The CORolla device for energy transfer from systole to diastole: a novel treatment for heart failure with preserved ejection fraction.

It is estimated that 30 to 50% of heart failure patients have heart failure with preserved ejection fraction (HFpEF). Mortality is high in this patient population, and morbidity and rate of hospitalization are similar to those of heart failure patients with reduced ejection fraction (HFrEF). The management of patients with HFpEF is essentially empirical, limited, and disappointing. HFpEF is characterized by diastolic dysfunction leading to increased left ventricular (LV) filling pressures. We have previously described how mechanical energy transfer from the systole phase to the diastole phase of the cardiac cycle can potentially reduce filling pressures during the diastolic phase which may improve clinical symptoms of HFpEF. The CORolla device is a novel device anatomically designed for positioning in the left ventricle (LV) and mechanically designed to apply an outward radial force on the LV endocardium thus transferring energy from the systolic phase, in which the device contracts, gaining potential energy, to the diastolic phase from its recoil. Here we summarize the present knowledge concerning the energy transfer therapeutic approach for HFpEF, describe the CORolla device, and depict its potential future clinical indications.

Strategies to overcome challenges of transradial coronary angiography and intervention.

The transradial approach has become the preferred route for performing coronary angiography and interventions. Several studies reported that radial access is associated with significant reduction in vascular complications compared with the femoral access. This technique allows also early ambulation, improves the patient's well-being, and is less expensive. One important limitation of radial access is that coronary engagement from transradial approach is more challenging than transfemoral approach. The increased susceptibility of the radial artery to spasm, the radial-brachial artery tortuosities, and the subclavian-aorta curves make catheter advancement and coronary artery cannulation difficult. Hereby, we suggest several techniques for recognising and overcoming potential challenges during transradial coronary angiography.

Performance of a novel artificial intelligence software developed to derive coronary fractional flow reserve values from diagnostic angiograms.

BACKGROUND: Although invasive measurement of fractional flow reserve (FFR) is recommended to guide revascularization, its routine use is underutilized. Recently, a novel non-invasive software that can instantaneously produce FFR values from the diagnostic angiograms, derived completely from artificial intelligence (AI) algorithms has been developed. We aim to assess the accuracy and diagnostic performance of AI-FFR in a real-world retrospective study. METHODS: Retrospective, three-center study comparing AI-FFR values with invasive pressure wire-derived FFR obtained in patients undergoing routine diagnostic angiography. The accuracy, sensitivity, and specificity of AI-FFR were analyzed. RESULTS: A total of 304 vessels from 297 patients were included. Mean invasive FFR was 0.86 vs. 0.85 AI-FFR (mean difference: -0.005, P  = 0.159). The diagnostic performance of AI-FFR demonstrated sensitivity of 91%, specificity 95%, positive predictive value 83% and negative predictive value 97%. Overall accuracy was 94% and the area under curve was 0.93 (95% CI 0.88-0.97). 105 lesions fell around the cutoff value (FFR = 0.75-0.85); in this sub-group, AI-FFR demonstrated sensitivity of 95%, and specificity 94%, with an AUC of 0.94 (95% CI 88.2-98.0). AI-FFR calculation time was 37.5 ±â€…7.4 s for each angiographic video. In 89% of cases, the software located the target lesion and in 11%, the operator manually marked the target lesion. CONCLUSION: AI-FFR calculated by an AI-based, angio-derived method, demonstrated excellent diagnostic performance against invasive FFR. AI-FFR calculation was fast with high reproducibility.

Abbreviated or Standard Antiplatelet Therapy in HBR Patients: Final 15-Month Results of the MASTER-DAPT Trial.

