Systolic Ejection Time Research Articles

Evaluation of global function of the heart in scleroderma patients.

Scleroderma is a connective tissue disease characterized by diffuse vascular lesions and fibrosis of the skin and major organs including lungs, kidneys, and heart. When cardiac involvement is clinically evident, it is recognized as a poor prognostic factor. The early detection of cardiac involvement in scleroderma would be desirable both for implementation of preventive measures in the early stages of the disease and for optimal treatment. Left (LV) and right (RV) ventricular function were examined in 31 scleroderma patients and 21 healthy controls. Conventional and tissue Doppler echocardiography was used to evaluate systolic and diastolic function. Systolic indices including systolic (S) velocity, isovolumetric acceleration (IVA), ejection time (ET), and isovolumetric contraction time (IVCT) were measured. Early diastolic (E) velocity, late diastolic (A) velocity, E/A and E'/A' ratios, isovolumetric relaxation time (IVRT), and deceleration time (DT) were the diastolic measurements obtained. Myocardial performance index (Tei index) calculated by 2 different methods was used to assess global ventricular function. In our study; mitral S velocity, biventricular ET, E', E/A, E'/A', RV IVA, LV IVA, and tricuspid S velocity were significantly lower in scleroderma patients. Mitral DT, IVCT, and biventricular IVRT, were significantly higher in scleroderma patients (P<0.0001). In addition, RV and LV Tei indices were significantly increased in scleroderma patients compared with the control group (P<0.0001 and P<0.001, respectively). In scleroderma patients, global function was depressed prior to the onset of clinical symptoms. Biventricular diastolic and systolic function abnormalities were also observed.

Small-Volume 7.5% NaCl Adenosine, Lidocaine, and Mg2+ Has Multiple Benefits During Hypotensive and Blood Resuscitation in the Pig Following Severe Blood Loss

Currently, there is no effective small-volume fluid for traumatic hemorrhagic shock. Our objective was to translate small-volume 7.5% NaCl adenosine, lidocaine, and Mg hypotensive fluid resuscitation from the rat to the pig. Pigs (35-40 kg) were anesthetized and bled to mean arterial pressure of 35-40 mm Hg for 90 minutes, followed by 60 minutes of hypotensive resuscitation and infusion of shed blood. Data were collected continuously. University hospital laboratory. Female farm-bred pigs. Pigs were randomly assigned to a single IV bolus of 4 mL/kg 7.5% NaCl + adenosine, lidocaine and Mg (n = 8) or 4 mL/kg 7.5% NaCl (n = 8) at hypotensive resuscitation and 0.9% NaCl ± adenosine and lidocaine at infusion of shed blood. At 60 minutes of hypotensive resuscitation, treatment with 7.5% NaCl + adenosine, lidocaine, and Mg generated significantly higher mean arterial pressure (48 mm Hg [95% CI, 44-52] vs 33 mm Hg [95% CI, 30-36], p < 0.0001), cardiac index (76 mL/min/kg [95% CI, 63-91] vs 47 mL/min/kg [95% CI, 39-57], p = 0.002), and oxygen delivery (7.6 mL O2/min/kg [95% CI, 6.4-9.0] vs 5.2 mL O2/min/kg [95% CI, 4.4-6.2], p = 0.003) when compared with controls. Pigs that received adenosine, lidocaine, and Mg/adenosine and lidocaine also had significantly lower blood lactate (7.1 mM [95% CI, 5.7-8.9] vs 11.3 mM [95% CI, 9.0-14.1], p = 0.004), core body temperature (39.3°C [95% CI, 39.0-39.5] vs 39.7°C [95% CI, 39.4-39.9]), and higher base excess (-5.9 mEq/L [95% CI, -8.0 to -3.8] vs -11.2 mEq/L [95% CI, -13.4 to -9.1]). One control died from cardiovascular collapse. Higher cardiac index in the adenosine, lidocaine, and Mg/adenosine and lidocaine group was due to a two-fold increase in stroke volume. Left ventricular systolic ejection times were significantly higher and inversely related to heart rate in the adenosine, lidocaine, and Mg/adenosine and lidocaine group. Thirty minutes after blood return, whole-body oxygen consumption decreased in pigs that received adenosine, lidocaine, and Mg/adenosine and lidocaine (5.7 mL O2/min/kg [95% CI, 4.7-6.8] to 4.9 mL O2/min/kg [95% CI, 4.2-5.8]), whereas it increased in controls (4.2 mL O2/min/kg [95% CI, 3.5-5.0] to 5.8 mL O2/min/kg [95% CI, 4.9-5.8], p = 0.02). After 180 minutes, pigs in the adenosine, lidocaine, and Mg/adenosine and lidocaine group had three-fold higher urinary output (2.1 mL//kg/hr [95% CI, 1.2-3.8] vs 0.7 mL//kg/hr [95% CI, 0.4-1.2], p = 0.001) and lower plasma creatinine levels. Small-volume resuscitation with 7.5% NaCl + adenosine, lidocaine, and Mg/adenosine and lidocaine provided superior cardiovascular, acid-base, metabolic, and renal recoveries following severe hemorrhagic shock in the pig compared with 7.5% NaCl alone.

