Progress in Experimental Cardiology – serie

Whenever the heart is challenged with an increased workload for a prolonged period, it responds by increasing its muscle mass - a phenomenon known as cardiac hypertrophy. Although cardiac hypertrophy is commonly seen under physiological conditions such as development and exercise, a wide variety of pathological situations such as hypertension (pressure overload), valvular defects (volume overload), myocardial infarction (muscle loss) and cardiomyopathy (muscle disease) are also known to result in cardiac hypertrophy. This text compiles state-of-the-art presentations in the area of molecular biology, cellular physiology and signal transduction in cardiac hypertrophy and heart failure to help in the formulation of new concepts and approaches for stimulating research. The book contains two sections: "Mechanisms of Cardiac Hypertrophy", and "Cardiac Failure in the Hypertrophied Heart". It is hoped that both students and scientists, as well as clinical and experimental cardiologists, will find this book useful in understanding the molecular and cellular events underlying the development of cardiac hypertrophy and the transition from cardiac hypertrophy to heart failure.

Over the past three decades, impressive progress in the field of pathogenesis, prevention and therapy of ischemic heart disease has resulted in a marked decline in mortality in the Western World. However, the incidence of this devastating disease is on the rise in developing countries. The Ischemic Heart is based upon a recent symposium in Tokyo on the subject. This volume is organized into two sections: (i) Pathophysiologic Mechanisms of Ischemia-Reperfusion Injury and (ii) Preconditioning and Protection of Ischemia-Reperfusion Injury, and contains up-to-date information concerning the current concepts of ischemia-reperfusion injury, the sequence of events resulting in the loss of contractile dysfunction, and mechanisms of cardioprotection by several drugs as well as the role of ischemic preconditioning in attenuating problems associated with ischemia-reperfusion injury.

The relationship between angiotensin II and hypertension was established in 1898 when angiotensin II was shown to modulate systemic blood pressure. Over the intervening decades, a complete characterization of the renin-angiotensin system (RAS) has been achieved, and our understanding of its biochemistry and physiology has led to the directed development of agents such as ACE inhibitors and receptor antagonists capable of controlling hypertension. More recently, it was shown that angiotensin II is secreted within certain tissues, and that these tissue-specific systems operate independently of the systemic RAS. The novel concept that angiotensin II regulates a number of cardiovascular processes that are unrelated to blood pressure has renewed the interest of both basic and clinical scientists in angiotensin II. The association between angiotensin II and cardiac growth, in particular, has indicated that therapies in use for hypertension may have direct application to the treatment of heart failure. This book focuses on developments in the molecular biology, cellular physiology and structure-function relationships of angiotensin II and its receptors.In addition, this volume covers the therapeutic uses for angiotensin receptor antagonists and considers their potential future applications. This volume aims to be a valuable resource for scientists, practising clinicians and students who are attempting to extend their knowledge in the field of hypertension and heart failure, and who are devoted to improving cardiovascular health.

In 1982, as chance would have it again, an opportunity appeared to Jom the Department of Physiology at Kuwait University. P. Braveny spend four years there, teaching, doing some research, recovering former international contacts. Coming back home, he faced the same gloomy, motionless disfavor as before. November 1989 turned P. Bravenfs career upside down. Immediately after the fall ofthe communist regime, he was elected vice-dean and later dean ofthe Faculty of Medicine, promoted full professor in physiology and appointed the head of the Department ofPhysiology. From 1992 to 1998 P. Braveny served as the vice-rector of Masaryk University. His professional career culminated in his presidency of the XIV World Congress of ISHR in Prague. Understandably, in the following years, he become interested (in his tutor's footsteps) in history of physiology and pub- lished two monoghaphs (E. Babak andV Kruta). This CV would be an incomplete one without mentioning his broad interests in natural sciences and in art, particu- larly music and painting. As a tutored amateur he has acquired certain success in the latter. When reviewing P.Bravenfs whole-life work, largely done under adverse cir- cumstances with minimum financial support, his almost two hundred papers, innu- merable essays and four monographs are a commensurate result. In appreciation, he was awarded honorary membership of the Czech Medical Society, Physiological Society and Cardiological Society, Gold Medal of Masaryk University, Ministry of Education Award etc. Bohuslav Ostadal Makoto Nagano Naranjan S.

