Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

Intra-myocardial growth hormone administration ameliorates arrhythmogenesis during ischemia-reperfusion in rats.

Growth hormone, currently under evaluation for the prevention of left ventricular remodeling post-myocardial infarction, displays antiarrhythmic properties in the acute setting. However, it is uncertain whether these actions are retained after ischemia/reperfusion. Using implanted telemetry transmitters, we examined the effects of prolonged, intra-myocardial growth hormone administration in conscious rats. During a 24-h observation period, ventricular tachyarrhythmias and sympathetic activation were attenuated in treated rats, whereas infarct-size was unchanged. These findings call for further study on the antiarrhythmic effects of growth hormone and on the underlying mechanisms.

Determinants of pulmonary hypertension in patients with Beta-thalassemia major and normal ventricular function.

BACKGROUND/AIMS: We sought to define the incidence and predictive factors of pulmonary hypertension in ß-thalassemia major. METHODS: We studied 27 consecutive patients (19 male, 38 ± 9 years of age) with ß-thalassemia major. All the patients had normal (left and right) ventricular (systolic and diastolic) function and underwent echocardiographic assessment of pulmonary artery systolic pressure. Univariate regression and discriminant function analyses were used to identify predictive factors of pulmonary hypertension. RESULTS: Pulmonary hypertension was observed in 18.5% of the patients, but clinically significant disease was detected in only 3.7%. A total of 14 (51.8%) patients had been receiving a combined administration of deferoxamine and deferiprone for 7.0 ± 1.3 years. Amidst a large number of variables examined, ferritin levels and delayed onset of chelation therapy were the only predictors of pulmonary hypertension. CONCLUSION: Pulmonary hypertension in ß-thalassemia major is relatively infrequent and generally mild due to improved chelation therapy. The role of hemochromatosis in pulmonary hypertension development merits further study.

Chronic skeletal muscle ischemia preserves coronary flow in the ischemic rat heart.

Chronic skeletal muscle ischemia confers cytoprotection to the ventricular myocardium during infarction, but the underlying mechanisms remain unclear. Although neovascularization in the left ventricular myocardium has been proposed as a possible mechanism, the functional capacity of such vessels has not been studied. We examined the effects of chronic limb ischemia on infarct size, coronary blood flow, and left ventricular function after ischemia-reperfusion. Hindlimb ischemia was induced in 65 Wistar rats by excision of the left femoral artery, whereas 65 rats were sham operated. After 4 wk, myocardial infarction was generated by permanent coronary artery ligation. Infarct size was measured 24 h postligation. Left ventricular function was evaluated in isolated hearts after ischemia-reperfusion, 4 wk after limb ischemia. Neovascularization was assessed by immunohistochemistry, and coronary flow was measured under maximum vasodilatation at different perfusion pressures before and after coronary ligation. Infarct size was smaller after limb ischemia compared with controls (24.4 ± 8.1% vs. 46.2 ± 9.5% of the ventricle and 47.6 ± 8.7% vs. 80.1 ± 9.3% of the ischemic area, respectively). Indexes of left ventricular function at the end of reperfusion (divided by baseline values) were improved after limb ischemia (developed pressure: 0.68 ± 0.06 vs. 0.59 ± 0.05, P = 0.008; maximum +dP/dt: 0.70 ± 0.08 vs. 0.59 ± 0.04, P = 0.004; and maximum -dP/dt: 0.86 ± 0.14 vs. 0.72 ± 0.10, P = 0.041). Coronary vessel density was markedly higher (P = 0.00021) in limb ischemic rats. In contrast to controls (F = 5.65, P = 0.00182), where coronary flow decreased, it remained unchanged (F = 1.36, P = 0.28) after ligation in limb ischemic rats. In conclusion, chronic hindlimb ischemia decreases infarct size and attenuates left ventricular dysfunction by increasing coronary collateral vessel density and blood flow.

Endothelin-B receptors and ventricular arrhythmogenesis in the rat model of acute myocardial infarction.