Abstract 392: Blood Pressure Variability: An Independent Marker to Morbimortality

Introdution: The purpose of this study was to investigate the mechanisms enrolled in the relationship between increased BP variability, heart damage and mortality in different pathophysiological conditions as hypertension, heart failure and myocardial infarction. Method: Wistar rats were divided into control and S (n=10, 8weeks). Sinoaortic denervation (S) was performed using the method previously described. BP and HR were analysed using a data acquisition system. BP variability was analyzed by spectral analysis. Left ventricle systolic ejection and diastolic isovolumetric relaxation time were evaluated by echocardiography. Cardiac fibrosis and cardiomyocytes diameter were quantified by histological analysis. CO, cardiac blood flow and cardiac index were evaluated using colored microspheres. Result: No difference was observed in BP and HR (C:104±2 vs 106±2 mmHg; C:313±7 vs 329±3 bpm), while BP variability was increased after S (C:29±2 vs 46*±5 mmHg). Left ventricle systolic ejection was decreased (C:72±0.9 vs 64*±1.5%) and diastolic isovolumetric relaxation time (C:21±1 vs 35*±1 ms) was increased in S group. Moreover, it was observed a reduction in CO (C:111±5 vs 81*±5 mL/min), an increase in cardiac resistance (C:35±1.8 vs 66*±2.6 mL/min/mmHg) and a decreased in cardiac index (C:320±9.7 vs 270*±8.1 l/min/m2) in S group. Those alterations resulted in decreased myocardial blood flow (C:3.47±0.21 vs 1.6*±0.3 mL/min/g). An increased cardiomyocytes diameter (C:14.9±0.3 vs 18.9*±0.3μm),fibrosis (C:0.85±0.08 vs 3.28*±0.2%) and cardiac hypertrophy index (C:3.07±0.06 vs 3.97*±0.1) were observed in S group.The association of all those changes lead to a 72% higher mortality in animals with increased blood pressure variability.(*p&lt;0.03) Conclusion: An increased BP variability resulted in a reduced cardiac blood flow, CO and cardiac index and an increased in myocardial resistance this adaptations occours as a attempt to homeostasis maintenance. Howerer, the morphofunctional alterations showed a diastolic dysfunction, increased cardiac hypertrophy index and fibrosis as a resulted. These adjustements could be a determinant factor in cardiac damage and in mortality in different pathological conditions, independently of BP levels.

Golden Ratio is beating in our heart

Definition of systole and diastole such as systolic time intervals, electromechanical systole, and left ventricular ejection time have been studied for decades in terms of left ventricular systolic and diastolic function by using methods such as electrocardiograms, phonocardiogram and plethysmographic carotid pulse, M mode and Doppler echocardiography. Physiological systole lasts from the onset of isovolumic contraction to the peak of the ejection phase, so that physiological diastole commences as the LV pressure starts to fall [1].

A New Approach to Inotropic Therapy in the Treatment of Heart Failure

Systolic heart failure remains a leading cause of death and disability, and available pharmacologic treatments for heart failure are limited in both safety and effectiveness. Existing drugs focus on diverse mechanisms related to the pathophysiology of heart failure, yet none directly target the central feature of systolic heart failure, decreased cardiac contractility. Cardiac myosin activators, specifically omecamtiv mecarbil (formerly CK-1827452), directly activate the enzymatic pathway within the cardiac myocyte leading to ventricular contraction. This unique inotropic agent has been shown in preclinical and clinical studies to be effective in improving cardiac contractility by increasing systolic ejection time without the unwanted effects of the currently available indirect inotropic drugs. Cardiac myosin activators show great promise and may prove to be a safer and more effective therapeutic approach for the treatment of systolic heart failure.

Doppler Flow Patterns in the Right Ventricle–to–Pulmonary Artery Shunt and Neo-Aorta in Infants with Single Right Ventricle Anomalies: Impact on Outcome after Initial Staged Palliations

A Pediatric Heart Network trial compared outcomes in infants with single right ventricle anomalies undergoing Norwood procedures randomized to modified Blalock-Taussig shunt (MBTS) or right ventricle-to-pulmonary artery shunt (RVPAS). Doppler patterns in the neo-aorta and RVPAS may characterize physiologic changes after staged palliations that affect outcomes and right ventricular (RV) function. Neo-aortic cardiac index (CI), retrograde fraction (RF) in the descending aorta and RVPAS conduit, RVPAS/neo-aortic systolic ejection time ratio, and systolic/diastolic (S/D) ratio were measured early after Norwood, before stage II palliation, and at 14 months. These parameters were compared with transplantation-free survival, length of hospital stay, and RV functional indices. In 529 subjects (mean follow-up period, 3.0 ± 2.1 years), neo-aortic CI and descending aortic RF were significantly higher in the MBTS cohort after Norwood. The RVPAS RF averaged <25% at both interstage intervals. Higher pre-stage II descending aortic RF was correlated with lower RV ejection fraction (R= -0.24; P=.032) at 14 months for the MBTS cohort. Higher post-Norwood CI (5.6 vs 4.4 L/min/m(2), P= .04) and lower S/D ratio (1.40 vs 1.68, P= .01) were correlated with better interstage transplantation-free survival for the RVPAS cohort. No other Doppler flow patterns were correlated with outcomes. After the Norwood procedure, infants tolerated significant descending aortic RF (MBTS) and conduit RF (RVPAS), with little correlation with clinical outcomes or RV function. Neo-aortic CI, ejection time, and S/D ratios also had limited correlations with outcomes or RV function, but higher post-Norwood neo-aortic CI and lower S/D ratio were correlated with better interstage survival in those with RVPAS.

