Biosensors with left ventricular assist devices.

Heart failure imposes a significant global health burden, standing as a primary contributor to mortality. Various indicators and physiological shifts within the body may hint at distinct cardiac conditions. Specific biosensors have the capability to identify these changes. Integrating or embedding these biosensors into mechanical circulatory support devices (MCSDs), such as left ventricular assist devices (LVADs), becomes crucial for monitoring alterations in biochemical and physiological factors subsequent to an MCSD implantation. Detecting abnormal changes early in the course of disease progression will allow for improved patient outcomes and prognosis following an MCSD implantation. The aim of this review is to explore the available biosensors that may be coupled or implanted alongside LVADs to monitor biomarkers and changes in physiological parameters. Different fabrication materials for the biosensors are discussed, including their advantages and disadvantages. This review also examines the feasibility of integrating feedback control mechanisms into LVAD systems using data from the biosensors. Challenges facing this emerging technology and future directions for research and development are outlined as well. The overarching goal is to provide an overview of how implanted biosensors may improve the performance and outcomes of LVADs through continuous monitoring and closed-loop control.

Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF).

Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF.

A European update on transcatheter aortic valve implantation (TAVI) in the COVID era.

Minimally invasive approaches for aortic valve replacement are now at the forefront of pathological aortic valve treatment. New trials show comparability of these devices to existing therapies, not only in high-risk surgical cohorts but also in low-risk and intermediate-risk cohorts. This review provides vital clinical and anatomical background to aortic valvular disease treatment guidelines, while also providing an update on transcatheter aortic valve implantation (TAVI) devices in Europe, their interventional trials and associated complications.

Advancements in left ventricular assist devices to prevent pump thrombosis and blood coagulopathy.

Mechanical circulatory support (MCS) devices, such as left ventricular assist devices (LVADs) are very useful in improving outcomes in patients with advanced-stage heart failure. Despite recent advances in LVAD development, pump thrombosis is one of the most severe adverse events caused by LVADs. The contact of blood with artificial materials of LVAD pumps and cannulas triggers the coagulation cascade. Heat spots, for example, produced by mechanical bearings are often subjected to thrombus build-up when low-flow situations impair washout and thus the necessary cooling does not happen. The formation of thrombus in an LVAD may compromise its function, causing a drop in flow and pumping power leading to failure of the LVAD, if left unattended. If a clot becomes dislodged and circulates in the bloodstream, it may disturb the flow or occlude the blood vessels in vital organs and cause internal damage that could be fatal, for example, ischemic stroke. That is why patients with LVADs are on anti-coagulant medication. However, the anti-coagulants can cause a set of issues for the patient-an example of gastrointestinal (GI) bleeding is given in illustration. On account of this, these devices are only used as a last resort in clinical practice. It is, therefore, necessary to develop devices with better mechanics of blood flow, performance and hemocompatibility. This paper discusses the development of LVADs through landmark clinical trials in detail and describes the evolution of device design to reduce the risk of pump thrombosis and achieve better hemocompatibility. Whilst driveline infection, right heart failure and arrhythmias have been recognised as LVAD-related complications, this paper focuses on complications related to pump thrombosis, especially blood coagulopathy in detail and potential strategies to mitigate this complication. Furthermore, it also discusses the LVAD implantation techniques and their anatomical challenges.

Anti-malarial, cytotoxicity and molecular docking studies of quinolinyl chalcones as potential anti-malarial agent.

The quinolinyl chalcones series (A1-A14) were screened for antimalarial activity. According to in vitro antimalarial studies, many quinolinyl chalcones are potentially active against CQ-sensitive and resistance P. falciparum strains with no toxicity against Vero cell lines. The most active quinolinyl chalcones A4 (with IC50 0.031 µM) made a stable A4-heme complex with - 25 kcal/mole binding energy and also showed strong π-π interaction at 3.5 Å. Thus, the stable A4-heme complex formation suggested that these quinolinyl chalcones act as a blocker for heme polymerization. The docking results of quinolinyl chalcones with Pf-DHFR showed that the halogenated benzene part of quinolinyl chalcones made strong interaction with Pf-DHFR as compared to quinoline part. A strong A4-Pf-DHFR complex was formed with low binding energy (- 11.04 kcal/mole). The ADMET properties of quinolinyl chalcones were also studied. The in vivo antimalarial studies also confirmed the A4 as an active antimalarial agent.

