Cell therapy in patients with heart failure: a comprehensive review and emerging concepts.

This review summarizes the results of clinical trials of cell therapy in patients with heart failure (HF). In contrast to acute myocardial infarction (where results have been consistently negative for more than a decade), in the setting of HF the results of Phase I-II trials are encouraging, both in ischaemic and non-ischaemic cardiomyopathy. Several well-designed Phase II studies have met their primary endpoint and demonstrated an efficacy signal, which is remarkable considering that only one dose of cells was used. That an efficacy signal was seen 6-12 months after a single treatment provides a rationale for larger, rigorous trials. Importantly, no safety concerns have emerged. Amongst the various cell types tested, mesenchymal stromal cells derived from bone marrow (BM), umbilical cord, or adipose tissue show the greatest promise. In contrast, embryonic stem cells are not likely to become a clinical therapy. Unfractionated BM cells and cardiosphere-derived cells have been abandoned. The cell products used for HF will most likely be allogeneic. New approaches, such as repeated cell treatment and intravenous delivery, may revolutionize the field. As is the case for most new therapies, the development of cell therapies for HF has been slow, plagued by multifarious problems, and punctuated by many setbacks; at present, the utility of cell therapy in HF remains to be determined. What the field needs is rigorous, well-designed Phase III trials. The most important things to move forward are to keep an open mind, avoid preconceived notions, and let ourselves be guided by the evidence.

Comparison of One and Three Intraventricular Injections of Cardiac Progenitor Cells in a Murine Model of Chronic Ischemic Cardiomyopathy.

Repeated doses of c-kit+ cardiac progenitor cells (CPCs) are superior to a single dose in improving LV function in rats with old myocardial infarction (MI). However, this concept needs testing in different species to determine whether it is generalizable. We used a new murine model of chronic ischemic cardiomyopathy whose unique feature is that cell therapy was started late (3 months) after MI. Mice received three echo-guided intraventricular infusions, 5 weeks apart, of vehicle, CPCs × 1, or CPCs × 3. Echocardiography demonstrated that the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (CPCs), but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group LVEF continued to improve, so that the final value was greater than in vehicle or single-dose groups (P < 0.05). Hemodynamic studies showed that compared with vehicle, both preload-dependent and preload-independent functional parameters were significantly increased in the multiple-dose group but not in the single-dose group. Thus, two independent methods of functional assessment (echocardiography and hemodynamic studies) consistently demonstrated the superiority of three doses of CPCs vs. one dose. Compared with the single-dose group, the multiple-dose group exhibited less LV hypertrophy, as evidenced by a greater reduction in LV/body weight ratio and cardiomyocyte cross-sectional area. Furthermore, unlike the single dose, three CPC doses reduced myocardial inflammatory cells in the risk region. This is the first study of echo-guided intraventricular infusion of CPCs in mice with chronic ischemic cardiomyopathy. The results demonstrate that the beneficial effects of three CPC doses are greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate cell therapy. Our findings indicate that this concept applies not only to rat models but also to murine models. The generalizability of this strategy greatly enhances its importance and provides a rationale for large animal studies. Graphical abstract.

Cell therapy for heart disease: current status and future directions.

Treatment of ischemic heart disease has evolved considerably over time, seeing a technological impetus in recent times. Prompt diagnosis and progressively earlier reperfusion of the infarct artery have become the cornerstone of the early myocardial ischemia management. However, treatment of post-infarction sequelae resulting from ischemic damage sustained within the myocardium remains a considerable challenge. In this setting, stem cell therapy has emerged as an exciting regenerative modality with a promise to arrest or even reverse the pathological myocardial remodeling. Multiple preclinical and clinical studies have thereafter reported use of various types of stem cells delivered through varying routes. While most of these studies reported positive results, some appropriate concerns were raised in others. This has resulted in considerable uncertainty regarding cell therapy and an inability to formulate therapeutic recommendations. Though there has been a considerable improvement in our understanding of stem cell properties, there is a need to identify specific mechanisms of actions in order to maximize the benefits of stem cell therapy in ischemic heart disease. With this review, we attempt to highlight some of the salient features of stem cell research, focusing on understanding the predominant types of stem cells, proposed mechanisms of action, routes of administration, and application of this exciting and innovative regenerative therapy offered by stem cells.

Lactate levels with glioblastoma multiforme.

A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation.

A rare case of bilateral lower extremity edema due to low dose gabapentin therapy in a young male patient.

46 year old male with past medical history of schizoaffective disorder and chronic lower back pain, was admitted for management of worsening depression and anxiety. He was started on gabapentin, 300mg twice daily for his back pain and anxiety symptoms. His only other medication was hydrocodone. Over next few days, he started developing worsening bilateral lower extremity edema. He did not have any cardiovascular related symptoms. Physical exam was only significant for 3+ pitting edema with all laboratory values and imaging being unremarkable. Gabapentin was discontinued and his lower extremity swelling improved over subsequent days. Incidence of pedal edema with gabapentin use is approximately 7 to 7.5% with all studies being in elderly patients receiving doses above 1200 mg/day. This case illustrates that lower doses of gabapentin can also cause this adverse effect. It is important to recognize this adverse effect because gabapentin is used in conditions like diabetic neuropathy, which is associated with multiple co-morbidities that can give rise to bilateral leg swelling. Presence of gabapentin induced leg swelling can thus confound the clinical picture.

Patterns of glycemic control using glycosylated hemoglobin in diabetics.

AIM: Till now estimation of blood glucose is the highly effective method for diagnosing diabetes mellitus but it provides a short-term picture of control. More evidence is required to prove that plasma glucose and glycosylated hemoglobin levels together gives a better estimate of glycemic control and compliance with treatment. Indian diabetes risk score (IDRS) is a simplified screening tool for identifying undiagnosed diabetic subjects, requires minimum time, and effort and can help to considerably reduce the costs of screening. OBJECTIVE: To study patterns of glycemic control using glycosylated hemoglobin in diabetic patients. To find out correlation between levels of plasma glucose and glycosylated hemoglobin in diabetics and to calculate IDRS of the study population. MATERIALS AND METHODS: A cross sectional study was conducted among 300 known diabetic patients attending outpatient department of a rural medical college in Haryana, India. Following standard procedures and protocols FPG and glycosylated hemoglobin were measured to find out a pattern of glycemic control in them after taking their written and informed consent. A correlation between the levels of glycosylated hemoglobin and fasting blood glucose was also calculated. These patients were made to fill a performa and their demographic and clinical risk factors were noted and based on this, their IDRS was calculated. This was done to validate the IDRS in Indian rural population. RESULTS: Fifty-two percent of the population had fasting plasma glucose level between 125-150 mg/dl, 21% had this level between 151-175 mg/dl. Thirteen percent of the study subjects had HbA1C between 6.5-7.5, more than half (57.3%) had this value between 7.5-8.5, 12% and 18% had values between 8.5-9.5 and 9.5-10.5, respectively. Twelve percent of the participants had HbA1C level higher than 10.5. Correlation of fasting plasma glucose level and HbA1C was also studied and found that correlation coefficient came out to be .311. This correlation was found to be statistically significant (P = .007). Sixty-five percent of the case had IDRS higher than 60. CONCLUSIONS: Glycaemic control in diabetics can be better assessed with glycosylated hemoglobin and FPG together. A positive correlation between FPG and HbA1c allows for the use of HbA1c along with FPG in diagnosing type 2 DM but the two should not be used interchangeably. IDRS can be used as a screening tool for diabetes.