Conceptual Foundations of Systems Biology Explaining Complex Cardiac Diseases.

Systems biology is an important concept that connects molecular biology and genomics with computing science, mathematics and engineering. An endeavor is made in this paper to associate basic conceptual ideas of systems biology with clinical medicine. Complex cardiac diseases are clinical phenotypes generated by integration of genetic, molecular and environmental factors. Basic concepts of systems biology like network construction, modular thinking, biological constraints (downward biological direction) and emergence (upward biological direction) could be applied to clinical medicine. Especially, in the field of cardiology, these concepts can be used to explain complex clinical cardiac phenotypes like chronic heart failure and coronary artery disease. Cardiac diseases are biological complex entities which like other biological phenomena can be explained by a systems biology approach. The above powerful biological tools of systems biology can explain robustness growth and stability during disease process from modulation to phenotype. The purpose of the present review paper is to implement systems biology strategy and incorporate some conceptual issues raised by this approach into the clinical field of complex cardiac diseases. Cardiac disease process and progression can be addressed by the holistic realistic approach of systems biology in order to define in better terms earlier diagnosis and more effective therapy.

Heart Failure in Patients with Preserved Ejection Fraction: Questions Concerning Clinical Progression.

Over the last two decades, important advances have been made in explaining some pathophysiological aspects of heart failure with preserved ejection fraction (HFpEF) with repercussions for the successful clinical management of the syndrome. Despite these gains, our knowledge for the natural history of clinical progression from the pre-clinical diastolic dysfunction (PDD) until the final clinical stages is significantly limited. The subclinical progression of PDD to the clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement, similar to heart failure with reduced ejection fraction (HFrEF), continue to be poorly understood. Prospective studies are needed to elucidate the natural history of clinical progression in patients with HFpEF and to identify the exact left ventricular remodeling mechanism that underlies this progression.

Heart failure: a complex clinical process interpreted by systems biology approach and network medicine.

Systems biology is founded on the principles of integrative computational analysis and on the data from genetic and molecular components. The integration of biological components produces interacting networks, modules and phenotypes with remarkable applications in the field of clinical medicine. The evolving concept of network medicine gives a more precise picture of the intrinsic complexity of failing myocardium and its clinical consequences. The present review is focused on the impact of network cardiology in explaining the progressive nature of the clinical syndrome of heart failure. The failing myocardium and the subsequent clinical syndrome of heart failure disclose a dynamical and non-linear system with a progressive picture of clinical deterioration. The classical description of heart failure is based on tissue pathology and clinical presentation, and lately on specific genetic and molecular modifications. This characterization of heart failure has significant limitations to recognize preclinical disease features and to explain the progressive nature of the syndrome. Systems biology detects and evaluates specific networks from molecular, cellular and tissue elements, and assesses their influence on the appearance of clinical phenotypes. The classical reductive concept of heart failure is inadequate to provide data for molecular dysfunctions or defective coordination of the interconnected network components that are central to the genesis and clinical deterioration of heart failure. In heart failure, the recognition of molecular targets within the complex networks will increase the conceptual basis of pharmacology and the identification of novel biomarkers and at the same time will accelerate the discovery of new drugs.

Systems biology and biomechanical model of heart failure.

Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies.

Incisional hernia postrepair of abdominal aortic occlusive and aneurysmal disease: five-year incidence.

The aim of this study was to report the five-year incidence of incisional hernia after vascular repair of abdominal aortic occlusive (AOD) and aneurysmal disease (AAA), and to determine the factors associated with the development of this complication. Consecutive patients who underwent AAA and AOD at the University of Manitoba, Canada, between January 1999 and December 2002, were recruited and evaluated by clinical examination one week, one month and six months after the surgery, and through medical records review thereafter. The development of postoperative incisional hernia was recorded and analyzed. Two-hundred four patients, with a mean age of 70.1 years, provided consent for the study. The overall five-year incidence of incisional hernia was 69.1% and the overall median failure time was 48 months. The median failure time was 48 months for AOD and 36 months for AAA (P < 0.01). The urgent and ruptured AAA repair had a higher five-year incidence of incisional hernia as compared with AOD or elective AAA repair (P < 0.01). A history of bilateral inguinal hernia was significantly associated with incisional hernia (P < 0.05). Men and patients who were 65 years and older had a higher five-year incidence of incisional hernia (P < 0.01). Age ≥65 years, male gender, hypertension and past bilateral inguinal hernia repair double the risk for the development of incisional hernia (hazard ratio = 2.1. 2.2, 1.7 and 2.8, respectively). In conclusion, the five-year incidence of incisional hernia after vascular repair of AOD or AAA is 69.1%, and tends to occur late after vascular repair.