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles - development, characterisation, and in vitro assessment of bioactivity for cardiac applications.

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP). Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method. Results: Spherical MPs showed an average particle size of 2 µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15 days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit+ cells. Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.

Outcomes of splenectomy for idiopathic thrombocytopenic purpura in adults: a developing country perspective.

OBJECTIVE: To determine the outcome of splenectomy done in adult patients of Idiopathic Thrombocytopenic Purpura over a period of 10 years and, secondarily, to determine the predictors of complete response to therapy. METHODS: The retrospective review comprised of adult patients over 14 years of age who underwent open or laparoscopic splenectomy for Idiopathic Thrombocytopenic Purpura at Aga Khan University Hospital, Karachi, from January 2000 to December 2010. Data was reviewed in January 2011 by a surgical resident. Outcome was the response to splenectomy as per new definition of response set by the American Society of Haematology 2011 evidence based practice guidelines for Idiopathic Thrombocytopenic Purpura. Assessment of response was done within 1 to 2 months of splenectomy and after withholding concomitant treatment. SPSS 17 was used for statistical analysis. RESULTS: A total of 27 patients were found eligible. Of them, 2 (7.4%) were males and 25 (92.6%) were females with an overall mean age at the time of splenectomy of 30.8±6.3 years (range: 15-55 years). Out of 27 cases, 23 (85.18%) patients underwent open splenectomy, 3 (11%) laparoscopic and 1 (3.7%) had laparoscopic converted to open splenectomy. Complete response was achieved in 20 (74.1%) patients, whereas 5 (18.5%) had response and 2 (7.4%) had no response. None of the predictors of response to splenectomy were found significant. CONCLUSION: Response to splenectomy in adult Idiopathic Thrombocytopenic Purpura patients was comparable to reported rate in literature with relatively lower morbidity and mortality. Splenectomy is a safe treatment option especially in patients who succumb to adverse effects of medical therapy.

Outcomes of Xanthogranulomatous cholecystitis in laparoscopic era: A retrospective Cohort study.

INTRODUCTION: Xanthogranulomatous cholecystitis (XGC) is a rare variant of cholecystitis and reported incidence of XGC varies from different geographic region from 0.7% -9%. Most of the clinicians are not aware of the pathology and less evidence is available regarding the optimal treatment of this less common form of cholecystitis in the present era of laparoscopic surgery. MATERIALS AND METHODS: A retrospective cohort study was conducted in a tertiary care university hospital from 1989 to 2009. Histopathologically confirmed XGC study patients (N=27) were compared with non-Xanthogranulomatous cholecystitis (NXGC) control group (N=27). The outcomes variables were operative time, complication rate and laparoscopic to open cholecystectomy conversion rate. The study group (XGC) was further divided in to three sub groups; group I open cholecystectomy (OC), laparoscopic cholecystectomy (LC) and laparoscopic converted to open cholecystectomy (LCO) for comparative analysis to identify the significant variables. RESULTS: During the study period 6878 underwent cholecystectomy including open cholecystectomy in 2309 and laparoscopic cholecystectomy in 4569 patients. Histopathology confirmed xanthogranulomatous cholecystitis in 30 patients (0.43% of all cholecystectomies) and 27 patients qualified for the inclusion criterion. Gallbladder carcinoma was reported in 100 patients (1.45%) during the study period and no association was found with XGC. The mean age of patients with XGC was 49.8 year (range: 29-79), with male to female ratio of 1:3. The most common clinical features were abdominal pain and tenderness in right hypochondrium. Biliary colic and acute cholecystitis were the most common preoperative diagnosis. Ultrasonogram was performed in all patients and CT scan abdomen in 5 patients. In study population (XGC), 10 were patients in group I, 8 in group II and 9 in group III. Conversion rate from laparoscopy to open was 53 % (n=9), surgical site infection rate of 14.8% (n=4) and common bile duct injury occurred one patient in open cholecystectomy group (3.7%). Statistically significant differences between group I and group II were raised total leukocyte count: 10.6±3.05 vs. 7.05±1.8 (P-Value 0.02) and duration of surgery in minutes: 248.75±165 vs. 109±39.7 (P-Value 0.04). The differences between group III and group II were duration of surgery in minutes: 208.75±58 vs. 109±39.7 (P-Value 0.03) and duration of symptoms in days: 3±1.8 vs. 9.8±8.8 (P-Value 0.04). The mean hospital stay in group I was 9.7 days, group II 5.6 days and in group III 10.5 days. Two patients underwent extended cholecystectomy based on clinical suspicion of carcinoma. No mortality was observed in this study population. Duration of surgery was higher in XGC group as compared to controls (NXGC) (203±129 vs.128±4, p-value=0.008) and no statistically significant difference in incidence proportion of operative complication rate were observed among the group (25.9% vs. 14.8%, p-value=0.25. Laparoscopic surgery was introduced in 1994 and 17 patients underwent laparoscopic cholecystectomy and higher conversion rate from laparoscopic to open cholecystectomy was observed in 17 study group (XGC) as compared to 27 Control group (NXGC) 53%vs.3.3% with P-value of < 0.023. CONCLUSION: XGC is a rare entity of cholecystitis and preoperative diagnosis is a challenging task. Difficult dissection was encountered in open as well in laparoscopic cholecystectomy with increased operation time. Laparoscopic cholecystectomy was carried out with high conversion rate to improve the safety of procedure. Per operative clinical suspicion of malignancy was high but no association of XGC was found with gallbladder carcinoma, therefore frozen section is recommended before embarking on radical surgery.