The arrhythmogenic effects of endothelin-1 (ET-1) are mediated via ETA-receptors, but the role of ETB-receptors is unclear. We examined the pathophysiologic role of ETB-receptors on ventricular tachyarrhythmias (VT/VF) during myocardial infarction (MI). MI was induced by coronary ligation in two animal groups, namely in wild-type (n = 63) and in ETB-receptor-deficient (n = 61) rats. Using a telemetry recorder, VT/VF episodes were evaluated during phase I (the 1st hour) and phase II (2-24 h) post-MI, with and without prior beta-blockade. Action potential duration at 90% repolarization (APD90) was measured from monophasic epicardial recordings and indices of sympathetic activation were assessed using fast-Fourier analysis of heart rate variability. Serum epinephrine and norepinephrine were measured with radioimmunoassay. MI size was similar in the two groups. There was a marked temporal variation in VT/VF duration; during phase I, it was higher (p = 0.0087) in ETB-deficient (1,519 +/- 421 s) than in wild-type (190 +/- 34 s) rats, but tended (p = 0.086) to be lower in ETB-deficient (4.2 +/- 2.0 s) than in wild-type (27.7 +/- 8.0 s) rats during phase II. Overall, the severity of VT/VF was greater in ETB-deficient rats, evidenced by higher (p = 0.0058) mortality (72.0% vs. 32.1%). There was a temporal variation in heart rate and in the ratio of low- to high-frequency spectra, being higher (<0.001) during phase I, but lower (p < 0.05) during phase II in ETB-deficient rats. Likewise, 1 h post-MI, serum epinephrine (p = 0.025) and norepinephrine (p < 0.0001) were higher in ETB-deficient (4.20 +/- 0.54, 14.24 +/- 1.39 ng/ml) than in wild-type (2.30 +/- 0.59, 5.26 +/- 0.67 ng/ml) rats, respectively. After beta-blockade, VT/VF episodes and mortality were similar in the two groups. The ETB-receptor decreases sympathetic activation and arrhythmogenesis during the early phase of MI, but these effects diminish during evolving MI.

Improved 'cut-down' technique for transvenous pacemaker lead implantation.

AIMS: We improved the cut-down approach aiming at minimizing the subclavian/axillary vein puncture during implantation of permanent pacemaker leads. METHODS AND RESULTS: We incorporated previously reported refinements of the cut-down approach, i.e. the use of a hydrophilic guidewire when direct lead insertion failed and cannulation of retro-pectoral veins in cases of insufficient calliper of the cephalic vein. In addition, we introduced two further techniques, namely the simultaneous use of two guidewires and the use of stiff angiography guidewires. The efficacy of this integrated 'no-puncture' strategy was assessed in the first consecutive 200 patients and was compared with the 'standard' approach in an equal number of consecutive preceding implantations. Puncture was required more often (P < 0.0001) in the 'standard'-approach group (40/200; 20.0%). The 'no-puncture' policy was successful in 192/200 (96%) of implantations over a course of 40 months with absence of major complications. This was due to more frequent (P < 0.0001) use of hydrophilic guidewires (49.0% vs. 9.5% of cases), as well as due to cannulation of retro-pectoral veins (3.5%), use of a second guidewire (16.0%) and use of stiff guidewires (7.0%). CONCLUSION: The improved cut-down approach obviates subclavian/axillary puncture in the vast majority of cases and improves the safety of pacemaker implantation.

CPVT: Arrhythmogenesis, Therapeutic Management, and Future Perspectives. A Brief Review of the Literature.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a primary electrical disease characterized by a normal resting electrocardiogram and induction of malignant arrhythmias during adrenergic stress leading to syncope or sudden cardiac death (SCD). CPVT is caused by mutations in the cardiac ryanodine receptor (RyR2) or in the sarcoplasmic reticulum protein calsequestrin 2 genes (CASQ2). The RyR2 mutations are responsible for the autosomal dominant form of CPVT, while CASQ2 mutations are rare and account for the recessive form. These mutations cause a substantial inballance in the homeostasis of intracellular calcium resulting in polymorphic ventricular tachycardia through triggered activity. Beta blockers were for years the cornerstone of therapy in these patients. Sodium channel blockers, especially flecainide, have an additive role in those not responding in beta blockade. Implantation of defibrillators needs a meticulous evaluation since inappropriate shocks may lead to electrical storm. Finally, cardiac sympathetic denervation might also be an alternative therapeutic option. Early identification and risk stratification is of major importance in patients with CPVT. The aim of the present review is to present the arrhythmogenic mechanisms of the disease, the current therapies applied and potential future perspectives.

