Andre Terzic

Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update A Scientific Statement From the American Heart Association

Cardiovascular diseases (CVDs) are a major source of morbidity and mortality worldwide. Despite a decline of ≈30% over the past decade, heart disease remains the leading killer of Americans.1 For rare and familial forms of CVD, we are increasingly recognizing single-gene mutations that impart relatively large effects on individual phenotype. Examples include inherited forms of cardiomyopathy, arrhythmias, and aortic diseases. However, the prevalence of monogenic disorders typically accounts for a small proportion of the total CVD observed in the population. CVDs in the general population are complex diseases, with several contributing genetic and environmental factors. Although recent progress in monogenic disorders has occurred, we have seen a period of intense investigation to identify the genetic architecture of more common forms of CVD and related traits.nnGenomics serves several roles in cardiovascular health and disease, including disease prediction, discovery of genetic loci influencing CVD, functional evaluation of these genetic loci to understand mechanisms, and identification of therapeutic targets. For single-gene CVDs, progress has led to several clinically useful diagnostic tests, extending our ability to inform the management of afflicted patients and their family members. However, there has been little progress in developing genetic testing for complex CVD because individual common variants have only a modest impact on risk. The study of the genomics of complex CVDs is further challenged by the influence of environmental variables, phenotypic heterogeneity, and pathogenic complexity. Characterization of the clinical phenotype requires consideration of the clinical details of the diseases and traits under study.nnThis update expands the prior scientific statement on the relevance of genetics and genomics for the prevention and treatment of CVDs.2 In the earlier report, we focused on the current status of the field, which consisted of predominantly family-based linkage studies and single-gene or mendelian mutations of relatively large phenotypic effect …

Induced pluripotent stem cells: advances to applications

Induced pluripotent stem cell (iPS) technology has enriched the armamentarium of regenerative medicine by introducing autologous pluripotent progenitor pools bioengineered from ordinary somatic tissue. Through nuclear reprogramming, patient-specific iPS cells have been derived and validated. Optimizing iPS-based methodology will ensure robust applications across discovery science, offering opportunities for the development of personalized diagnostics and targeted therapeutics. Here, we highlight the process of nuclear reprogramming of somatic tissues that, when forced to ectopically express stemness factors, are converted into bona fide pluripotent stem cells. Bioengineered stem cells acquire the genuine ability to generate replacement tissues for a wide-spectrum of diseased conditions, and have so far demonstrated therapeutic benefit upon transplantation in model systems of sickle cell anemia, Parkinson’s disease, hemophilia A, and ischemic heart disease. The field of regenerative medicine is therefore primed to adopt and incorporate iPS cell-based advancements as a next generation stem cell platforms.

Regenerative Medicine Primer

The pandemic of chronic diseases, compounded by the scarcity of usable donor organs, mandates radical innovation to address the growing unmet needs of individuals and populations. Beyond life-extending measures that are often the last available option, regenerative strategies offer transformative solutions in treating degenerative conditions. By leveraging newfound knowledge of the intimate processes fundamental to organogenesis and healing, the emerging regenerative armamentarium aims to boost the aptitude of human tissues for self-renewal. Regenerative technologies strive to promote, augment, and reestablish native repair processes, restituting organ structure and function. Multimodal regenerative approaches incorporate transplant of healthy tissues into damaged environments, prompt the body to enact a regenerative response in damaged tissues, and use tissue engineering to manufacture new tissue. Stem cells and their products have a unique aptitude to form specialized tissues and promote repair signaling, providing active ingredients of regenerative regimens. Concomitantly, advances in materials science and biotechnology have unlocked additional prospects for growing tissue grafts and engineering organs. Translation of regenerative principles into practice is feasible and safe in the clinical setting. Regenerative medicine and surgery are, thus, poised to transit from proof-of-principle studies toward clinical validation and, ultimately, standardization, paving the way for next-generation individualized management algorithms.