Laparoscopic splenectomy for haematological disorder: our experience.

Laparoscopic splenectomy has universal acceptance due to less morbidity and decreased incidence of peroperative and postoperative complication. It is not a popular procedure in Pakistan due to technical challenges. Here, we are presenting our experience of laparoscopic splenectomy for haematological disorders at Aga Khan University Hospital. A total of seven cases, underwent elective laparoscopic splenectomy for haematological disorders. The operative time was less than 3 hours with minimal blood loss with rapid and uneventful recovery. There was no procedure related morbidity or mortality; however, one patient expired due to overwhelming post splenectomy sepsis. Our initial report highlights the safety of laparoscopic splenectomy and we propose it to be the procedure of choice in elective splenectomy.

Diuretic therapy in congestive heart failure.

In heart failure, fluid overload is a major pathological mechanism leading to vascular congestion, pulmonary congestion and elevated jugular venous pressures. Diuretics play a significant role in the management of patients with congestive heart failure. It is used to relieve the congestive symptoms of heart failure. However, the appropriate use of diuretics remains challenging due to various complications like electrolyte abnormalities, worsening renal function and diuretic resistance. This has prompted towards the search of safer and effective alternatives. This review evaluates the use of diuretics in congestive heart failure and discusses the complications of different types of diuretics, which is essential for successful management of congestion in patients with heart failure and hence to optimise the outcome for the patients.

In vitro benchtop mock circulatory loop for heart failure with preserved ejection fraction emulation.

In this work, a novel mock circulatory loop (MCL) is presented that is capable of simulating both healthy cardiac function and Heart Failure with preserved Ejection Fraction (HFpEF). This MCL differs from others presented in the literature as it features two independently actuated heart chambers, representing the left atrium and the left ventricle. This is an important improvement over other designs as it allows for potential HFpEF treatments to be examined, not just in relation to their effect on the left ventricle but also on the left atrium. The aim of this work was to show that novel MCL designs could be developed to allow for testing of new mechanical circulatory support devices for the treatment of HFpEF. Two loop configurations are presented, one featuring hard PVC cylindrical chambers and one that features soft silicone chambers which are anatomically analogous to the native heart. We show that both MCLs are capable of simulating the onset of HFpEF with a sustained increase in diastolic pressure of 62.03% and a sustained decrease in end diastolic volume (EDV) of 14.24%.

Terrorist bombings: medical response in a developing country.

