Comparing the effects of chemical Ca2+ dyes and R-GECO on contractility and Ca2+ transients in adult and human iPSC cardiomyocytes.

We compared commonly used BAPTA-derived chemical Ca2+ dyes (fura2, Fluo-4, and Rhod-2) with a newer genetically encoded indicator (R-GECO) in single cell models of the heart. We assessed their performance and effects on cardiomyocyte contractility, determining fluorescent signal-to-noise ratios and sarcomere shortening in primary ventricular myocytes from adult mouse and guinea pig, and in human iPSC-derived cardiomyocytes. Chemical Ca2+ dyes displayed dose-dependent contractile impairment in all cell types, and we observed a negative correlation between contraction and fluorescence signal-to-noise ratio, particularly for fura2 and Fluo-4. R-GECO had no effect on sarcomere shortening. BAPTA-based dyes, but not R-GECO, inhibited in vitro acto-myosin ATPase activity. The presence of fura2 accentuated or diminished changes in contractility and Ca2+ handling caused by small molecule modulators of contractility and intracellular ionic homeostasis (mavacamten, levosimendan, and flecainide), but this was not observed when using R-GECO in adult guinea pig left ventricular cardiomyocytes. Ca2+ handling studies are necessary for cardiotoxicity assessments of small molecules intended for clinical use. Caution should be exercised when interpreting small molecule studies assessing contractile effects and Ca2+ transients derived from BAPTA-like chemical Ca2+ dyes in cellular assays, a common platform for cardiac toxicology testing and mechanistic investigation of cardiac disease physiology and treatment.

The Future of LAAC-In 5, 10, and 20 Years.

Early experience with percutaneous LAA closure documented complication rates of ∼10%, with failure to implant devices in ∼10% of patients. These numbers are unrecognizable in contemporary practice due to the iterative changes made largely in the last 10 years. Here we look forward to ask what might change, and when, to bring percutaneous LAA closure out of the niche early adopter centers into routine use. We consider the opportunity to incorporate different technologies into LAAc devices in the context of managing patient with atrial fibrillation. Finally, we consider how to make the procedure safer and more effective.

The Future of LAAC-In 5, 10, and 20 Years.

Early experience with percutaneous LAA closure documented complication rates of ∼10%, with failure to implant devices in ∼10% of patients. These numbers are unrecognizable in contemporary practice due to the iterative changes made largely in the last 10 years. Here we look forward to ask what might change, and when, to bring percutaneous LAA closure out of the niche early adopter centers into routine use. We consider the opportunity to incorporate different technologies into LAAc devices in the context of managing patient with atrial fibrillation. Finally, we consider how to make the procedure safer and more effective.

High-Throughput Optical Controlling and Recording Calcium Signal in iPSC-Derived Cardiomyocytes for Toxicity Testing and Phenotypic Drug Screening.

Understanding how excitable cells work in health and disease and how that behavior can be altered by small molecules or genetic manipulation is important. Genetically encoded calcium indicators (GECIs) with multiple emission windows can be combined (e.g., for simultaneous observation of distinct subcellular events) or used in extended applications with other light-dependent actuators in excitable cells (e.g., combining genetically encoded optogenetic control with spectrally compatible calcium indicators). Such approaches have been used in primary or stem cell-derived neurons, cardiomyocytes, and pancreatic beta-cells. However, it has been challenging to increase the throughput, or duration of observation, of such approaches due to limitations of the instruments, analysis software, indicator performance, and gene delivery efficiency. Here, a high-performance green GECI, mNeonGreen-GECO (mNG-GECO), and red-shifted GECI, K-GECO, is combined with optogenetic control to achieve all-optical control and visualization of cellular activity in a high-throughput imaging format using a High-Content Imaging System. Applications demonstrating cardiotoxicity testing and phenotypic drug screening with healthy and patient-derived iPSC-CMs are shown. In addition, multi-parametric assessments using combinations of spectral and calcium affinity indicator variants (NIR-GECO, LAR-GECO, and mtGCEPIA or Orai1-G-GECO) are restricted to different cellular compartments are also demonstrated in the iPSC-CM model.

An assessment of annual procedure volumes and therapy adoption of transcatheter closure of patent foramen ovale in four European countries.