BACKGROUND: Clinical outcomes and treatment selection after completing the randomized phase of modern trials, investigating antiplatelet therapy (APT) after percutaneous coronary intervention (PCI), are unknown. OBJECTIVES: The authors sought to investigate cumulative 15-month and 12-to-15-month outcomes after PCI during routine care in the MASTER DAPT trial. METHODS: The MASTER DAPT trial randomized 4,579 high bleeding risk patients to abbreviated (n = 2,295) or standard (n = 2,284) APT regimens. Coprimary outcomes were net adverse clinical outcomes (NACE) (all-cause death, myocardial infarction, stroke, and BARC 3 or 5 bleeding); major adverse cardiac and cerebral events (MACCE) (all-cause death, myocardial infarction, and stroke); and BARC type 2, 3, or 5 bleeding. RESULTS: At 15 months, prior allocation to a standard APT regimen was associated with greater use of intensified APT; NACE and MACCE did not differ between abbreviated vs standard APT (HR: 0.92 [95% CI: 0.76-1.12]; P = 0.399 and HR: 0.94 [95% CI: 0.76-1.17]; P = 0.579; respectively), as during the routine care period (HR: 0.81 [95% CI: 0.50-1.30]; P = 0.387 and HR: 0.74 [95% CI: 0.43-1.26]; P = 0.268; respectively). BARC 2, 3, or 5 was lower with abbreviated APT at 15 months (HR: 0.68 [95% CI: 0.56-0.83]; P = 0.0001) and did not differ during the routine care period. The treatment effects during routine care were consistent with those observed within 12 months after PCI. CONCLUSIONS: At 15 months, NACE and MACCE did not differ in the 2 study groups, whereas the risk of major or clinically relevant nonmajor bleeding remained lower with abbreviated compared with standard APT. (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen [MASTER DAPT]; NCT03023020).

Vascular Complications Among Patients Undergoing Trans-femoral Transcatheter Aortic Valve Implantation: Prostar vs ProGlide Parallel Technique.

Reliable femoral artery closure devices are essential for the success of trans-femoral Transcatheter Aortic Valve Implantation (TAVI) procedures. Accordingly, device choice might affect vascular complications and bleeding rates. This was a retrospective analysis, comparing vascular complication rates among patients who underwent trans-femoral TAVI with vascular access closure using either the ProGlide parallel suture or Prostar closure devices. We included 191 patients: 106 were treated with Prostar and 85 with ProGlide. The ProGlide group had higher rate of diabetes, chronic kidney disease, peripheral arterial disease, and significantly smaller femoral arteries that were treated via larger sheaths. Valve Academic Research Consortium (VARC)-2 major complications were similar between the groups. (4.7% for ProGlide vs 3.8% for Prostar, P=1), with similar incidence of closure device failure (2 vs 3, P=1). No differences were found after univariant analysis and propensity-score matching in the incidence of major and minor bleeding nor in the rate of in-hospital mortality between ProGlide and Prostar (4.7 vs 2.8%, P=.7, 1.2 vs 2.8%, P=.63, and 1.2 vs .0%, P=.45, respectively). Parallel suture technique using two ProGlide sutures showed comparable rates of vascular complications to the Prostar closure device in higher risk population of TAVI patients.

Early Feasibility of Automated Artificial Intelligence Angiography Based Fractional Flow Reserve Estimation.

Despite the evidence of improved patients' outcome, fractional flow reserve (FFR) is underused in current everyday practice. We aimed to evaluate the feasibility of a novel automated artificial intelligence angiography-based FFR software (AutocathFFR) as a decision supporting tool for interventional cardiologists. AutocathFFR was performed on angiographic images of patients who underwent coronary angiography with a pressure wire FFR measurement. Sensitivity and specificity for detection of FFR cut-off of 0.8 were calculated. Thirty-one patients were included in the present study, with a mean age of 64 ± 10 years, 80% were males, 32% patients had diabetes, 39% had previous percutaneous coronary intervention. The left anterior descending artery was the target vessel in 80% of patients. Automatic lesion detection was successful in all of the lesions with FFR value of ≤0.8. The sensitivity of AutocathFFR for predicting a wire based FFR ≤0.8 was 88% and the specificity for FFR >0.8 was 93%, with a positive predictive value of 94% and negative predictive value of 87%, indicating an accuracy level of 90% and area under the curve of 0.91. AutocathFFR has excellent accuracy in prediction of wire based FFR and is a promising technology that may facilitate appropriate decision and treatment choices for coronary artery disease patients.

Novel Technique for the Treatment of Coronary Artery Perforation.

Coronary artery perforation is a rare complication of percutaneous coronary intervention (PCI); its rate is estimated at 0.4- 0.7% of all PCIs. Fast recognition and response are imperative for the treatment of this potentially life-threatening complication. Available techniques for the treatment of perforations have moderate success rates and often necessitate dedicated equipment and expertise. In the case report presented, we describe a novel technique used to treat coronary perforations with readily available equipment.