OBJECTIVE: To evaluate the process of transport and immediate Emergency Department (ER) management of mass casualties following the recent bomb blasts in Karachi and review in detail the medical response and management of victims undertaken in these two incidents. METHODS: Eyewitness accounts of the victims, medical personnel and newspaper clippings were used to understand and identify difficulties faced during the rescue process. Data regarding presenting injuries and their outcomes was also collected from all victims presenting to the emergency department at Aga Khan University Hospital. RESULTS: Seventy nine individuals died and over 250 victims were injured in the two incidents. All victims and dead bodies were shifted to the nearest public sector hospital overwhelming the health care facility. Subsequently all victims were evacuated to private sector hospitals creating similar difficulties. Over half of the victims presenting at the emergency department had minor injuries and did not require admission. Most patients requiring admission needed orthopaedic intervention. CONCLUSION: A comprehensive disaster plan with a centralized command and control system is required for the city of Karachi, involving all stake holders including charity ambulance services, security agencies, and trauma management facilities. Training courses and exercises for health care personnel should also be made mandatory to achieve professional excellence.

Interesting presentation of a broad complex tachycardia during the head up tilt table test.

Broad complex tachycardia (BCT) during head up tilt test (HUTT) is infrequent. Electrophysiology Study (EPS) plays an important part in further differentiation of BCT. We present a case of BCT during HUTT in a patient presenting with presyncope which later on EPS with 3D mapping was diagnosed as ventricular tachycardia. This case highlights the unusual occurrence of BCT during HUTT, the differential diagnosis of BCT and the utility of EPS to reliably identify the type and origin of BCT.

Resveratrol significantly improves cell survival in comparison to dexrazoxane and carvedilol in a h9c2 model of doxorubicin induced cardiotoxicity.

Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they can often result in side effects with cardiovascular complications being the most severe. Dexrazoxane is the only currently approved treatment for prevention of anthracycline induced cardiotoxicity but there are concerns about its use due to the development of secondary malignancies and myelodysplastic syndrome. Additionally, it is only recommended in patients who are due to receive a total cumulative dose of 300 mg/m2 of doxorubicin or 540 mg/m2 of epirubicin. Thus, there exists an urgent need to develop new therapeutic strategies to counteract anthracycline induced cardiotoxicity. The h9c2 cardiomyoblast was investigated for its differentiation capacity and used to screen and compare promising prophylactics for doxorubicin induced cardiotoxicity. The half maximal inhibitory concentration of doxorubicin was determined in differentiated h9c2 cells after 24 h of exposure, to establish a model for drug screening. Cells were treated with dexrazoxane, resveratrol, and carvedilol either 3 h or 24 h prior to doxorubicin treatment. The ability of these cardioprotectants to prevent cardiotoxicity was analysed using the cck-8 cell viability assay and the dichlorofluorescin diacetate (DCFDA) reactive oxygen species (ROS) assay. There was no significant increase in survival in treatment groups after 3 h, however, at 24 h, resveratrol significantly improved survival compared to all other groups (p < 0.05). Additionally, dexrazoxane and resveratrol significantly decreased ROS formation at 3 h (p < 0.05) and all groups significantly decreased ROS production at 24 h (p < 0.001). This work is the first comparison of these cardioprotectants and suggests that resveratrol may be a more effective treatment in the prevention of anthracycline induced cardiotoxicity, compared to dexrazoxane and carvedilol. However, further work will be needed in order to decipher the exact mechanism and potential of this drug in the clinic.

A multidirectional two-tube method for chemical pleurodesis could improve distribution of the sclerosing agent within the pleural cavity - A pilot study.

