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Journal of the American College of... May 2014Inotropes have been fundamental to resuscitation of acute cardiogenic shock for decades. Heart failure and cardiogenic shock, in severe cases, are syndromes... (Review)
Review
Inotropes have been fundamental to resuscitation of acute cardiogenic shock for decades. Heart failure and cardiogenic shock, in severe cases, are syndromes characterized in many patients by a reduction in myocardial contractile force. While inotropes successfully increase cardiac output, their use has been plagued by excessive mortality due to increased tachycardia and myocardial oxygen consumption leading to arrhythmia and myocardial ischemia. There is a pressing need for new inotropic agents that avoid these harmful effects. This review describes the mechanism of action and the clinical utility of some of the older inotropic agents, which are still commonly used, and provides an update for physicians on the development of newer inotropic drugs. The field is rapidly changing, and it is likely that new agents will be designed that improve systolic performance without necessarily increasing the myocardial oxygen consumption.
Topics: Cardiotonic Agents; Heart Failure; Humans; Myocardial Contraction; Shock, Cardiogenic; Systole; Treatment Outcome
PubMed: 24530672
DOI: 10.1016/j.jacc.2014.01.016 -
Critical Care (London, England) 2008Cardiac output is the amount of blood the heart pumps in 1 minute, and it is dependent on the heart rate, contractility, preload, and afterload. Understanding of the...
Cardiac output is the amount of blood the heart pumps in 1 minute, and it is dependent on the heart rate, contractility, preload, and afterload. Understanding of the applicability and practical relevance of each of these four components is important when interpreting cardiac output values. In the present article, we use a simple analogy comparing cardiac output with the speed of a bicycle to help appreciate better the effects of various disease processes and interventions on cardiac output and its four components.
Topics: Animals; Cardiac Output; Heart Rate; Humans; Myocardial Contraction; Practice Guidelines as Topic; Stroke Volume
PubMed: 18771592
DOI: 10.1186/cc6975 -
Journal of the American College of... Apr 2021The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor... (Review)
Review
The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart.
Topics: Animals; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Myocardial Contraction; Myocardium; Review Literature as Topic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 33888253
DOI: 10.1016/j.jacc.2021.02.057 -
Circulation Nov 2022Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to...
BACKGROUND
Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails, and the underlying molecular mechanisms are not well studied.
METHODS
To discover potential missing factors for human direct reprogramming, we performed transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes.
RESULTS
We identified (T-box transcription factor 20) as the top cardiac gene that is unable to be activated by the MGT133 reprogramming cocktail (, , , and ). TBX20 is required for normal heart development and cardiac function in adult cardiomyocytes, yet its role in cardiac reprogramming remains undefined. We show that the addition of TBX20 to the MGT133 cocktail (MGT+TBX20) promotes cardiac reprogramming and activates genes associated with cardiac contractility, maturation, and ventricular heart. Human induced cardiomyocytes produced with MGT+TBX20 demonstrated more frequent beating, calcium oscillation, and higher energy metabolism as evidenced by increased mitochondria numbers and mitochondrial respiration. Mechanistically, comprehensive transcriptomic, chromatin occupancy, and epigenomic studies revealed that TBX20 colocalizes with MGT reprogramming factors at cardiac gene enhancers associated with heart contraction, promotes chromatin binding and co-occupancy of MGT factors at these loci, and synergizes with MGT for more robust activation of target gene transcription.
CONCLUSIONS
TBX20 consolidates MGT cardiac reprogramming factors to activate cardiac enhancers to promote cardiac cell fate conversion. Human induced cardiomyocytes generated with TBX20 showed enhanced cardiac function in contractility and mitochondrial respiration.
Topics: Humans; Cellular Reprogramming; Chromatin; Fibroblasts; Mitochondria; Myocardium; Myocytes, Cardiac; T-Box Domain Proteins; Myocardial Contraction; Cardiovascular Agents
PubMed: 36102189
DOI: 10.1161/CIRCULATIONAHA.122.059713 -
American Journal of Physiology. Heart... Dec 2010Since the pioneering work of Henry Pickering Bowditch in the late 1800s to early 1900s, cardiac muscle contraction has remained an intensely studied topic for several... (Review)
Review
Since the pioneering work of Henry Pickering Bowditch in the late 1800s to early 1900s, cardiac muscle contraction has remained an intensely studied topic for several reasons. The heart is located centrally in our body, and its pumping motion demands the attention of the observer. The contraction of the heart encompasses a complex interplay of mechanical, chemical, and electrical properties, and its function can thus be studied from any of these viewpoints. In addition, diseases of the heart are currently killing more people in the Westernized world than any other disease. When combined with the increasing emphasis of research to be clinically relevant, this contributes to the heart remaining a topic of continued basic and clinical investigation. Yet, there are significant aspects of cardiac muscle contraction that are still not well understood. A big complication of the study of cardiac muscle contraction is that there exists no equilibrium among many of the important governing parameters, which include pre- and afterload, intracellular ion concentrations, membrane potential, and velocity and direction of movement. Thus the classic approach of perturbing an equilibrium or a steady state to learn about the role of the perturbing factor in the system cannot be unambiguously interpreted, since each of the parameters that govern contraction are constantly changing, as well as constantly changing their interaction with each other. In this review, presented as the 54th Bowditch Lecture at Experimental Biology meeting in Anaheim in April 2010, I will revisit several governing factors of cardiac muscle relaxation by applying newly developed tools and protocols to isolated cardiac muscle tissue in which the dynamic interactions between the governing factors of contraction and relaxation can be studied.