A conceptual paradigm of heart failure and systems biology approach.

PURPOSE OF REVIEW: The understanding of heart failure syndrome is increased and the interpretation of the related underlying mechanisms is improved by the integrated molecular, network and phenotype analyses of systems biology methodology. Heart failure can be explained as a complex, unstable, adaptive and self-organized biological phenomenon with intrinsic regulatory mechanisms. RECENT FINDINGS: The systems biology approach, that synthesizes information from biological molecules and networks involved in heart failure progression, leads from the regulatory modules of natriuretic peptide system and RAAS, to a more comprehensive network-based biological system with clinical significance. This kind of biological and clinical analysis of heart failure is based: a) in three fields of research or disciplines, modeling, omics and complex networks, and b) in the two directions of systems biology, functional composition (bottom-up direction) and functional decomposition (top-down direction). SUMMARY: This systems biology approach, with a new conceptual paradigm of heart failure progression and mechanisms, is explaining the physiological and pathological conditions of heart failure with an integrated and more meaningful method.

Difference in the topography of atherosclerosis in the left versus right coronary artery in patients referred for coronary angiography.

BACKGROUND: We sought to determine the difference in the localization of coronary artery disease (CAD) between the left and right coronary artery system and investigate the effect of sex and age on that difference. METHODS: We retrospectively analyzed 17,323 consecutive angiographies from January 1st, 1984 to December 31st, 2003. The demographic parameters, in particular age and sex of the investigated cases as well as the angiographic results were recorded and summarized. RESULTS: Of 13,305 cases with CAD, 861 (6.5%) had right coronary artery (RCA)-only disease, 4,621 (34.7%) had left coronary artery (LCA)-only disease, while 7,823 (58.8%) cases had concomitant RCA and LCA disease. LCA-only disease was more frequent than RCA-only disease [LCA-only/RCA-only odds ratio (OR): 5.37, 95% CI: 4.99 to 5.77, p < 0.001]. Women were more likely to have LCA-only disease (men/women OR 0.75 95% CI: 0.68 to 0.82, p < 0.001) compared with men who were more likely to present with concomitant RCA and LCA disease (men/women OR 1.33 95% CI: 1.21 to 1.45, p < 0.001). RCA-only and LCA-only disease were both more frequent in patients aged from 51 to 60 years, while concomitant RCA and LCA disease in patients between 61 and 70 years of age. CONCLUSIONS: LCA-only disease is more frequent than RCA-only disease. Men have a higher probability than women to present with concomitant RCA and LCA disease while women are more likely than men to be found with LCA-only disease.

Metabolic syndrome and angiographic coronary artery disease prevalence in association with the Framingham risk score.

BACKGROUND: The association of metabolic syndrome with coronary artery disease (CAD) has been studied extensively. However, little is known about the effect of Framingham risk score (FRS) and metabolic syndrome components on the association of metabolic syndrome with angiographically significant CAD. Our aim was to investigate whether that relationship is influenced by individual's 10-year CAD risk profile as assessed by FRS. Furthermore, we sought to elucidate whether metabolic syndrome is associated with angiographically significant CAD independently of its individual components. METHODS: We studied a consecutive sample of 150 patients undergoing coronary angiography for the evaluation of chest pain. Metabolic syndrome was defined according to the revised National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, and the 10-year CAD risk was estimated by the FRS. RESULTS: Metabolic syndrome patients had a 2-fold higher CAD prevalence compared to those without metabolic syndrome [odds ratio (OR), 2.004; 95% confidence interval (CI), 1.029-3.905] but this finding was attenuated after adjustment for FRS (OR, 1.770; 95% CI, 0.872-3.594). Stratification of patients into three groups according to FRS revealed that metabolic syndrome predictive ability was confined in those being at <10% 10-year CAD risk. Including metabolic syndrome and its individual components into the same logistic regression model, only the glucose criterion was an independent predictor of angiographically significant CAD (OR, 4.137; 95% CI, 1.477-11.583). CONCLUSIONS: Metabolic syndrome is an independent determinant of angiographically significant CAD only among those individuals at low 10-year risk for future coronary events. Individual components of the syndrome, such as impaired fasting glucose, have a stronger association with CAD than the syndrome as a whole.