INTRODUCTION: Malignant pleural effusion (MPE) affects approximately 200,000 people in the United States per annum. Chemical pleurodesis is a recommended first line treatment in the management of MPE, however, success rates as low as 43% has been reported. A bedside chemical pleurodesis can cost up to $11,224 and an estimated inpatient annual expenditure of more than $5 billion in the US alone. This study aims to assess the distribution of the talc slurry within the pleural space using human cadaveric models and to determine the force required to push the talc slurry though a 14 Fr chest tube. MATERIALS AND METHODS: The force required to administer the talc slurry through a 14 Fr chest tube was tested using a Zwick/Roelle Z005 mechanical tester, using a porcine thoracic biomodel. Talc slurry distribution within the pleural cavity was assessed by direct visualisation following administration to the human cadaveric models using single and multidirectional two-tube methods. RESULTS: Maximum force required to push the talc slurry through a 14 Fr chest tube was 11.36 N ± 2.79 N. Distribution of the talc slurry within the pleural cavity was found to be poor with a single tube method. Multidirectional two-tube method of administration showed more even distribution. CONCLUSION: The experimental multidirectional two-tube method results in wider distribution of the talc slurry within the pleural cavity and could further improve success rate of the talc pleurodesis.

Towards the use of localised delivery strategies to counteract cancer therapy-induced cardiotoxicities.

Cancer therapies have significantly improved cancer survival; however, these therapies can often result in undesired side effects to off target organs. Cardiac disease ranging from mild hypertension to heart failure can occur as a result of cancer therapies. This can warrant the discontinuation of cancer treatment in patients which can be detrimental, especially when the treatment is effective. There is an urgent need to mitigate cardiac disease that occurs as a result of cancer therapy. Delivery strategies such as the use of nanoparticles, hydrogels, and medical devices can be used to localise the treatment to the tumour and prevent off target side effects. This review summarises the advancements in localised delivery of anti-cancer therapies to tumours. It also examines the localised delivery of cardioprotectants to the heart for patients with systemic disease such as leukaemia where localised tumour delivery might not be an option.

The role of anti-inflammatory drugs and nanoparticle-based drug delivery models in the management of ischemia-induced heart failure.

Ongoing advancements in the treatment of acute myocardial infarction (MI) have significantly decreased MI related mortality. Consequently, the number of patients experiencing post-MI heart failure (HF) has continued to rise. Infarction size and the extent of left ventricular (LV) remodeling are largely determined by the extent of ischemia at the time of myocardial injury. In the setting of MI or acute phase of post-MI LV remodeling, anti-inflammatory drugs including intravenous immunoglobulin (IVIG) and Pentoxifylline have shown potential efficacy in preventing post-MI remodeling in-vitro and in some clinical trials. However, systemic administration of anti-inflammatory drugs are not without their off-target side effects. Herein, we explore the clinical feasibility of targeted myocardial delivery of anti-inflammatory drugs via biodegradable polymers, liposomes, hydrogels, and nano-particle based drug delivery models (NDDM) based on existing pre-clinical and clinical models. We summarize the barriers to clinical application of targeted anti-inflammatory delivery post-MI, including challenges in achieving sufficient retention and distribution, as well as the potential need for multiple dosing. Collectively, we suggest that localized delivery of anti-inflammatory agents to the myocardium using NDDM is a promising approach for successful treatment of ischemic HF. Future studies will be instrumental in determining the most effective target and delivery modalities for orchestrating NDDM-mediated treatment of HF.

Device-Based Solutions to Improve Cardiac Physiology and Hemodynamics in Heart Failure With Preserved Ejection Fraction.

Characterized by a rapidly increasing prevalence, elevated mortality and rehospitalization rates, and inadequacy of pharmaceutical therapies, heart failure with preserved ejection fraction (HFpEF) has motivated the widespread development of device-based solutions. HFpEF is a multifactorial disease of various etiologies and phenotypes, distinguished by diminished ventricular compliance, diastolic dysfunction, and symptoms of heart failure despite a normal ejection performance; these symptoms include pulmonary hypertension, limited cardiac reserve, autonomic imbalance, and exercise intolerance. Several types of atrial shunts, left ventricular expanders, stimulation-based therapies, and mechanical circulatory support devices are currently under development aiming to target one or more of these symptoms by addressing the associated mechanical or hemodynamic hallmarks. Although the majority of these solutions have shown promising results in clinical or preclinical studies, no device-based therapy has yet been approved for the treatment of patients with HFpEF. The purpose of this review is to discuss the rationale behind each of these devices and the findings from the initial testing phases, as well as the limitations and challenges associated with their clinical translation.