Regenerative medicine: On the vanguard of health care

The World Health Organization reports that a staggering 36 million of the 57 million annual global deaths are due to a rampant pandemic of chronic diseases.1 Success in managing acute conditions has reduced early mortality but has concurrently precipitated a higher incidence of chronic diseases among survivors. Current evidence-based and cost-effective interventions are insufficient to meet the growing challenge posed by noncommunicable chronic conditions, driven in part by the aging of the population and the associated increase in degenerative diseases.2 Reparative therapies targeting the cause of progressive cell destruction and irreversible loss of tissue function are largely lacking. Transformation of the health care horizon will require unprecedented innovation to extend the reach of clinical practice beyond the current standard of care. n nNew knowledge on disease causes and cures will enable delivery of high-quality care that more effectively addresses the unmet needs of our patients.

CHAPTER 47 – K+ Channel Openers

This chapter focuses on potassium channel openers target adenosine triphosphate-sensitive potassium (K ATP ) channels. These channels couple cellular metabolism with membrane excitability, and have been implicated in the regulation of vascular tone and cardioprotection under metabolic stress. Potassium channel openers have a unique therapeutic potential as combined cardioprotective and vasodilatory agents. Potassium channel openers include benzopyrans, thioformamides, nicotinamides, cyanoguanidines, pyrimidines, and benzothiadiazines. Specific binding sites for potassium channel openers have been identified on the SUR subunit of the K ATP channel in both vascular smooth muscle and cardiac muscle. Potassium channel openers preferentially activate K + channels in smooth muscle cells, leading to membrane hyperpolarization. Thereby, the primary pharmacodynamic effect of potassium channel openers is the relaxation of vascular smooth muscle, resulting in vasodilatation. Potassium channel openers also open K ATP channels in the myocardium, the effect of which is more pronounced during ischemia. Opening of cardiac K ATP channels shortens the action potential duration, with diminished time available for Ca 2+ influx. This can reduce the force of contraction, but also preserves energy expenditure associated with the maintenance of cellular Ca 2+ homeostasis. Potassium channel openers improve the recovery of myocardial function following metabolic insult, decrease loss of adenine nucleotides, and diminish infarct size. Such a protective effect is independent from changes in collateral blood flow, which suggests a direct cytoprotective action on the cardiomyocyte.

Heart Regeneration: The Developmental and Stem Cell Biology Approach

Regenerative Medicine is a discipline that aims at reinstating physical and functional integrity of a damaged organ via rejuvenation with endogenous stem cells, replacement with bioengineered tissues, and regeneration with transplantation of exogenous stem cells. In the case of the heart, the possibility of replacing dysfunctional myocardium with de novo tissue offers a curative approach to augment traditional management strategies to prevent disease progression toward heart failure. Across a broad range of acquired and/or congenital cardiac diseases, regenerative strategies are being optimized for individual patients with the goal of providing disruptive technology that aims to transform therapeutic outcomes and reduce the overall expenditure required for life-long disease management. Developmental biology provides a firm foundation to accelerate stem cell technologies toward cardiac clinical applications for transplant medicine and surgery.

Antiarrhythmic Drugs and Future Direction

Antiarrhythmic agents play an important role in the termination and suppression of both atrial and ventricular arrhythmias as primary or adjunctive therapy. The use of hybrid treatment, combining drugs with radiofrequency ablation or ICD implantation, is expected to rise as the number of patients with complex arrhythmias continues to increase (1,2). In this evolving management scenario, selection of an effective yet safe pharmacologic agent is challenging. The challenge arises from factors intrinsic to the patient, disease condition or the drug itself. These factors primarily include variability in the pathophysiologic substrate, diverse arrhythmia mechanisms, multiple clinical presentation with differing prognostic implications, along with variability in drug disposition and/or response in a highly heterogeneous patient population. Moreover, the availability of multiple therapeutic options and the narrow therapeutic index with limited ability to determine satisfactory endpoints further emphasize the need for better understanding of interactions between drug, end target, and disease condition.