Effects of dual endothelin receptor blockade on sympathetic activation and arrhythmogenesis during acute myocardial infarction in rats.

The effects of dual (ETA and ETB) endothelin receptor blockade on ventricular arrhythmogenesis during acute myocardial infarction are not well defined. We randomly allocated Wistar rats to bosentan (100 mg/kg daily, n=24), a dual endothelin receptor antagonist, or vehicle (n=23). After 7 days of treatment, myocardial infarction was induced by permanent coronary ligation. Ventricular tachyarrhythmias were evaluated for 24 h following ligation, using a miniature telemetry electrocardiogram recorder. Action potential duration was measured from monophasic epicardial recordings and sympathetic activation was assessed by heart rate variability and catecholamine serum level measurements. Compared to controls (1012+/-185 s), bosentan (59+/-24 s) markedly decreased (P<0.00001) the total duration of ventricular tachyarrhythmias during the delayed (1-24 h) phase post-ligation, with a modest effect during the early (0-1 h) phase (132+/-38 s, versus 43+/-18 s, respectively, P=0.053). Treatment did not affect infarct size or total mortality. Action potential duration at 90% repolarization prolonged in controls (from 93.1+/-4.7 ms to 117.6+/-6.9 ms), displaying increased temporal dispersion (from 4.14+/-0.45 ms to 10.42+/-2.51 ms, both P<0.001), but was preserved in treated animals. Bosentan decreased norepinephrine, but increased epinephrine levels 24 h post-ligation. Low frequency spectra of heart rate variability, an index of net sympathetic tone, were lower in bosentan-treated rats. Dual endothelin-1 receptor blockade decreases ventricular tachyarrhythmias during myocardial infarction without reperfusion, by preventing repolarization inhomogeneity. Diverse treatment effects on sympathetic activation may ameliorate the antiarrhythmic action.

Autonomic responses during acute myocardial infarction in the rat model: implications for arrhythmogenesis.

Background Autonomic responses participate in the pathophysiology of acute myocardial infarction, but their precise time course remains unclear. Here, we investigated the autonomic activity and ventricular tachyarrhythmias in conscious, unrestrained rats post-infarction. Methods The left coronary artery was ligated in 12 Wistar rats, and six rats were sham operated, followed by 24-h electrocardiographic recording via implanted telemetry transmitters. Sympathetic activity was assessed by detrended fluctuation analysis and vagal activity by time- and frequency-domain analysis of heart rate variability. The duration of the ventricular tachyarrhythmias was measured, and voluntary motion served as a marker of heart failure. Results In sham-operated rats, heart rate and sympathetic activity remained low, whereas vagal activity rose progressively after the fourth hour. Post-ligation, medium-sized antero-septal necrosis was observed, reaching ~20% of the left ventricular volume; tachyarrhythmias were frequent, displaying a bimodal curve, and motion counts were low. Vagal activity decreased early post-ligation, coinciding with a high incidence of tachyarrhythmias, but tended to rise subsequently in rats with higher motion counts. Sympathetic activity increased after the third hour, along with a second tachyarrhythmia peak, and remained elevated throughout the 24-h period. Conclusions Vagal withdrawal, followed by gradual sympathetic activation, may participate in arrhythmogenesis during acute myocardial infarction.

Growth hormone decreases phase II ventricular tachyarrhythmias during acute myocardial infarction in rats.

GH (growth hormone) administration during acute MI (myocardial infarction) ameliorates subsequent LV (left ventricular) dysfunction. In the present study, we examined the effects of such treatment on arrhythmogenesis. A total of 53 Wistar rats (218+/-17 g) were randomized into two groups receiving two intraperitoneal injections of either GH (2 international units/kg of body weight; n=26) or normal saline (n=27), given at 24 h and 30 min respectively, prior to MI, which was generated by left coronary artery ligation. A single-lead ECG was recorded for 24 h post-MI, using an implanted telemetry system. Episodes of VT (ventricular tachyarrhythmia) and VF (ventricular fibrillation) during the first hour (phase I) and the hours following (phase II) MI were analysed. Monophasic action potential was recorded from the lateral LV epicardium at baseline and 24 h post-MI, and APD90 (action duration at 90% of repolarization) was measured. Infarct size was calculated 24 h post-MI. Infarct size and phase I VT+VF did not differ significantly between groups, but phase II hourly duration of VT+VF episodes was 82.8+/-116.6 s/h in the control group and 18.3+/-41.2 s/h in the GH group (P=0.0027), resulting in a lower arrhythmic (P=0.016) and total (P=0.0018) mortality in GH-treated animals. Compared with baseline, APD90 was prolonged significantly 24 h post-MI in the control group, displaying an increased beat-to-beat variation, but remained unchanged in the GH group. We conclude that GH decreases phase II VTs during MI in the rat. This finding may have implications in cardiac repair strategies.