First-in-man Safety and Efficacy of the ClearRing Implant for the Treatment of Benign Prostatic Hyperplasia.

BACKGROUND: Although effective for benign prostatic hyperplasia (BPH), transurethral resection of the prostate (TURP) can be associated with side effects including prolonged recovery, storage and voiding symptoms, and a risk of acute urinary retention. OBJECTIVE: To test a new minimally invasive device for the treatment of lower urinary tract symptoms (LUTS) due to BPH, involving implantation of a C-shaped nitinol ring (ClearRing) in a circular incision in the prostatic tissue using an electrocuting blade over a dilatation balloon. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter single-arm clinical trial involving 29 men with severe symptomatic BPH. INTERVENTION: Implantation of a ClearRing device under regional anesthesia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Effectiveness in alleviating LUTS was assessed in terms of International Prostate Symptom Score (IPSS) at baseline and 3, 6, and 12 mo after the procedure. To evaluate changes from baseline, a general estimating equation model was fitted to IPSS, the Quality of Life (QOL) scale, Benign Prostatic Hyperplasia Impact Index, maximum flow rate (Qmax), and postvoid residual volume. Statistical significance was defined as p<0.05. RESULTS AND LIMITATIONS: The average age was 71.4 yr, prostate size was 35-50cm3, and IPSS was 21.6. All procedures were successfully completed with one implant in 28 patients and two implants in one patient. No serious complications occurred. Patients experienced symptom relief by 3 mo that was sustained to 12 mo. Mean IPSS, QOL, and Qmax improved by 45%, 41%, and 40% by 3 mo, and 53%, 52%, and 49% by 12 mo, respectively (p<0.05). Adverse events were mild and transient. There were no reports of loss of antegrade ejaculation or any effects on erectile function. Implantation positioning failed in 11/29 patients, who then underwent uneventful TURP. After modification of the delivery device, the success rate for implant positioning improved from 5/13 patients to 13/16 patients. Study limitations include the single-arm nature and the low patient number. CONCLUSIONS: We demonstrated preliminary feasibility of the ClearRing device for minimally invasive treatment of BPH in men. Further studies are needed to confirm the safety and efficacy of this approach. PATIENT SUMMARY: In this study we tested outcomes after implantation of a ClearRing device in patients with benign prostatic hyperplasia. We found that the device was safe and effective. However, there was a high rate of implantation failure due to malpositioning, which was significantly improved following modification of the delivery device.

Cell therapy for modification of the myocardial electrophysiological substrate.

BACKGROUND: Traditional antiarrhythmic pharmacological therapies are limited by their global cardiac action, low efficacy, and significant proarrhythmic effects. We present a novel approach for the modification of the myocardial electrophysiological substrate using cell grafts genetically engineered to express specific ionic channels. METHODS AND RESULTS: To test the aforementioned concept, we performed ex vivo, in vivo, and computer simulation studies to determine the ability of fibroblasts transfected to express the voltage-sensitive potassium channel Kv1.3 to modify the local myocardial excitable properties. Coculturing of the transfected fibroblasts with neonatal rat ventricular myocyte cultures resulted in a significant reduction (68%) in the spontaneous beating frequency of the cultures compared with baseline values and cocultures seeded with naive fibroblasts. In vivo grafting of the transfected fibroblasts in the rat ventricular myocardium significantly prolonged the local effective refractory period from an initial value of 84+/-8 ms (cycle length, 200 ms) to 154+/-13 ms (P<0.01). Margatoxin partially reversed this effect (effective refractory period, 117+/-8 ms; P<0.01). In contrast, effective refractory period did not change in nontransplanted sites (86+/-7 ms) and was only mildly increased in the animals injected with wild-type fibroblasts (73+/-5 to 88+/-4 ms; P<0.05). Similar effective refractory period prolongation also was found during slower pacing drives (cycle length, 350 to 500 ms) after transplantation of the potassium channels expressing fibroblasts (Kv1.3 and Kir2.1) in pigs. Computer modeling studies confirmed the in vivo results. CONCLUSIONS: Genetically engineered cell grafts, transfected to express potassium channels, can couple with host cardiomyocytes and alter the local myocardial electrophysiological properties by reducing cardiac automaticity and prolonging refractoriness.