Prevalence, clinical correlates and treatment of permanent atrial fibrillation among the elderly: insights from the first prospective population-based study in rural Greece.

To investigate the prevalence of permanent atrial fibrillation (AF), its clinical associated conditions and treatment status in the elderly population in rural Greece. 720 people (46.1% males) older than 65 years (mean age: 72.5 +/- 5.7 years) living in four villages in rural Greece were screened with an electrocardiogram (response rate: 90.5%) for the presence of permanent AF. They underwent a physical examination, including blood pressure (BP) measurement, and body mass index (BMI) calculation, in addition to an interview about their medical history, physical activity, smoking habits, alcohol consumption and medication use. Subjects with AF for whom anticoagulants were contraindicated were identified and stroke risk stratification was performed using the CHADS2 algorithm. The prevalence of permanent AF was 5% (6.6% among men and 3.6% among women) and it increased with age. In the entire population, ECG evidence of myocardial ischaemia and ventricular premature beats were independently associated with the presence of permanent AF (OR 5.266; 95% CI 2.22-12.49, P = 0.0001 and OR 2.61; 95% CI 1.059-6.432, P = 0.037, respectively), while female sex was independently associated with the absence of the AF (OR 0.327; CI 0.147-0.729, P = 0.006). From those patients who were eligible for anticoagulation, 40.6% were treated with anticoagulants, 34.3% were given antiplatelets therapy and the rest received no antithrombotic treatment. This is the first prospective study demonstrating the prevalence, clinical correlates and treatment status of permanent AF in Greece. These results confirm the high prevalence of permanent AF among the elderly and underscore the issue regarding anticoagulants underutilization.

The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.

Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta(1)-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta(2)-ARs and alpha(1)-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome.

Adult congenital heart disease investigated with cardiac catheterization over a 20-year period.

BACKGROUND: Recent advances in diagnosis and treatment have increased the life expectancy of patients with congenital heart disease. METHODS: To investigate the prevalence of adult congenital heart disease (ACHD) in a large registry of patients over a 20-year period, we retrospectively assessed data of 14,012 males and 4,461 females who underwent clinically indicated cardiac catheterization from 1984 to 2003. RESULTS: ACHD was recorded in 234 subjects aged from 18 to 66 years, [95 males (40.7%) and 139 females (59.3%)]. Females were more likely to present with ACHD than males (p<0.001). Atrial septal defect was the most common defect (43.3%) followed by partial anomalous pulmonary venous return (12.0%), pulmonary valve stenosis (11.3%) ventricular septal defect (8.0%), coarctation of aorta (5.5%) patent ductus arteriosus (4.0%) and Fallot's tetralogy (3.3%). Atrial septal defect was more common in females (p<0.01), while pulmonary valve stenosis was more frequent in males (p<0.05). No difference across sexes was found in the other forms of ACHD. Females with ACHD were significantly older than males at the time of catheterization (median age 41 years, interquartile range 26 to 53 years vs. median age 35 years, interquartile range 22 to 48 years, p<0.05). CONCLUSIONS: In adulthood ACHD is found more commonly in females and is diagnosed later in life than in males. Atrial septal defect is the most prevalent form of ACHD and occurs most commonly in females.

Current drugs and medical treatment algorithms in the management of acute decompensated heart failure.

