefact images of the lung parenchyma after gating.

Implications of concomitant obstructive or restrictive pulmonary diseases on functional and clinical results after MitraClip.

OBJECTIVES: We investigated the impact of underlying pulmonary limitations (PL) on symptoms and clinical outcomes after transcatheter mitral valve repair (TMVr). BACKGROUND: Patients with pulmonary disease and patients with symptomatic mitral regurgitation (MR) suffer common symptoms like dyspnea and reduced exercise capacity. METHODS: Datasets from the TMVr Ulm registry were retrospectively analyzed by a blinded specialist in pneumology. Patients were dichotomized according to an unambiguous manifestation of concomitant pulmonary disease in a PL-group and a non-PL-group and were analyzed regarding baseline characteristics and clinical follow-up. RESULTS: Overall, 483 patients were included in the study of which 32.3% (n = 156) showed an underlying pulmonary disease. Patients in the PL-group were similar to patients in the non-PL-group, including Euro SCORE II (8.2 vs. 8.4, p = 0.39), New York Heart Association (NYHA) classification (3.2 ± 0.7 in both groups, p = 0.65) and the incidence of moderate-to-severe or severe MR after TMVr (5.8 vs. 8.3%, p = 0.32). Equal and significant symptom relief after TMVr was experienced in both cohorts according to NYHA functional class (2.24 ± 0.84 vs. 2.24 ± 0.86, p = 0.93) and rate of hospitalization during 2 years of follow-up decreased comparably from 61.1 to 19.3%. However, all-cause mortality for 2 year follow-up was significantly higher in the PL-group compared to the non-PL-group (31.4 vs. 21.4%, p = 0.018). CONCLUSION: In patients with MR and concomitant pulmonary disorders, a significant increase of exercise capacity and a significant decrease of rehospitalization rate were observed after TMVr. Nevertheless, all-cause mortality remains significantly increased within a follow-up period of 2 years compared to patients without pulmonary disorders.

Immunoadsorption for heart failure is associated with normalization of iron metabolism.

AIMS: In heart failure (HF) patients, early stages are associated with increased iron levels, whereas iron deficiency is a common feature of chronic HF. We investigated the acute and long-term changes in iron metabolism in HF patients after immunoadsorption treatment and intravenous immunoglobulin (IVIG) administration. METHODS AND RESULTS: Twenty-seven patients with HF with reduced ejection fraction (HFrEF) received a single cycle of immunoadsorption followed by IVIG administration. Left ventricular ejection fraction (LVEF) and iron biomarker (ferritin, hepcidin and interleukin-6) were evaluated at baseline, after immunoadsorption and during long-term follow-up of 29.3 months. LVEF improved significantly after immunoadsorption treatment from baseline 27% to 43% at long-term follow-up. Ferritin decreased from baseline 300.2 to 201.3 ng/mL (p < 0.0001) during immunoadsorption treatment and normalized during long-term to 207.9 ng/mL. Hepcidin showed a V-shaped course, with a significant decrease after immunoadsorption and normalization during long-term. Interleukin-6 levels showed no relevant inflammation. CONCLUSIONS: Our data suggest that initial high serum ferritin and hepcidin levels indicate elevated iron levels characteristic of early stages of HFrEF, without inflammation. Normalization of hepcidin and ferritin was paralleled by restoration of systolic cardiac function after immunoadsorption treatment, without development of iron deficiency, as usually observed in chronic HF.

Impact of extent of coronary artery disease and percutaneous revascularization assessed by the SYNTAX score on outcomes following transcatheter aortic valve replacement.

OBJECTIVES: The aim of the study was to analyze the impact of concomitant coronary artery disease (CAD) assessed by the SYNTAX score (SS) and periprocedural percutaneous coronary intervention (PCI) on outcomes after transcatheter aortic valve replacement (TAVR). BACKGROUND: Due to controversial data regarding the effect of CAD on outcomes after TAVR, proper revascularization strategies remain a matter of debate. METHODS: 553 patients with severe aortic stenosis undergoing TAVR were included in this study. SS was calculated for each patient at baseline and after PCI. Primary outcome was one-year all-cause mortality. RESULTS: 60.2% of patients (N = 333) exhibited CAD with a mean SS of 10.8 ± 8.8. Of those, 120 patients (36.0%) received periprocedural PCI. In the treatment group, mean SS was decreased from 14.9 ± 9.1 to 6.3 ± 6.7. Patients with concomitant CAD suffered more frequently from myocardial infarction (MI) post TAVR compared to those without CAD (2.1% vs. 0.0%; P < 0.01). In the CAD cohort, MI rates were comparable between patients with and without PCI (2.2% vs. 2.5%; P = 0.71). Regarding SS, patients with a residual SS < 8 showed significant lower rates of one-year mortality (9.0% vs. 18.2%; P = 0.016) and MACCE (16.5% vs. 32.2%; P = 0.001). Besides left bundle brunch, predictors for an increased one-year mortality were a residual SS ≥ 8 in the CAD group (OR = 3.17; P = 0.011) and a EuroSCORE ≥ 4% in the entire study population (OR = 2.18; P = 0.017). CONCLUSION: Our results suggest that a residual SS-guided revascularization strategy may improve prognosis after TAVR in patients with concomitant CAD. PCI aiming for a residual SS < 8 was associated with improved one-year clinical outcomes.

Safety of conscious sedation in electroanatomical mapping procedures and cryoballoon pulmonary vein isolation.

Immobilization of patients during electrophysiological procedures, to avoid complications by patients' unexpected bodily motion, is achieved by moderate to deep conscious sedation using benzodiazepines and propofol for sedation and opioids for analgesia. Our aim was to compare respiratory and hemodynamic safety endpoints of cryoballoon pulmonary vein isolation (PVI) and electroanatomical mapping (EAM) procedures. Included patients underwent either cryoballoon PVI or EAM procedures. Sedation monitoring included non-invasive blood pressure measurements, transcutaneous oxygen saturation (tSpO2) and transcutaneous carbon-dioxide (tpCO2) measurements. We enrolled 125 consecutive patients, 67 patients underwent cryoballoon atrial fibrillation ablation and 58 patients had an EAM and radiofrequency ablation procedure. Mean procedure duration of EAM procedures was significantly longer (p < 0.001) and propofol doses as well as morphine equivalent doses of administered opioids were significantly higher in EAM patients compared to cryoballoon patients (p < 0.001). Cryoballoon patients display higher tpCO2 levels compared to EAM patients at 30 min (cryoballoon: 51.1 ± 7.0 mmHg vs. EAM: 48.6 ± 6.2 mmHg, p = 0.009) and at 60 min (cryoballoon: 51.4 ± 7.3 mmHg vs. EAM: 48.9 ± 6.6 mmHg, p = 0.07) procedure duration. Mean arterial pressure was significantly higher after 60 min (cryoballoon: 84.7 ± 16.7 mmHg vs. EAM: 76.7 ± 13.3 mmHg, p = 0.017) in cryoballoon PVI compared to EAM procedures. Regarding respiratory and hemodynamic safety endpoints, no significant difference was detected regarding hypercapnia, hypoxia and episodes of hypotension. Despite longer procedure duration and deeper sedation requirement, conscious sedation in EAM procedures appears to be as safe as conscious sedation in cryoballoon ablation procedures regarding hemodynamic and respiratory safety endpoints.