Assessing the Safety and Efficacy of the ClearRing™ Implant for the Treatment of Benign Prostatic Hyperplasia in a Canine Model.

BACKGROUND: Transurethral resection of the prostate is the most common procedure for the treatment of benign prostatic hyperplasia (BPH). Although effective, transurethral resection of the prostate can be associated with side effects including prolonged recovery, storage and voiding symptoms, risk of acute urinary retention. OBJECTIVES: In this study, we describe a new minimally invasive device for the treatment of lower urinary track symptoms due to BPH, implanting a nitinol C shape ring in a circular incision in the prostatic tissue, surrounding the urethra, done by electrocuting blade over a dilatation balloon. METHODS: Two groups of dogs (4/ group) were implanted with the device under anesthesia. Clinical observation, body weight and weekly blood and urinary tests were performed throughout the study period to evaluate safety. Fluoroscopy and cystoscopy were used throughout the study period to evaluate implant condition and urethral dilatation. At the end of 3 weeks (Group I) or 3 months (Group II), the animals were sacrificed. The implantation site was examined macroscopically and histologically to evaluate urethral dilatation and tissue response. RESULTS: The presence of the ClearRing™ implant in an animal's prostate was associated with significant dilatation of the prostatic urethra. Fever, pain, behavior disturbances or gross hematuria, when occurred, resolved within 72 hours post procedure and no severe adverse events were observed. There was no evidence of prostatic hyperplasia associated to ring implantation. Partial epithelial coverage of the implant surface was observed without evidence of encrustation. CONCLUSION: The ClearRing™ implant seems a feasible minimally invasive procedure for relieving lower urinary track symptoms due to BPH.

A Novel Intra-aortic Device Designed for Coronary Blood Flow Amplification in Unrevascularizable Patients.

Patients with unrevascularizable coronary artery disease represent a substantial number of all patients with coronary disease. However, their therapeutic options are limited; they endure recurrent hospitalizations, a poor quality of life and prognosis. We aim to investigate a novel alternative approach to the treatment of this common medical condition by using a specialized intra-aortic device with coiling properties capable of enhancing diastolic coronary flow. Both a mathematical analysis and in vitro study presented in the current study have yielded enhanced coronary diastolic blood flow and energetic advantages. We suggest that this original approach might be implicated in severely symptomatic unrevascularizable patients.

Electrophysiological modulation of cardiomyocytic tissue by transfected fibroblasts expressing potassium channels: a novel strategy to manipulate excitability.

BACKGROUND: Traditional pharmacological therapies aiming to modify the abnormal electrophysiological substrate underlying cardiac arrhythmias may be limited by their relatively low efficacy, global cardiac activity, and significant proarrhythmic effects. We suggest a new approach, in which transfected cellular grafts expressing various ionic channels may be used to manipulate the local electrophysiological properties of cardiac tissue. To examine the feasibility of this concept, we tested the hypothesis that transfected fibroblasts expressing the voltage-sensitive potassium channel Kv1.3 can modify the electrophysiological properties of cardiomyocytic cultures. METHODS AND RESULTS: A high-resolution multielectrode mapping technique was used to assess the electrophysiological and structural properties of primary cultures of neonatal rat ventricular myocytes. The transfected fibroblasts, added to the cardiomyocytic cultures, caused a significant effect on the conduction properties of the hybrid cultures. These changes were manifested by significant reduction in extracellular signal amplitude and by the appearance of multiple local conduction blocks. The location of all conduction blocks correlated with the spatial distribution of the transfected fibroblasts assessed by vital staining. All electrophysiological changes were reversed after the application of Charybdotoxin, a specific Kv1.3 blocker. In contrast, conduction remained uniform in the control hybrid cultures when nontransfected fibroblasts were used. CONCLUSIONS: Transfected fibroblasts are able to electrically couple with cardiac myocytes, causing a significant local and reversible modification of the tissue's electrophysiological properties. More broadly, this study suggests that transfected cellular grafts expressing various ionic channels may be used to modify cardiac excitability, providing a possible future novel cell therapy strategy.

Effects of fibroblast transplantation into the internal pallidum on levodopa-induced dyskinesias in parkinsonian non-human primates.

