Emerging advances in gene and cell therapy for heart failure: a systematic review

Under normal physiological conditions, the heart must be able to increase its output 5-fold to supply the required blood flow to the coronary circulation and skeletal muscles during severe stress. This is normally met by ≈5-fold increases in myocardial contractility, ≈3-fold increases in heart rate, and additional increases in stroke volume.1 This increased load requires a commensurate increase in myocardial blood flow, because oxygen extraction across the heart is nearly complete, even under normal conditions. Accordingly, the design of the cardiovascular system evolved to conserve myocardial metabolic demand, and consequently coronary blood flow, at rest, but with considerable reserve that can be called on rapidly in times of stress. There is a host of compensatory adjustments, including changes in metabolic substrates and kinetics, as well as oxygen-carrying capacity, that may be recruited in response to stress. However, none is more important than the autonomic nervous system in general, and the sympathetic arm in particular, in terms of providing large, rapid changes in cardiac function. When this compensatory mechanism is unavailable, eg, after treatment with propranolol, the 3-fold increases in heart rate and 5-fold increases in myocardial contractility in response to exercise cannot be achieved.1 In this connection, it is recognized that heart failure is a state characterized by enhanced sympathetic tone, but when the failing myocardium is challenged by β-adrenergic stimulation in vivo or in vitro, the most frequent result is β-adrenergic downregulation or desensitization.2 3 4 5 An impairment of cardiac function leads to autocrine, paracrine, and neurohormonal adjustments, including a strong sympathetic component (Figure 1⇓); under acute conditions, these reflex adjustments are beneficial, as noted above. However, when the sympathetic nervous system is chronically and tonically stimulated, as occurs in the pathogenesis of heart failure, desensitization mechanisms are called into play, such that the …

Stem Cell Engraftment and Survival in the Ischemic Heart

The goal of "Recent Developments" is to provide a concise but comprehensive overview of new advances in cardiovascular research, which we hope will keep our readers abreast of recent scientific discoveries and facilitate discussion, interpretation, and integration of the findings.This will enable readers who are not experts in a particular field to grasp the significance and effect of work performed in other fields.It is our hope and expectation that these "Recent Development" articles will help readers to gain a broader awareness and a deeper understanding of the status of research across the vast landscape of cardiovascular research-The Editors.

Recognizing the challenges faced by researchers and clinicians working in the field of cellular therapy, the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, established the Production Assistance for Cellular Therapies (PACT) program in 2003 and expanded it in 2010. The PACT program provides both clinical product manufacturing support that furthers the mission of NHLBI in the areas of cardiac, lung, and blood diseases and broad support of translational development across all disease areas to serve the entire cell therapy community. The program also provides access to expertise in project management, regulatory affairs, and quality assurance and control. Education initiatives include webinars, cell processing facility-hosted workshops, national workshops, and active participation and leadership within the cell therapy community through collaboration with other cell therapy organizations and academia. So far, over 650 PACT-manufactured cell therapy products have been administered in 32 clinical trials for a range of illnesses and diseases such as acute myocardial infarction, sickle cell disease, and graft-versus-host disease.

Heart failure is a common condition responsible for at least 290 000 deaths each year in the United States alone.1 A small minority of heart failure cases are attributed to Mendelian or familial cardiomyopathies. The majority of systolic heart failure cases are not familial but represent the end result of 1 or many conditions that primarily injure the myocardium sufficiently to diminish cardiac output in the absence of compensatory mechanisms. Paradoxically, because they also injure the myocardium, it is the chronic actions of the compensatory mechanisms that in many instances contribute to the progression from simple cardiac injury to dilated cardiomyopathy and overt heart failure. Thus, the epidemiology of common heart failure appears to be just as sporadic as its major antecedent conditions (atherosclerosis, diabetes, hypertension, and viral myocarditis). Familial trends in preclinical cardiac remodeling2 and risk of developing heart failure3 reveal an important role for genetic modifiers in addition to clinical and environmental factors. Candidate gene studies performed over the past 10 years have identified a few polymorphic gene variants that modify risk or progression of common heart failure.4 Whole-genome sequencing will lead to the discovery of other genetic modifiers that were not candidates.5 The imminent availability of individual whole-genome sequences at a cost competitive with available genetic tests for familial cardiomyopathy will no doubt further expand the list of putative genetic heart failure modifiers. Heart failure risk alleles along with traditional clinical factors will need to be considered by clinical cardiologists in their design of optimal disease surveillance and prevention programs and in individually tailoring heart failure management. The use of individual genetic make-up is likely to have the earliest and greatest impact on managing patients with heart failure by tailoring available pharmacotherapeutics to optimize patient response and minimize adverse effects (ie, the …

Cardiac stem cell therapy: Does a newborn infant's heart have infinite potential for stem cell therapy?