Topics: Animals; Cardiomegaly; Diastole; Excitation Contraction Coupling; Humans; Kinetics; Membrane Potentials; Myocardial Contraction; Myocardium; Sarcomeres; Systole
PubMed: 20852049
DOI: 10.1152/ajpheart.00759.2010 -
The Journal of Physiology Aug 2022The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and...
The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and pharmacological conditions. This provides a reduced preparation in which to isolate sarcomere mechanisms. However, it is unclear how changes in the F-pCa curve impact emergent whole-heart mechanics quantitatively. We study the link between sarcomere and whole-heart function using a multiscale mathematical model of rat biventricular mechanics that describes sarcomere, tissue, anatomy, preload and afterload properties quantitatively. We first map individual cell-level changes in sarcomere-regulating parameters to organ-level changes in the left ventricular function described by pressure-volume loop characteristics (e.g. end-diastolic and end-systolic volumes, ejection fraction and isovolumetric relaxation time). We next map changes in the sarcomere-regulating parameters to changes in the F-pCa curve. We demonstrate that a change in the F-pCa curve can be caused by multiple different changes in sarcomere properties. We demonstrate that changes in sarcomere properties cause non-linear and, importantly, non-monotonic changes in left ventricular function. As a result, a change in sarcomere properties yielding changes in the F-pCa curve that improve contractility does not guarantee an improvement in whole-heart function. Likewise, a desired change in whole-heart function (i.e. ejection fraction or relaxation time) is not caused by a unique shift in the F-pCa curve. Changes in the F-pCa curve alone cannot be used to predict the impact of a compound on whole-heart function. KEY POINTS: The force-pCa (F-pCa) curve is used to assess myofilament calcium sensitivity after pharmacological modulation and to infer pharmacological effects on whole-heart function. We demonstrate that there is a non-unique mapping from changes in F-pCa curves to changes in left ventricular (LV) function. The effect of changes in F-pCa on LV function depend on the state of the heart and could be different for different pathological conditions. Screening of compounds to impact whole-heart function by F-pCa should be combined with active tension and calcium transient measurements to predict better how changes in muscle function will impact whole-heart physiology.
Topics: Animals; Calcium; Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Rats; Sarcomeres
PubMed: 35737959
DOI: 10.1113/JP283352 -
Journal of Molecular and Cellular... Jun 2018In the late 19th century, German physiologist Otto Frank (1865-1944) embarked on a near life-long research program of laying down the mathematical, methodological, and... (Review)
Review
In the late 19th century, German physiologist Otto Frank (1865-1944) embarked on a near life-long research program of laying down the mathematical, methodological, and theoretical foundations in order to understand and define the performance of the heart and circulatory system in all their complexity. The existence of the "Frank-Starling law" testifies to this. Two of his seminal publications have been translated into English previously, introducing Frank's research on the dynamics of the heart and the arterial pulse to a wider audience. It is likely that there are a host of other comparable achievements and publications of Frank that are still unknown to the international scientific (cardiological and physiological) community. However, their influence can still be felt and seen in modern cardiology and cardio-physiology, such as in the development of modern interactive simulating and teaching programs. We have translated and commented on ten of these papers, which can be read in parallel with the German originals. These publications show a wealth of theoretical assumptions and projections regarding the importance of the sarcomere, the development of models of contraction, thermo-dynamical considerations for muscular activity, differences between cardiac and skeletal muscles, problems related to methodology and measurement, and the first pressure-volume diagram (published 120 years ago). These topics were envisioned by Frank long before they became a focus of subsequent modern research. Nowadays, frequent measurements of pressure-volume relationships are made in research using the pressure-volume conductance catheter technique. In commenting Frank's scientific topics, we try to show how interconnected his thinking was, and thus how it enabled him to cover such a wide range of subjects.