Recent studies have shown that fibroblast transplantation can modify the activity of basal ganglia networks in models of Parkinson's disease. To determine its effects on parkinsonian motor symptoms, we performed autologous dermal fibroblast transplantation into the internal pallidum (GPi) in two parkinsonian rhesus monkeys with stable levodopa-induced dyskinesias (LIDs). Levodopa responses were assessed every week after transplantation for three months. A reduction of between 58% and 64% in total LIDs on the contralateral side was observed in both animals. No clear LID changes were observed on the ipsilateral side. These effects lasted the entire 3-month period in one monkey, but declined after 6-8 weeks in the other. The antiparkinsonian effects of levodopa did not diminish. The results of this pilot study indicate that fibroblast transplantation into the GPi may have beneficial effects on LIDs and warrant further investigation for potential therapeutic use.

Energy transfer from systole to diastole: a novel device-based approach for the treatment of diastolic heart failure.

UNLABELLED: We hypothesized that attachment of elastic coil to the left ventricular (LV) wall, capable of exerting outward forces may allow the transfer of energy from systole to diastole and improve diastolic function. METHODS AND RESULTS: An extra-ventricular-device, composed of a series of elastic elements interposed between spiral screws attached to the epimyocardium of the LV free-wall was developed. The hemodynamic and mechanical effects of the device were tested using a computerized model, an in vitro model utilizing a computerized-controlled fluid pump, eight healthy sheep and 10 mini-pigs induced with diastolic dysfunction by renal wrapping. The computerized and in vitro models predicted a reduction of the LV diastolic pressure curve and partial normalization of the pressure-volume loop. The sheep study demonstrated preservation of animal's wellbeing including maintaining cardiac mechanical function with stable energy transfer from systole to diastole throughout the 6 months follow-up. The mini-pigs study showed an increase in the early diastolic to systolic strain-rate ratio in the mid-endocardial level (23 ± 10%, P = 0.008) and an increase in early apical reverse rotation rate of 50% (P = 0.016 compared to control). CONCLUSIONS: This study presents a novel concept of using a mechanical device to transfer energy from systole to diastole, potentially enhancing diastolic function.

Modulation of excessive neuronal activity by fibroblasts: potential use in treatment of Parkinson's disease.

PURPOSE: A number of neurological disorders are marked by increased or aberrant frequency of neuronal discharge in specific parts of the brain. Administration of drugs such as antiepileptic compounds results in the depression of neuronal activity in the whole brain, with the potential for serious side-effects. In the search for additional therapies to reduce the unphysiological electrical activity of over-active brain foci, we have examined the effect of fibroblasts transplanted to areas responsible for motor dysfunction in hemi-parkinsonian rats, since bursting synchronous discharges in internal segment of globus pallidus (GPi) are thought to be partially responsible for the movement disorders of PD. Fibroblasts express gap junctions and ion channels, and so, when transplanted to brain tissue, can potentially modulate excessive electrical activity. METHODS: Neonatal cortical neurons were cultured on multi-electrode arrays, and their electrical activity was evaluated before and after fibroblast seeding. Unilateral 6-hydroxydopamine (6-OHDA) lesion was carried out in Fischer rats. Lesioned or control rats were transplanted with either syngeneic dermal fibroblasts, microfine glass beads, ibotenic acid, or physiological saline, in the entopeduncular nucleus (EP). Apomorphine-induced rotational behavior and L-dopa-induced dyskinetic movements were evaluated before transplantation (baseline) and 2, 4, 8, 12, and 24 weeks following transplantation. Following behavioral experiments, rats were perfused with 4% formaldehyde in PBS for immunohistochemical study of the brain. RESULTS: We demonstrate in vitro that the introduction of fibroblasts into a network of neurons does not interfere with overall functional measures of activity, while moderately altering the characteristics of synchronous neuronal discharge. In rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal dopaminergic pathway, apomorphine-induced rotations were reduced by more than 60% following ipsilateral transplantation of fibroblasts to the EP. L-Dopa-induced dyskinesia was also significantly reduced. Transplantation of inert microspheres, or chemical lesion of the same area with ibotenic acid, did not produce beneficial effects on parkinsonian symptomatology. CONCLUSION: Fibroblast transplantation could be an alternative treatment strategy for the parkinsonian patient.