In the year 1990, cardiovascular disease surpassed infectious diseases as the leading cause of death worldwide, and by the year 2020 it is predicted to be the leading cause of all disability.1,2 In the United States, cardiovascular disease has been estimated to account for 44% of the nation’s mortality and is a leading cause of morbidity.3,4 Heart failure afflicts an estimated 5 million Americans, with ≈400 000 new individuals diagnosed each year at an annual cost of more than $20 billion.4–6 The alarming reality behind these statistics is our current lack of an effective therapy to repair or otherwise reverse severe forms of cardiac dysfunction and pathological remodeling associated with heart failure. Typically, heart failure is the final culmination of protracted disease states precipitated by underlying hypertension, ischemic disease and atherosclerosis, valvular insufficiency, viral myocarditis, or mutations in genes encoding sarcomeric proteins.6 Given these diverse etiologies, it is not surprising that the final phenotypic manifestations of heart failure can also vary considerably, although dilated cardiomyopathy is the most common. This syndrome is characterized by a progressive loss in contractility and ejection fraction, ventricular chamber dilatation, ventricular wall thinning, increased peripheral vascular resistance, and dysregulated fluid homeostasis. The predominant therapeutic strategy used over the past two decades for treating such patients has been based in pharmacological manipulation of cardiac contractility.7–9 Initially, positive inotropic agents were used as a means of enhancing cardiac pump function aimed at alleviating congestive symptomology. However, use of positive inotropes is now indicated only as a means of acutely bridging patients in severe heart failure because these agents actually worsen prognosis in individuals with somewhat more stable heart failure.8 More recently, pharmacological blockade of β-adrenergic receptors has emerged as the favored treatment for individuals in heart failure. β-Adrenergic receptor antagonists initially …

Received July 2, 2009; accepted October 5, 2009. Heart failure (HF) is a major health problem in Western countries. Despite significant progress in pharmacological and device-based treatment, the disease burden imposed continues to increase, particularly as the population ages. HF incidence approaches 10 per 1000 after age 65 years.1 Congestive HF is the final consequence of diverse cardiovascular disorders, including atherosclerosis, cardiomyopathy, and hypertension. Described as a complex pathophysiological syndrome that involves interactions of the circulatory, neurohormonal, and renal systems, HF is first a disease of the myocardium, although it soon induces defects in other systems. Current treatments for HF, focused on blocking neurohormonal pathways, improve survival, but they do not halt the progression of HF. Late-stage HF has a poor prognosis, and therapeutic options are limited. Faced with these challenges, researchers are exploring novel therapeutic options. Chronic HF is associated with increased sympathetic outflow, which may be compensatory early on, but long-term neurohormonal activation induces significant damage to the heart; in addition, it results in multiple alterations in the β-adrenergic receptor (β-AR) signaling cascade, including receptor downregulation, upregulation of receptor kinases, and increased inhibitory G-protein function.2 The amplitude and velocity of Ca2+ cycling are regulated by a dynamic balance of phosphorylation and dephosphorylation through kinases and phosphatases. Activation of β-ARs stimulates cAMP production and results in protein kinase A (PKA) phosphorylation of key regulators of excitation-contraction coupling, such as L-type Ca2+ channels, phospholamban, troponin I, ryanodine receptors (RyR), myosin-binding protein C, and protein phosphatase inhibitor-1 (I-1; Figure), which leads to increased amplitude and velocity of Ca2+ cycling and increased contractility on a beat-to-beat basis.3 Protein phosphatases PP1 and PP2A counterbalance phosphorylation of these proteins. There is clear evidence that alterations in sarcoplasmic reticulum (SR) Ca2+ cycling are a component of the impaired …

The heart works as a driving force to deliver oxygen and nutrients to the whole body. Interrupting this function for only several minutes can cause critical and permanent damage to the human body. Thus, heart failure (HF) or attenuated cardiac function is an important factor that affects both patient's the quality of life and longevity. Numerous clinical and basic studies have been performed to clarify the complex pathophysiology of HF and to develop effective therapies. Modulating the β-adrenergic receptor-mediated signaling pathway has been one of the most crucial targets for HF therapy. Impressively, recent reports identified p53, a well-known tumor suppressor, as a major player in the development of HF. The present review highlights the apoptosis of cardiomyocytes, which is one of the important mechanisms that leads to HF and can be induced by both β-adrenergic signaling and p53. Consideration of the cross-talk among these major pathways will be important when developing effective and safe therapies for HF.

D iabetes mellitus impairs physiological angiogenesis, which may be manifested as nonhealing foot ulcers or refractory angina.Multiple molecular mechanisms have been proposed.Hyperglycemia induces the generation of reactive oxygen species that cause endothelial derangements, 1 including the reduced synthesis 2 and accelerated degradation 3 of endothelium-derived nitric oxide (NO).The bioactivity of NO is critical for angiogenic processes such as the survival, proliferation, and migration of endothelial cells. 4The impairment in NO bioactivity may also explain in part the reduced expression of a major angiogenic cytokine, vascular endothelial growth factor (VEGF), in hyperglycemic states, because NO and VEGF have a reinforcing and reciprocal relationship. 5Glucose intolerance also reduces the number and function of bone marrow-derived endothelial progenitor cells, 6 circulating cells that participate in the angiogenic response.In addition to generating reactive oxygen species, hyperglycemia may impair cytoprotective mechanisms against oxidative stress.In particular, the thioredoxins play a key role in angiogenic processes by maintaining endothelial redox homeostasis, with favorable effects on protein folding, activity of reductive and metabolic enzymes, energy utilization, and transcription factor activity. 7Emerging evidence indicates that hyperglycemia upsets this cytoprotective mechanism by increasing the expression of the endogenous inhibitor thioredoxin-interacting protein (TXNIP). Article see p 282Is it possible that these and other disparate mechanisms for the impaired angiogenesis in diabetes mellitus have a common genomic basis?This question logically follows from the work of Caporali and colleagues in the current issue of Circulation. 8They have discovered a novel genomic mechanism for hyperglycemia-induced impairment of angiogenesis, ie, the increased expression of a specific microRNA (miRNA) that appears to orchestrate a pathophysiological response in diabetes mellitus.