The importance of the developmental approach for experimental and clinical cardiology is indisputable. Clinical-epidemiological studies have clearly shown that the risk factors of serious cardiovascular diseases, such as atherosclerosis and ischemic heart disease, are already present during the early phases of ontogenetic development. Furthermore, congenital cardiovascular malformations remain the single largest cause of infant mortality from congenital defects in industrial countries. It is therefore not surprising that the interest of theoretical and clinical cardiologists in the developmental approach keeps increasing. Advances in molecular biology accelerated this trend substantially. This book is based on contributions presented at the international symposium The Developing Heart in Prague in May 2000. It should stimulate the curiosity of cardiovascular scientists in gaining insight into the mechanisms of normal and pathological development.

Evidence suggests that the ischemic preconditioning response is a multi-factorial process consisting of an initial early trigger, an intermediate mediator, and an end effector. Each of these steps in is now its own intense area of investigation. The need to render the heart ischemic for a brief period to invoke the preconditioning response is currently the major factor limiting clinical application of this powerful cardioprotective strategy. Research efforts have utilized brief exposures to pharmacological agents, in lieu of a brief preconditioning ischemia, to trigger/mimic the ischemic preconditioning-induced response. The World Heart Congress held in Winnipeg in July 2001 provided a forum for the presentation of insights into the basic mechanisms of ischemia and reperfusion injury, as well as novel strategies to protect the heart from cell death, ventricular arrhythmias, and contractile dysfunction. Many pioneers in the fields of ischemia-reperfusion injury and preconditioning-induced protection presented there and the chapters in this book represent selected papers from these symposia.

The limitation in number of donor hearts led to the establishment of alternative treatments such as left ventricular assist devices (LVAD), which have been used. Although several reports suggest the native ventricular function recovers after long-term LVAD support - a process called "reverse remodelling" - the underlying biological mechanisms are unclarified. Various molecular pathways of the human myocardium associated with apoptosis, response to stress, or matrix changes are known to be altered under conditions of heart failure and some of them have been shown to be reversible regulated during left ventricular mechanical support. This suggests that the "reverse remodelling" is actually, at least in part, a reverse mechanism. One explanation may be, under mechanical circulatory assist, volume and pressure overload is reduced, and thus ventricular wall stress decreases, leading to improved myocardial blood supply. This may be one explanation for the molecular myocardial changes, and may reflect a possible cause of "reverse remodelling".

Thistext, as the tide states, is acompilationofpapersdevoted to the studyofath- erosclerosis,hypertensionanddiabetes.Thesethree distinctdisease entities,although not entirely unrelated, are three ofthe most important disease conditions in the world today.As such, this volumeofresearch papers isofobvious medical impor- tance.Thejustificationofthe energy,time and financial resources directed towards the studyofeachofthese three diseases requiressome discussion. The majority of papers amongst the three diseases that are discussed in this volume are dedicated to the studyofatherosclerosis.This is not by accident.Car- diovasculardisease isthenumberonekillertodayintheworld. IntheUnitedStates almost61 millionAmericanshaveoneormoreformsofcardiovasculardisease.These diseases claimed nearly 1million lives in 1998 alone.Although approximately 80% ofthosewho dieofcardiovasculardisease are 65 yearsofageorolder,asignificant numberofpeople are killed by cardiovascular disease below the ageof65.Ather- osclerotic heart disease in the eoronary vaseulature eausedapproximately~ million deaths in the United States in 1998.At least 12,400,000people are alive todayin the United States with a historyofmyocardial infarctions or ehest pain or both.Clearly,atherosclerotie disease inthe heart isamajormedicalproblem.This disease affeetsbothmenandwomen.Althoughmen are more likelyto experienee aheart attaekand are atgreater risk for eardiovaseular disease,more then ~ofthe people alive today with a historyofheart attacks or angina are females. As weIl,women whodo havemyoeardialinfarctionsare twice aslikely to diefromtheeventwithin afew weeks.Atheroscleroticvasculardisease isnotlimitedtojustthe heart.Anath- erosclerotic ischemic event is the primary causeofstroke today.Although it isnot weIl appreciated, stroke is the number 3 killer inAmerica today and the leading causeofdebilitatingneurological damage.Atherosclerotic vascular disease therefore, has acostintermsofhuman life,qualityoflifeandfinancialburden today thatno otherdisease canmatch.Theseriousnessofthis medicalproblemdemands research attention.