Comparative antiarrhythmic efficacy of amiodarone and dronedarone during acute myocardial infarction in rats.

The effects of dronedarone, a non-iodinated derivative of amiodarone, on ventricular tachycardia and ventricular fibrillation post-myocardial infarction are not well established. Fifty-five Wistar rats were randomly allocated to a 2-week oral treatment with either vehicle (n=18), amiodarone (30 mg/kg, n=20), or dronedarone (30 mg/kg, n=17). After acute coronary artery ligation, a single-lead electrocardiogram was continuously recorded for 24 h and episodes of ventricular tachycardia/fibrillation as well as mortality rates were analysed. Monophasic action potential recordings were obtained from the left ventricular epicardium at baseline and 24 h post-myocardial infarction. Thyroid hormones and catecholamines were measured using radioimmunoassay. Thyroid function was similar in the 3 groups. Compared to controls, amiodarone and dronedarone equally decreased the number of ventricular tachycardia/fibrillation episodes by approximately 75%. Both agents prevented the increase in monophasic action potential duration and in beat-to-beat variation. Norepinephrine levels were lower only after amiodarone treatment. Despite the observed antiarrhythmic effect, total mortality did not differ between groups (38.8% in controls, 30.0% in the amiodarone group and 58.8% in the dronedarone group), because of excess bradyarrhythmic mortality in both drug groups that reached significance in the dronedarone group. Dronedarone and amiodarone display similar antiarrhythmic efficacy post-myocardial infarction, partly by preventing repolarization inhomogeneity. However, dronedarone increases bradyarrhythmic mortality possibly secondary to its negative inotropic effects.

Comparative effects of acute vs. chronic oral amiodarone treatment during acute myocardial infarction in rats.

AIMS: This study investigated whether chronic and acute amiodarone treatment has differential effects on ventricular arrhythmogenesis during acute myocardial infarction in rats. METHODS AND RESULTS: Forty-six rats were randomly allocated into vehicle, chronic oral amiodarone (30 mg/kg daily for 2 weeks), or acute amiodarone (a single dose, 100 mg/kg). Five additional rats were sham-operated. Myocardial infarction was generated by left coronary artery ligation 2 weeks after chronic treatment. Amiodarone was administered acutely 5 min post-ligation. The electrocardiogram was recorded for 24 h, using an implanted telemetry transmitter. Episodes of ventricular tachyarrhythmias and mortality rates were analysed. Serum catecholamines and infarct size were measured 24 h post-ligation. No differences were found in infarct size. Compared with controls (22.7 +/- 10.9), there was a similar reduction in the number of tachyarrhythmia episodes after either chronic (2.6 +/- 1.6, P = 0.0011) or acute (3.6 +/- 1.7, P = 0.031) amiodarone administration. Norepinephrine levels were lower only after chronic treatment. Mortality in both amiodarone treatment arms was exclusively due to bradyarrhythmia secondary to cardiac failure, whereas mortality in controls was mainly attributed to tachyarrhythmic death. CONCLUSIONS: A rapid antiarrhythmic effect was observed after acute amiodarone administration in the rat. Norepinephrine levels decreased after chronic treatment and may be associated with bradyarrhythmic mortality.

Local conduction during acute myocardial infarction in rats: Interplay between central sympathetic activation and endothelin.