BACKGROUND: Acute decompensated heart failure (ADHF) is associated with increased hospitalization rates and high in-hospital mortality, and has emerged as a major public health problem over the past decade. In recent years, several new drugs and therapeutic approaches have failed to reduce short- and long-term morbidity and mortality in ADHF patients. New agents and strategies are under investigation in order to effectively reduce the mortality and morbidity in these patients. OBJECTIVE: To review the recent experimental and clinical evidence on existing therapeutic algorithms and investigational drugs used for the treatment of ADHF. METHODS: A systematic search of peer-reviewed publications was performed on Medline and EMBASE from January 1995 to January 2009. The results of unpublished trials were obtained from presentations at national and international meetings. RESULTS: Renal dysfunction and low systolic blood pressure (SBP) remain the main predictors of adverse clinical outcomes in ADHF patients. Thus, therapy should be tailored according to the level of SBP at admission, renal function and fluid retention. ADHF due to hypertensive disease should be treated with intravenous vasodilators and diuretics at low doses, while patients with low output syndrome need mainly inotropic support. However, few agents currently employed in the treatment of ADHF have been shown in large prospective randomized clinical trials to improve clinical outcomes. The calcium sensitizer levosimendan is superior than traditional inotropes in improving central hemodynamics and neurohormonal response in ADHF patients, without increasing their long-term survival. Vasopressin antagonists also seem to be promising and safe drugs in the treatment of ADHF patients, facilitating diuresis on top of standard-care therapy. Encouraging novel therapies include adenosine receptor antagonists, ularitide, istaroxime, cardiac myosin activators and relaxin. CONCLUSIONS: Clinical scenarios based on SBP are essential determinants of therapeutic approaches used for the management of ADHF. Traditional drugs (diuretics, dobutamine and milrinone) have several limitations in real clinical practice, and increase mortality rates. Investigational drugs targeting to novel pathophysiologic concepts are promising treatment approaches and ongoing trials will define their clinical efficacy and safety.

Impaired right ventricular systolic function demonstrated by reduced atrioventricular plane displacement in adults with Marfan syndrome.

AIMS: The right ventricle (RV) ejects the same volume of blood at the same rate as the left ventricle (LV). Mild LV dysfunction has been demonstrated in Marfan syndrome (MFS). However, little attention has been paid to the functioning of the RV. The aim of this study was to assess RV function in unoperated adult MFS patients. METHODS AND RESULTS: In 66 unoperated (15-58 years) MFS patients and 61 controls, rate of pressure rise (dp/dt) in RV, and tricuspid annular motion (TAM) were studied using conventional echocardiography and tissue Doppler imaging (TDI). When compared with controls, MFS patients showed impaired RV systolic function as expressed by a reduced dp/dt, TAM obtained by M-mode echocardiography, and peak TDI systolic velocities at the basal lateral wall (745.36+/-37.85 vs. 1103.30+/-27.30 mmHg, P<0.001; 2.2+/-0.05 vs. 2.5+/-0.05 cm, P<0.001; and 0.13+/-0.002 vs. 0.16+/-0.002 m/s, P<0.001, respectively). CONCLUSION: This study demonstrated a primary impairment of RV systolic function in MFS. This is the first study to report RV dysfunction in MFS. Such data could prove valuable during the peri-operative and long-term medical management of MFS patients.

Low-Density Lipoprotein concentration in the normal Left Coronary Artery tree.

BACKGROUND: The blood flow and transportation of molecules in the cardiovascular system plays a crucial role in the genesis and progression of atherosclerosis. This computational study elucidates the Low Density Lipoprotein (LDL) site concentration in the entire normal human 3D tree of the LCA. METHODS: A 3D geometry model of the normal human LCA tree is constructed. Angiographic data used for geometry construction correspond to end-diastole. The resulted model includes the LMCA, LAD, LCxA and their main branches. The numerical simulation couples the flow equations with the transport equation applying realistic boundary conditions at the wall. RESULTS: High concentration of LDL values appears at bifurcation opposite to the flow dividers in the proximal regions of the Left Coronary Artery (LCA) tree, where atherosclerosis frequently occurs. The area-averaged normalized luminal surface LDL concentrations over the entire LCA tree are, 1.0348, 1.054 and 1.23, for the low, median and high water infiltration velocities, respectively. For the high, median and low molecular diffusivities, the peak values of the normalized LDL luminal surface concentration at the LMCA bifurcation reach 1.065, 1.080 and 1.205, respectively. LCA tree walls are exposed to a cholesterolemic environment although the applied mass and flow conditions refer to normal human geometry and normal mass-flow conditions. CONCLUSION: The relationship between WSS and luminal surface concentration of LDL indicates that LDL is elevated at locations where WSS is low. Concave sides of the LCA tree exhibit higher concentration of LDL than the convex sides. Decreased molecular diffusivity increases the LDL concentration. Increased water infiltration velocity increases the LDL concentration. The regional area of high luminal surface concentration is increased with increasing water infiltration velocity. Regions of high LDL luminal surface concentration do not necessarily co-locate to the sites of lowest WSS. The degree of elevation in luminal surface LDL concentration is mostly affected from the water infiltration velocity at the vessel wall. The paths of the velocities in proximity to the endothelium might be the most important factor for the elevated LDL concentration.