Understanding the pathophysiology; cellular mechanisms of disease progression; different risk factors for cardiovascular disease; dietary effects on cardiovascular health and cultural differences are as important as dealing with the economic burden of cardiovascular mortality and morbidity. "Frontiers in Cardiovascular Health" discusses the factors that lead to cardiovascular death and strategies for their prevention from molecule to population.

Pathophysiology of Cardiovascular Disease has been divided into four sections that focus on heart dysfunction and its associated characteristics (hypertrophy, cardiomyopathy and failure); vascular dysfunction and disease; ischemic heart disease; and novel therapeutic interventions. This volume is a compendium of different approaches to understanding cardiovascular disease and identifying the proteins, pathways and processes that impact it.

Thistext, as the tide states, is acompilationofpapersdevoted to the studyofath- erosclerosis,hypertensionanddiabetes.Thesethree distinctdisease entities,although not entirely unrelated, are three ofthe most important disease conditions in the world today.As such, this volumeofresearch papers isofobvious medical impor- tance.Thejustificationofthe energy,time and financial resources directed towards the studyofeachofthese three diseases requiressome discussion. The majority of papers amongst the three diseases that are discussed in this volume are dedicated to the studyofatherosclerosis.This is not by accident.Car- diovasculardisease isthenumberonekillertodayintheworld. IntheUnitedStates almost61 millionAmericanshaveoneormoreformsofcardiovasculardisease.These diseases claimed nearly 1million lives in 1998 alone.Although approximately 80% ofthosewho dieofcardiovasculardisease are 65 yearsofageorolder,asignificant numberofpeople are killed by cardiovascular disease below the ageof65.Ather- osclerotic heart disease in the eoronary vaseulature eausedapproximately~ million deaths in the United States in 1998.At least 12,400,000people are alive todayin the United States with a historyofmyocardial infarctions or ehest pain or both.Clearly,atherosclerotie disease inthe heart isamajormedicalproblem.This disease affeetsbothmenandwomen.Althoughmen are more likelyto experienee aheart attaekand are atgreater risk for eardiovaseular disease,more then ~ofthe people alive today with a historyofheart attacks or angina are females. As weIl,women whodo havemyoeardialinfarctionsare twice aslikely to diefromtheeventwithin afew weeks.Atheroscleroticvasculardisease isnotlimitedtojustthe heart.Anath- erosclerotic ischemic event is the primary causeofstroke today.Although it isnot weIl appreciated, stroke is the number 3 killer inAmerica today and the leading causeofdebilitatingneurological damage.Atherosclerotic vascular disease therefore, has acostintermsofhuman life,qualityoflifeandfinancialburden today thatno otherdisease canmatch.Theseriousnessofthis medicalproblemdemands research attention.

According to the World Health Report (2000 http:/ /www. who. int/whr), of the 55 million deaths worldwide in 1999, more than 16 million were secondary to car­ diovascular complications. With the prospect of world population increasing from the current level of 6 billion to 9 billion by the middle of this century, the burden of cardiac disease is going to increase astronomically. Furthermore, scientists are being challenged not only to reduce mortality, but also to improve quality of life. Thus, more than ever, intellectuals from different disciplines including biology, sociology, informatics and health care have to join forces to meet the mandate. The World Heart Congress with a focus on "Frontiers in Cardiovascular Health" held in Winnipeg during July 6-11, 2001, made a unique attempt to bring these specialists together to brainstorm and map out the course of action for cardiovascular research and health in the next century. Anytime there is a relative increase in the workload on the heart, there are adap­ tive myocardial as well as humoral responses. When these adaptations or remodel­ ing at the organ, subcellular or gene level, become inadequate for a proper tissue perfusion, the condition of heart failure ensues. Prevention of the factors leading to the relative increase in workload as well as a better understanding of the adap­ tive responses and their failure are some of the hopes to combat the morbidity and mortality due to heart failure.