INTRODUCTION: Patent foramen ovale closure reduces recurrence of cryptogenic ischaemic stroke compared to anti-platelet therapy. Our goal was to determine procedure volumes and closure utilisation as a proportion of candidates in four large European countries. PATIENTS AND METHODS: National statistics were obtained for Germany, England, France, and Italy for the last available five years (2014-2018). Eligibility was aligned to the enrolment criteria of pivotal trials and current consensus documents. Stroke and transient ischaemic attack incidences were obtained from epidemiological registries and claims data. The eligible candidate pool for analysis included current year candidates plus untreated patients from the prior two years. Absolute strokes avoided assumed the hazard ratio for ischaemic stroke recurrence from a recent meta-analysis. RESULTS: In 2018, closure incidence rates were 5.64, 0.53, 2.94 and 5.26 per 100,000 in Germany, England, France and Italy, respectively. This reflects five-year increases of 128% in Germany, 462% in France and 36% in Italy (p < 0.05 for all), and a decline of 37% in England. The proportions of treated patients versus candidates for the combined stroke and transient ischaemic attack pool were 55%, 30%, 80%, and 6%, respectively. DISCUSSION: Patent foramen ovale closure volumes increased after the 2017 announcement of positive trial results but still differ substantially across large European countries. If all closure candidates in 2018 with prior ischaemic stroke were treated, the resulting absolute reduction of recurrent ischaemic strokes, compared to anti-platelet therapy alone, would be between 782 and 2295 across the four countries over five years. CONCLUSION: Many eligible patients at risk for a recurrent cryptogenic event might remain untreated due to regional practice variations.

Sustainable Resumption of Cardiac Catheterization Laboratory Procedures, and the Importance of Testing, During Endemic COVID-19.

PURPOSE: As second and third waves of the COVID-19 pandemic challenge healthcare in North America and Europe once again, we analyze the impact of the first wave on routine elective cardiovascular care, and the differential COVID risk emerging within our patient groups and staff. PERSPECTIVE: We describe the need to sustainably resume, and temporarily expand, routine elective cardiac services in the face of resurgent COVID-19. Some, but not all, cardiac patient groups are particularly vulnerable to adverse outcomes following COVID-19 infection. We explore mitigation measures at the institutional level to increase resilience within cardiac services to enable them to operate deep into subsequent waves of COVID infection which place unprecedented demands on intensive care infrastructure. As measures to eradicate the virus appear to have failed in many countries, and vaccine roll-out will take many months we take the view that the threat imposed by endemic COVID-19 alters the way elective procedural care should be offered to cardiovascular patients. CONCLUSION: Our patients are at definite risk from their cardiovascular disease, and a return to suspension of proven prognostic interventional treatments on an elective basis - the default for the first wave - must be avoided at all costs.

Outcomes of Percutaneous and Surgical Pulmonary Valve Implantation.

BACKGROUND: The objective of this study is to describe the recent trends and in-hospital outcomes with percutaneous pulmonic valve implantation (PPVI) and surgical pulmonic valve replacement (SPVR) in adult hospitals in the US after the availability of both the Melody valve (Medtronic Inc., Minneapolis, Minnesota) and the Sapien XT valve (Edwards Lifesciences, Irvine, CA). METHODS: We queried the National Inpatient Sample database (NIS) from January 2016 to December 2017 to identify hospitalizations for PPVI and SPVR. RESULTS: We identified 5455 weighted discharges with PPVI and SPVR (PPVI=1140, SPVR=4305). PPVI procedures had increased in number over 2016 and 2017 (115 procedure at the first quarter of 2016, 195 procedures in the final quarter of 2017, P-trend=0.086), while SPVR volume remained constant. The incidence of in-hospital mortality was low with both procedures (SPRV: 1.6% vs. PPVI: 0.9%, p=0.071). SPVR had worse in-hospital outcomes, was associated with a longer length of stay [5 days vs. 1 day, p<0.001], and comparable cost of index hospitalization [$51,657 vs. $51,193] compared with PPVI. CONCLUSION: After approval of the Sapien valve for commercial use in 2016, PPVI procedures have increased in frequency. PPVI is associated with lower procedural complications than SPVR, however, both carry a low risk of mortality. Despite the higher cost of the valves and delivery systems, PPVI is associated with a slightly lower cost of index hospitalization compared with SPVR, likely due to the higher in-hospital complications and LOS of the latter.