Gender-specific differences in hypertension prevalence, treatment, control, and associated conditions among the elderly: data from a Greek population.

PURPOSE: In the present study we sought to assess the gender-specific prevalence, treatment rates, and control of hypertension, as well as to identify its associated conditions and additional cardiovascular (CV) risk factors, in a Greek population aged > or = 65 years old. METHODS: This is a population-based study including a clinical interview, an ECG recording, and blood pressure (BP) measurements by sphygmomanometer. RESULTS: The overall prevalence of hypertension was 83.3%, higher in females and increasing with age. In males, hypertension was independently associated with increased body mass index (BMI), a history of stroke, and myocardial infarction, while in females increased age, BMI, and a history of diabetes were independently associated with hypertension. A considerable proportion of hypertensives were treated (77.3%), while an effective control of BP was achieved in 42.5% of treated subjects. Despite the fact that hypertension treatment rates did not differ between the genders, control rates were lower among females. Finally, more hypertensive females presented additional CV risk factors than normotensives. CONCLUSION: Elderly females exhibit a higher prevalence of hypertension and are characterized by lower hypertension control compared to hypertensive males.

Sex-related differences in the angiographic results of 14,500 cases referred for suspected coronary artery disease.

OBJECTIVE: To investigate sex differences of angiographic results in patients undergoing coronary angiography for suspected coronary artery disease (CAD). METHODS: We retrospectively assessed the coronary angiograms of 2840 women and 11,610 men from 1984 to 2003. We examined sex differences regarding the extent and topography of significant stenoses (SS) (i.e. > or =50% of the luminal diameter), the age of presentation, and the variation of the annual frequency of the angiographic findings across the study period. RESULTS: SS were recorded in 1817 women and 9984 men (64 vs. 86%, P<0.001). Women were more likely to present with nonsignificant stenoses (i.e. <50% of the luminal diameter) or angiographically normal coronaries (P<0.001). In patients with SS, women had a higher chance to present with one-vessel (P<0.001) or peripheral branches (P<0.05) disease, whereas men were more likely to have two-vessel disease (P<0.005). Compared with men, women were less likely to exhibit SS in the right coronary artery (P<0.001), left circumflex (P<0.01), intermediate artery (P<0.01) and first obtuse marginal branch (P<0.01). No significant sex differences were recorded in the frequency of SS in the left anterior descending artery. In patients aged from 31 to 60 years, SS were more common in men, whereas in patients 61-80 years of age SS were more common in women. The annual frequency of SS in women gradually increased throughout the study period. CONCLUSION: SS were less common in women, were found later in life, and were less likely to involve the right coronary artery, left circumflex, intermediate artery and first obtuse marginal branch than in men.

In vivo comparative study of linear versus geometrically correct three-dimensional reconstruction of coronary arteries.

Although conventional linear 3-dimensional (3D) reconstruction of coronary arteries by intravascular ultrasound has been widely used for the assessment of plaque volume and progression; the volumetric error (VE) that is produced has not been adequately studied. Linear and geometrically correct 3D reconstruction was applied in 16 coronary arterial segments from 9 patients. Using geometrically correct reconstruction as reference, VE was assessed in 1-mm-long arterial slices. Although for the entire length of the coronary arteries VEs for lumen, external elastic membrane (EEM), and intima-media volumes were minimal (lumen VE 0.4%, -0.8 to 1.8; EEM VE 0.3%, -0.9 to 1.9; intima-media VE 0.4%, -1.4 to 2.2), the VE in each arterial slice exhibited a large variation from -15.6% to 36.2% for lumen volume, from -12.9% to 33.1% for EEM volume, and from -17.2% to 46.7% for intima-media volume, suggesting that linear reconstruction over- or underestimates the true arterial volumes. Lumen VE, EEM VE, and intima-media VE were also significantly higher in curved arterial subsegments than in relatively straight arterial subsegments (p <0.05). In conclusion, in highly curved arterial subsegments, the VE that is produced by linearly stacking the intravascular ultrasound images may be not negligible. Geometrically correct reconstruction of coronary arteries provides more reliable arterial reconstructions and plaque volume measurements. It is anticipated that clinical application of this technique will contribute to more accurate follow-up of the progression of atherosclerosis and assessment of arterial remodeling.