Cellular signaling in cardiac muscle refers to the myriad of stimuli and responses that direct and control the physiological operation of this organ. Our understand­ ing of these complex signaling cascades has increased dramatically over the past few decades with the advent of molecular tools for their dissection. Moreover, this infor­ mation is beginning to provide tangible targets towards manipulating cardiac func­ tion in the setting of cardiovascular disease. The mechanisms and factors that regulate cardiac cell growth are of particular interest as both adaptive and maladaptive responses can occur during cardiac hypertrophy. Cardiac hypertrophy describes the increase in individual cardiac myocyte size that is accomplished through the series and/or parallel addition of sarcomeres. The ability of cardiac muscle to increase in size through hyperplasia becomes highly restricted or negligible shortly after birth. Consequently, the increase in heart size associated with development and growth of an individual occurs through hypertrophy. In response to a chronic increase in workload, cardiac muscle cells can dramatically increase in size to face their increasing contractile demands. While this plasticity is clearly a ben­ eficial response under many conditions, it can be highly deleterious and inappropri­ ate under others. For example, cardiac hypertrophy associated with endurance exercise clearly enhances athletic performance. In contrast, the hypertrophy associated with chronic hypertension, stenotic or regurgitant heart valves, or following a myocardial infarction often continues far beyond the period where this adaptive response is ben­ eficial.

Current evidence suggests that the ischemic preconditioning response is a multi-factorial process consisting of an initial early trigger, an intermediate mediator, and an end effector. Each of these steps in is now its own intense area of investigation. The need to render the heart ischemic for a brief period to invoke the preconditioning response is currently the major factor limiting clinical application of this powerful cardioprotective strategy. Recent research efforts have utilized brief exposures to pharmacological agents, in lieu of a brief preconditioning ischemia, to trigger/mimic the ischemic preconditioning-induced response. The World Heart Congress held in Winnipeg in July 2001 provided a forum for the presentation of new insights into the basic mechanisms of ischemia and reperfusion injury, as well as novel strategies to protect the heart from cell death, ventricular arrhythmias, and contractile dysfunction. Many pioneers in the fields of ischemia-reperfusion injury and preconditioning-induced protection presented there and the chapters in this book represent selected papers from these symposia.

Pathophysiology of Cardiovascular Disease has been divided into four sections that focus on heart dysfunction and its associated characteristics (hypertrophy, cardiomyopathy and failure); vascular dysfunction and disease; ischemic heart disease; and novel therapeutic interventions. This volume is a compendium of different approaches to understanding cardiovascular disease and identifying the proteins, pathways and processes that impact it.

The Frontiers in Cardiovascular Health varies between and within nations, depend­ ing upon the level at which the battle is fought for better cardiovascular health. According to the 1997 World Health Report, 15 million deaths (i. e. 30% of the total number of deaths) were attributable to cardiovascular diseases and this number is on the rise. The projection for the year 2020 is quite alarming with an expected cardiovascular mortality reaching 50 million. Much of this burden is projected to occur in developing countries, more specifically in the most populous countries of the world, namely China and India. These countries are already burdened with infectious and parasitic diseases and are trying to eradicate such diseases. With increasing life expectancies people all over the world, especially in developing coun­ tries, are exposed to degenerative atherosclerosis resulting in increased cardiovascu­ lar mortality and morbidity. In developing countries, resources available for health care are very limited. For example many of the African countries spend less than $10 per person per year on his/her entire health care let alone cardiovascular health. The average health care budget for nearly two thirds of the global population is well below $100 per year, on a per capita basis. Therefore, in developing countries health promotion and primary prevention are the frontiers by necessity. Improving awareness and health education is not only a matter of choice but is an absolute necessity.