Homozygous familial hypercholesterolemia with an update on cholesterol management.

Familial hypercholesterolemia (FH) is an autosomal dominant condition that increases the risk of premature cardiovascular disease. Despite advances in treatment, it remains under detected and under treated. As an inherited condition, it poses a risk to the patient and family members. Most cases are due to defective low-density lipoprotein receptor (LDLR) activity. Heterozygous mutations are common (1:250-1:300). Homozygous FH is very rare (2-3 in a million), with higher circulating cholesterol levels and a poorer cardiovascular prognosis. We present the management of a case of homozygous hypercholesterolemia due to homozygous LDLR mutation. The patient subsequently developed severe coronary artery and aortic valve disease despite aggressive lipid-lowering therapy. We review advanced lipid management options that include lipoprotein apheresis, Proprotein Convertase Subtilisin/Kexin type 9 inhibition, and the microsomal triglyceride transfer protein inhibitor lomitapide.

Hot topics in interventional cardiology: Proceedings from the society for cardiovascular angiography and interventions 2020 think tank.

The society for cardiovascular angiography and interventions (SCAI) think tank is a collaborative venture that brings together interventional cardiologists, administrative partners, and select members of the cardiovascular industry community for high-level field-wide discussions. The 2020 think tank was organized into four parallel sessions reflective of the field of interventional cardiology: (a) coronary intervention, (b) endovascular medicine, (c) structural heart disease, and (d) congenital heart disease (CHD). Each session was moderated by a senior content expert and co-moderated by a member of SCAI's emerging leader mentorship program. This document presents the proceedings to the wider cardiovascular community in order to enhance participation in this discussion, create additional dialogue from a broader base, and thereby aid SCAI and the industry community in developing specific action items to move these areas forward.

Meta-analysis Comparing Transradial Versus Transfemoral Secondary Access in Transcatheter Aortic Valve Implantation.

Up to a quarter of vascular complications during transcatheter aortic valve implantation (TAVI) result from secondary access via the femoral artery (FA). The radial artery (RA) is increasingly used as an alternative to the FA for secondary access in TAVI. Limited data exist on the outcomes of RA secondary access versus FA secondary access. We therefore conducted a systematic review and meta-analysis comparing secondary access sites. PubMed, EMBASE, Scopus, Cochrane library and CINAHL were searched systematically for studies comparing RA and FA as secondary access sites for TAVI. Primary outcomes of interest were vascular complications and major bleeding. Secondary outcomes included all-cause mortality, stroke and myocardial infarction (MI). Risk ratio (RR), standardized mean difference and corresponding 95% confidence intervals (CI) were calculated using a random effects model. Six observational studies comprising 6,373 patients (RA: 1,514, FA: 4,859) met inclusion criteria. Secondary access was utilized for aortography during valve deployment and to manage primary access site complications. Procedural characteristics were similar in both groups. RA was associated with a lower risk of major bleeding (RR: 0.51, 95% CI: 0.40 to 0.64, p <0.00001). No statistically significant difference was observed in the incidence of overall vascular complications, however, the risk of major vascular complications was lower with RA (RR: 0.45, 95% CI: 0.32 to 0.63, p <0.00001). The incidence of stroke and all-cause mortality was lower in RA, whereas no difference was observed in the risk of MI. In conclusion, our meta-analysis suggests that RA secondary access is associated with better outcomes for TAVI than FA.

Considerations for cardiac catheterization laboratory procedures during the COVID-19 pandemic perspectives from the Society for Cardiovascular Angiography and Interventions Emerging Leader Mentorship (SCAI ELM) Members and Graduates.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly infectious, carries significant morbidity and mortality, and has rapidly resulted in strained health care system and hospital resources. In addition to patient-related care concerns in infected individuals, focus must also relate to diminishing community spread, protection of staff, case selection, and concentration of resources. The current document based on available data and consensus opinion addresses appropriate catheterization laboratory preparedness for treating these patients, including procedure-room readiness to minimize external contamination, safe donning and doffing of personal protective equipment (PPE) to eliminate risk to staff, and staffing algorithms to minimize exposure and maximize team availability. Case selection and management of both emergent and urgent procedures are discussed in detail, including procedures that may be safely deferred or performed bedside.