We investigated the effects of autonomic dysfunction and endothelin on local conduction and arrhythmogenesis during myocardial infarction. We recorded ventricular tachyarrhythmias, monophasic action potentials, and activation sequences in wild-type and ETB-deficient rats displaying high endothelin levels. Central sympathetic inputs were examined after clonidine administration. Clonidine mitigated early and delayed arrhythmogenesis in ETB-deficient and wild-type rats, respectively. The right ventricular activation delay increased in clonidine-treated ETB-deficient rats and slightly decreased in wild-type rats. The left ventricular voltage rise decreased in all groups, whereas the activation delay increased mainly in clonidine-treated ETB-deficient rats. Central sympathetic activation and endothelin modulate ischemia-induced arrhythmogenesis. Ischemia alters excitability, whereas endothelin impairs local conduction, an action partly counterbalanced by central sympathetic activity.

Endothelin receptor--a blockade decreases ventricular arrhythmias after myocardial infarction in rats.

OBJECTIVE: Endothelin-1 (ET-1) production increases during acute myocardial infarction (MI) and may contribute to the genesis of ventricular tachycardia (VT) and ventricular fibrillation (VF). However, the antiarrhythmic effects of ET-1 receptor blockade, examined shortly after MI, have been debated. In the present study, we examined the effects of such treatment on VT/VF during the first 24 h post-MI. METHODS: Thirty-five Wistar rats (223+/-22 g) were randomly allocated to either the ET-1 receptor-A (ETA) antagonist BQ-123 (0.4 mg/kg, BQ-123 group, n=17), or normal saline (control group, n=18) and were subjected to coronary artery ligation. A single-lead electrocardiogram was continuously recorded for 24 h post-MI, using an implanted telemetry system, and episodes of VT/VF were analyzed. Monophasic action potential (MAP) recordings were obtained from the left (LV) and right (RV) ventricular epicardium at baseline, 5 min after treatment and 24 h post-MI. RESULTS: There were 15.94+/-19.35 episodes/h/rat of VT/VF in the control group and 1.66+/-2.22 in the BQ-123 group (p=0.010), resulting in a lower (p=0.030) arrhythmic mortality in treated animals. The mean episode duration was 7.40+/-7.16 s for the control group and 2.30+/-1.37 s for the BQ-123 group (p=0.011). The maximum decrease in VT/VF was observed during the 1st, 5th and 6th hours post-MI. In the control group, LV MAP duration increased 24 h post-MI, displaying an increased beat-to-beat variation, but remained unchanged in the BQ-123 group. CONCLUSION: Acute ETA blockade reduces the incidence of VT/V F during the first 24-h post-MI in the rat, through a decrease in the dispersion of repolarization.

Effects of central sympathetic activation on repolarization-dispersion during short-term myocardial ischemia in anesthetized rats.

AIMS: Sympathetic activation during myocardial ischemia enhances arrhythmogenesis, but the underlying pathophysiologic mechanisms remain unclear. We investigated the central sympathetic effects on ventricular repolarization during the early-period post-coronary artery occlusion. MAIN METHODS: We studied 12 Wistar rats (254±2 g) for 30 min following left coronary artery ligation, with (n=6) or without (n=6) pretreatment with the central sympatholytic agent clonidine. Mapping of left and right ventricular epicardial electrograms was performed with a 32-electrode array. As an index of sympathetic activation, heart rate variability in the frequency domain was calculated. Heart rate and repolarization duration were measured with a custom-made recording and analysis software, followed by calculation of intra- and inter-ventricular dispersion of repolarization. KEY FINDINGS: Heart rate and heart rate variability indicated lower sympathetic activation in clonidine-treated rats during ischemia. Repolarization duration in the left ventricle prolonged after clonidine at baseline, independently of heart rate, but no differences were present 30 min post-ligation. Dispersion of repolarization in the right ventricle remained stable during ischemia, whereas it increased in the left ventricle, equally in both groups. A similar trend was observed for inter-ventricular dispersion, without differences between groups. SIGNIFICANCE: In addition to intra-ventricular repolarization-dispersion, anterior-wall myocardial ischemia may also increase inter-ventricular repolarization-dispersion. Progressive central sympathetic activation occurs during myocardial ischemia, but it does not affect intra- or inter-ventricular dispersion of ventricular repolarization during the early phase. Further research is warranted on the potential effects during subsequent time-periods.

Central Sympathetic Activation and Arrhythmogenesis during Acute Myocardial Infarction: Modulating Effects of Endothelin-B Receptors.