People's ability to use their desired contraception is necessary for reproductive autonomy. We conducted longitudinal in-depth interviews over two years with 34 women in Iowa who sought contraceptive and related care at publicly supported sites in 2018/2019 to understand how state-level shifts in funding for these services affected their access to contraception. Twenty-seven of 34 respondents faced cost, access, and quality barriers relevant to policy and health care contexts, and we assessed the overall level of impact of these on access to preferred contraception over the study period. Cost barriers such as high fees for visits and methods as well as restrictive or inadequate insurance coverage, and access barriers such as long appointment wait times were most common; barriers compounded one another. Policies that support funding for contraceptive care, and that limit the need to interact with health systems for routine care, can decrease vulnerability to barriers and increase reproductive autonomy.

In chronic heart failure, a number of compensatory mechanisms are activated in order to maintain circulation and thus supply of the body with blood and oxygen. One important mechanism is the activation of the sympathetic nervous system, resulting in increased β-adrenergic signaling. This leads to both adaptive and pathological processes within the cell, including a desensitization of the β-adrenergic signal transduction cascade, the induction of hypertrophy, apoptosis and necrosis. It is currently a matter of debate whether a desensitization of the β-adrenergic signal transduction cascade is adaptive or maladaptive. In other words, it is not entirely clear whether in heart failure, decreased β-adrenergic signaling due to desensitization of the signaling cascade per se is a cause for cardiac dysfunction. In order to elucidate this issue, this review will focus on the consequences of increased β-adrenergic signaling, investigated by selective overexpression of distinct cascade components in mouse models. Furthermore, the impact of partial and inverse agonism of β-blockers on β-adrenergic signaling in human myocardium in vitro as well as in vivo in the clinical situation in patients with heart failure is highlighted. It is discussed whether the fact that not all β-blockers improve survival in heart failure patients may be due to their respective degree of inverse agonism.

Fibrin microbeads (FMB) as a 3D platform for kidney gene and cell therapy

Although beta-adrenergic stimuli are essential for myocardial contractility, beta-blockers have a proven beneficial effect on the treatment of heart failure, but the mechanism is not fully understood. The stimulatory G protein alpha-subunit (Gsalpha) couples the beta-adrenoreceptor to adenylyl cyclase and the intracellular cAMP response. In a mouse model of conditional Gsalpha deficiency in the cardiac muscle (Gsalpha-DF), we demonstrated heart failure phenotypes accompanied by increases in the level of a truncated cardiac troponin I (cTnI-ND) from restricted removal of the cTnI-specific N-terminal extension. To investigate the functional significance of the increase of cTnI-ND in Gsalpha-DF cardiac muscle, we generated double transgenic mice to overexpress cTnI-ND in Gsalpha-DF hearts. The overexpression of cTnI-ND in Gsalpha-DF failing hearts increased relaxation velocity and left ventricular end diastolic volume to produce higher left ventricle maximum pressure and stroke volume. Supporting the hypothesis that up-regulation of cTnI-ND is a compensatory rather than a destructive myocardial response to impaired beta-adrenergic signaling, the aberrant expression of beta-myosin heavy chain in adult Gsalpha-DF but not control mouse hearts was reversed by cTnI overexpression. These data indicate that the up-regulation of cTnI-ND may partially compensate for the cardiac inefficiency in impaired beta-adrenergic signaling.

Cell therapies have the potential to bring a paradigm shift to the treatment of heart failure (HF). Since the initial report of cell therapy with skeletal myoblasts in HF, a number of preclinical and clinical studies have been conducted, which support the ability of various stem cell populations to improve cardiac function and reduce the infarct size in HF. However, it is still too early in this new era of regenerative cell therapy as the novel modality. To address the fact that no cell therapy has been conclusively shown to be effective, the important issues involved have been discussed. First, the types of stem cells to be clinically investigated in HF have been reviewed; skeletal myoblasts, bone marrow-derived mononuclear and mesenchymal stem cells, adipose tissue-derived cells, and pluripotent stem cells have been discussed with their cell characteristics. Second, differentiation into cardiac lineage or paracrine effects as potential modes of action of stem cells in HF has been discussed. Finally, the routes of administration, cell dose and cell survival, and long-term engraftment have been discussed as current challenges and future directions. The purpose of this chapter is to review the preclinical and clinical studies carried out with respect to the use of stem cells in HF, and to discuss current unresolved issues and future directions.