Topics: Cardiology; History, 19th Century; History, 20th Century; Humans; Myocardial Contraction
PubMed: 29727607
DOI: 10.1016/j.yjmcc.2018.04.017 -
Journal of Molecular and Cellular... Apr 2012A large body of evidence has demonstrated that there is a close coupling between regional myocardial perfusion and contractile function. When ischemia is mild, this can... (Review)
Review
A large body of evidence has demonstrated that there is a close coupling between regional myocardial perfusion and contractile function. When ischemia is mild, this can result in the development of a new balance between supply and energy utilization that allows the heart to adapt for a period of hours over which myocardial viability can be maintained, a phenomenon known as "short-term hibernation". Upon reperfusion after reversible ischemia, regional myocardial function remains depressed. The "stunned myocardium" recovers spontaneously over a period of hours to days. The situation in myocardium subjected to chronic repetitive ischemia is more complex. Chronic dysfunction can initially reflect repetitive stunning with insufficient time for the heart to recover between episodes of spontaneous ischemia. As the frequency and/or severity of ischemia increases, the heart undergoes a series of adaptations which downregulate metabolism to maintain myocyte viability at the expense of contractile function. The resulting "hibernating myocardium" develops regional myocyte cellular hypertrophy as a compensatory response to ischemia-induced apoptosis along with a series of molecular adaptations that while regional, are similar to global changes found in advanced heart failure. As a result, flow-function relations become independently affected by tissue remodeling and interventions that stimulate myocyte regeneration. Similarly, chronic vascular remodeling may alter flow regulation in a fashion that increases myocardial vulnerability to ischemia. Here we review our current understanding of myocardial flow-function relations during acute ischemia in normal myocardium and highlight newly identified complexities in their interpretation in viable chronically dysfunctional myocardium with myocyte cellular and molecular remodeling. This article is part of a Special Issue entitled "Coronary Blood Flow".
Topics: Animals; Coronary Circulation; Humans; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion
PubMed: 21889943
DOI: 10.1016/j.yjmcc.2011.08.019 -
The Journal of Physiology Oct 2022The formulation by Starling of The Law of the Heart states that 'the [mechanical] energy of contraction, however measured, is a function of the length of the muscle...
The formulation by Starling of The Law of the Heart states that 'the [mechanical] energy of contraction, however measured, is a function of the length of the muscle fibre'. Starling later also stated that 'the oxygen consumption of the isolated heart … is determined by its diastolic volume, and therefore by the initial length of its muscular fibres'. This phrasing has motivated us to extend Starling's Law of the Heart to include consideration of the efficiency of contraction. In this study, we assessed both mechanical efficiency and crossbridge efficiency by studying the heat output of isolated rat ventricular trabeculae performing force-length work-loops over ranges of preload and afterload. The combination of preload and afterload allowed us, using our modelling frameworks for the end-systolic zone and the heat-force zone, to simulate cases by recreating physiologically feasible loading conditions. We found that across all cases examined, both work output and change of enthalpy increased with initial muscle length; hence it can only be that the former increases more than the latter to yield increased mechanical efficiency. In contrast, crossbridge efficiency increased with initial muscle length in cases where the extent of muscle shortening varied greatly with preload. We conclude that the efficiency of cardiac contraction increases with increasing initial muscle length and preload. An implication of our conclusion is that the length-dependent activation mechanism underlying the cellular basis of Starling's Law of the Heart is an energetically favourable process that increases the efficiency of cardiac contraction. KEY POINTS: Ernest Starling in 1914 formulated the Law of the Heart to describe the mechanical property of cardiac muscle whereby force of contraction increases with muscle length. He subsequently, in 1927, showed that the oxygen consumption of the heart is also a function of the length of the muscle fibre, but left the field unclear as to whether cardiac efficiency follows the same dependence. A century later, the field has gained an improved understanding of the factors, including the distinct effects of preload and afterload, that affect cardiac efficiency. This understanding presents an opportunity for us to investigate the elusive length-dependence of cardiac efficiency. We found that, by simulating physiologically feasible loading conditions using a mechano-energetics framework, cardiac efficiency increased with initial muscle length. A broader physiological importance of our findings is that the underlying cellular basis of Starling's Law of the Heart is an energetically favourable process that yields increased efficiency.
Topics: Animals; Heart; Heart Ventricles; Male; Myocardial Contraction; Myocardium; Rats; Starlings
PubMed: 35998082
DOI: 10.1113/JP283632 -
Journal of Biomechanical Engineering Feb 2014Cardiac mechanical contraction is triggered by electrical activation via an intracellular calcium-dependent process known as excitation-contraction coupling.... (Review)
Review
Cardiac mechanical contraction is triggered by electrical activation via an intracellular calcium-dependent process known as excitation-contraction coupling. Dysregulation of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, electrical dyssynchrony leads to mechanical alterations and exacerbates pump dysfunction in heart failure. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred as cardiac mechanoelectric feedback and thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. At the cellular scale, most investigations of myocyte mechanoelectric feedback have focused on the roles of stretch-activated ion channels, though mechanisms that are independent of ionic currents have also been described. Here we review excitation-contraction coupling and mechanoelectric feedback at the cellular and organ scales, and we identify the need for new multicellular tissue-scale model systems and experiments that can help us to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart.
Topics: Animals; Excitation Contraction Coupling; Feedback, Physiological; Heart Conduction System; Humans; Models, Cardiovascular; Myocardial Contraction; Myocytes, Cardiac; Ventricular Function
PubMed: 24337452
DOI: 10.1115/1.4026221