Sympathetic activation during acute myocardial infarction (MI) is an important arrhythmogenic mechanism, but the role of central autonomic inputs and their modulating factors remain unclear. Using the in vivo rat-model, we examined the effects of clonidine, a centrally acting sympatholytic agent, in the presence or absence of myocardial endothelin-B (ETB) receptors. We studied wild-type (n = 20) and ETB-deficient rats (n = 20) after permanent coronary ligation, with or without pretreatment with clonidine. Cardiac rhythm was continuously recorded for 24 h by implantable telemetry devices, coupled by the assessment of autonomic and heart failure indices. Sympathetic activation and arrhythmogenesis were more prominent in ETB-deficient rats during the early phase post-ligation. Clonidine improved these outcomes throughout the observation period in ETB-deficient rats, but only during the delayed phase in wild-type rats. However, this benefit was counterbalanced by atrioventricular conduction abnormalities and by higher incidence of heart failure, the latter particularly evident in ETB-deficient rats. Myocardial ETB-receptors attenuate the arrhythmogenic effects of central sympathetic activation during acute MI. ETB-receptor deficiency potentiates the sympatholytic effects of clonidine and aggravates heart failure. The interaction between endothelin and sympathetic responses during myocardial ischemia/infarction and its impact on arrhythmogenesis and left ventricular dysfunction merits further investigation.

Arrhythmogenesis after acute myocardial necrosis with and without preceding ischemia in rats.

BACKGROUND: The relative role of acute myocardial ischemia and infarction in ventricular arrhythmogenesis is incompletely understood. We compared the arrhythmia pattern after ischemia/infarction to that observed after direct myocardial necrosis without preceding ischemia in rats. METHODS: Coagulation necrosis was induced in Wistar rats (n=20, 280±3 g) by radiofrequency current application (for 15 s) from a 4-mm-tip ablation catheter. Myocardial infarction was induced by coronary artery ligation with (n=10) or without (n=10) reperfusion. Using 24-h telemetry recording, we examined ventricular arrhythmias, voluntary motor activity and indices of sympathetic activation. RESULTS: The coagulation-necrosis volume was 24.4%±0.6%, comparable to the infarct size in the absence of reperfusion. Acute left ventricular failure and sympathetic activation were similar in the three groups. Coagulation necrosis induced ventricular fibrillation immediately, followed by a second peak after ∼1 h. Reperfusion decreased ventricular arrhythmias, whereas a second arrhythmogenic period (between the third and the eight hour) was noted in non-reperfused infarcts (mainly monomorphic ventricular tachycardia). CONCLUSIONS: Distinct arrhythmia patterns occur after myocardial infarction (with or without reperfusion) and after direct necrosis. They are not produced by differences in sympathetic activation and are likely related to the evolution of myocardial injury. The necrosis rat model may be useful in studies of arrhythmogenesis.

Novel next-generation sequencing and networks-based therapeutic targets: realistic and more effective drug design and discovery.

Reductionist approaches and linear experimentation have expanded our knowledge in biology over the past century and represent till today the basis for the prevention, diagnosis and treatment of all diseases in clinical medicine. However, major diseases still remain incurable. All currently available drugs target a single gene or protein ignoring dynamics of highly complex biomolecular networks driving collectively gene expression and cell's function. No surprise that most of these agents don't cure common multifactorial disorders while available diagnostics and biomarkers are unable to predict tissue-specific cellular reactions to genetic and epigenetic alterations as well as drug effects in individual patients and populations. In this review we discuss latest advances in genome localization of genomewide association studies variants, whole genome/whole exome data analysis, protein-protein interactions networks databases, and more recent Encyclopedia of DNA Elements (ENCODE) data on regulatory networks including transcription factors-binding sites and genegene interactions. In addition challenges for a comprehensive analysis of intracellular signaling pathways network is described. Such analysis, despite genome-scale scarce data and lack of sophisticated methods to predict dynamics of a global hierarchy or 'cloud"of biological networks, appears essential for the discovery of new therapeutic network targets, which could dramatically increase treatment efficacy, while minimizing at the same time major adverse effects. In this review we describe potential and challenges of modern approaches for applying next-generation sequencing and patient's personal whole genome analysis for personalized treatment using available drugs. Additionally, we report why the discovery of next-generation drugs should be shifted from our linear world to motifsand network-associated disease integrating genome science and dynamics of network biology advances.