In 1982, as chance would have it again, an opportunity appeared to Jom the Department of Physiology at Kuwait University. P. Braveny spend four years there, teaching, doing some research, recovering former international contacts. Coming back home, he faced the same gloomy, motionless disfavor as before. November 1989 turned P. Bravenfs career upside down. Immediately after the fall ofthe communist regime, he was elected vice-dean and later dean ofthe Faculty of Medicine, promoted full professor in physiology and appointed the head of the Department ofPhysiology. From 1992 to 1998 P. Braveny served as the vice-rector of Masaryk University. His professional career culminated in his presidency of the XIV World Congress of ISHR in Prague. Understandably, in the following years, he become interested (in his tutor's footsteps) in history of physiology and pub- lished two monoghaphs (E. Babak andV Kruta). This CV would be an incomplete one without mentioning his broad interests in natural sciences and in art, particu- larly music and painting. As a tutored amateur he has acquired certain success in the latter. When reviewing P.Bravenfs whole-life work, largely done under adverse cir- cumstances with minimum financial support, his almost two hundred papers, innu- merable essays and four monographs are a commensurate result. In appreciation, he was awarded honorary membership of the Czech Medical Society, Physiological Society and Cardiological Society, Gold Medal of Masaryk University, Ministry of Education Award etc. Bohuslav Ostadal Makoto Nagano Naranjan S.

Whenever the heart is challenged with an increased work load for a prolonged period, it responds by increasing its muscle mass--a phenomenon known as cardiac hypertrophy. Although cardiac hypertrophy is commonly seen under physiological conditions such as development and exercise, a wide variety of pathological situa­ tions such as hypertension (pressure overload), valvular defects (volume overload), myocardial infarction (muscle loss), and cardiomyopathy (muscle disease) are also known to result in cardiac hypertrophy. Various hormones such as catecholamines, thyroid hormones, angiotensin II, endothelin, and growth factors have also been shown to induce cardiac hypertrophy. Although the exact mechanisms underlying or pathological forrns of cardiac hypertrophy are poorly under­ the physiological stood, an increase in the intraventricular pressure is believed to represent the major stimulus for the development of cardiac hypertrophy. In this regard, stretching of the cardiac muscle has been shown to induce the hypertrophic response, but the role of metabolic influences in this process cannot be ruled out. Furthermore, different hormones and other interventions in the absence of stretch have been observed to stimulate protein synthesis in both isolated cardiomyocyte and vascular myocyte preparations. Nonetheless, it is becoming dear that receptor as well as phospholipid­ linked signal transduction pathways are activated in some specific manner depend­ ing upon the initial hypertrophic stimulus, and these then result in an increase in the size and mass of cardiomyocytes.

The relationship between angiotensin II and hypertension was established in 1898 when angiotensin II was shown to modulate systemic blood pressure. Over the intervening decades, a complete characterization of the renin-angiotensin system (RAS) has been achieved, and our understanding of its biochemistry and physiology has led to the directed development of agents such ·as ACE inhibitors and receptor antagonists capable of controlling hypertension. More recently, it was shown that angiotensin II is secreted within certain tissues and that these tissue-specific systems operate independently of the systemic RAS. The novel concept that angiotensin II regulates a number of cardiovascular processes that are unrelated to blood pressure has renewed the interest of both basic and clinical scientists in angiotensin II. The association between angiotensin II and cardiac growth, in particular, has indicated that therapies currently in use for hypertension may have direct application to the treatment of heart failure. The Manitoba Cardiovascular Forum on Angiotensin Receptor Blockade in Winnipeg was convened October 18-20, 1996 to examine the clinical and basic aspects of angiotensin receptor biology as they apply to hypertension and heart failure. In addition, the potential treatment of these conditions using specific angio­ tensin receptor antagonists was addressed within the context of their immediate therapeutic application and future potential.