Abstract 4: Small-Volume 7.5% NaCl Adenocaine/Mg2+ Preserves Cardiac Function During Hypotensive Resuscitation in the Pig Following Severe Hemorrhagic Shock

Background: Cardiac rescue is critical for successful resuscitation. Previously, we reported that ~1 ml/kg 7.5% NaCl with Adenocaine (adenosine and lidocaine) and Mg2+ (ALM) successfully resuscitated rats following severe hemorrhagic shock, and that in pigs ALM significantly reduced the volume of Ringers acetate required to raise MAP to a target of 50 mmHg following 74% blood loss. The present study examines the effect of small volume 7.5% NaCl ALM on cardiac function during 60 min hypotensive resuscitation following 90 min shock in the porcine model. Methods: Pigs (35-40kg) were subjected to pressure-controlled hemorrhage at a mean arterial pressure (MAP) of 35-40mmHg for 90 min (~75% blood loss). Pigs were randomly assigned to receive either 4 ml/kg 7.5% NaCl ALM (ALM n=8) or 4 ml/kg 7.5% NaCl (Control n=8). Cardiac output (CO), stroke volume, left-ventricular pressures and hemodynamics were collected continuously. Significance *p&lt;0.05. Results: MAP, end-systolic pressure and CO were significantly higher in the ALM pigs at the end of hypotensive resuscitation (Table). The higher CO was due to a higher stroke volume (SV) maintained at a significantly lower heart rate (HR). Paradoxically dP/dtmax tended to be higher in the Control group during the first 45min of hypotensive resuscitation (p=0.066) with no difference at 60min. Systolic ejection times were significantly increased in the ALM group and inversely related to HR. There was no difference in LV end-diastolic pressure between the two groups indicating that preload was similar during hypotensive resuscitation. LV blood flow at 30min resuscitation was comparable in the two groups (Control: 2.86±0.6 vs. ALM: 4.1±1.4 ml/min/g; p=0.7) Conclusion: Superior cardiac rescue was achieved in ALM by a higher SV and CO, lower HR and longer ejection times vs Controls. Longer isovolumic contraction and ejection times may be due to suppression of SA nodal activity or rebalancing of sympathetic/parasympathetic control.

Does Initial Shunt Type for the Norwood Procedure Affect Echocardiographic Measures of Cardiac Size and Function During Infancy?

Background— The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle–pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age. Methods and Results— A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5±13.4 days), before stage II procedure (age 4.8±1.8 months), and at 14 months (age 14.3±1.2 months). Mean right ventricular ejection fraction was &lt;50% at all intervals for both groups and was higher in the RVPAS group after Norwood procedure (49±7% versus 44±8%; P &lt;0.001) but was similar by 14 months. Tricuspid and neoaortic regurgitation, diastolic function, and pulmonary artery and arch dimensions were similar in the 2 groups at all intervals. Neoaortic annulus area (4.2±1.2 versus 4.9±1.2 cm 2 /m 2 ), systolic ejection times (214.0±29.4 versus 231.3±28.6 ms), neoaortic flow (6.2±2.4 versus 9.4±3.4 L/min per square meter), and peak arch velocity (1.9±0.7 versus 2.2±0.7 m/s) were lower at both interstage examinations in the RVPAS compared with the modified Blalock-Taussig shunt group ( P &lt;0.001 for all), but all were similar at 14 months. Conclusions— Indices of cardiac size and function after the Norwood procedure are similar for modified Blalock-Taussig shunt and RVPAS by 14 months of age. Interstage differences between shunt types can likely be explained by the physiology created when the shunts are in place rather than by intrinsic differences in cardiac function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00115934.

Shortening of atrioventricular delay at increased atrial paced heart rates improves diastolic filling and functional class in patients with biventricular pacing

BackgroundUse of rate adaptive atrioventricular (AV) delay remains controversial in patients with biventricular (Biv) pacing. We hypothesized that a shortened AV delay would provide optimal diastolic filling by allowing separation of early and late diastolic filling at increased heart rate (HR) in these patients.Methods34 patients (75 ± 11 yrs, 24 M, LVEF 34 ± 12%) with Biv and atrial pacing had optimal AV delay determined at baseline HR by Doppler echocardiography. Atrial pacing rate was then increased in 10 bpm increments to a maximum of 90 bpm. At each atrial pacing HR, optimal AV delay was determined by changing AV delay until best E and A wave separation was seen on mitral inflow pulsed wave (PW) Doppler (defined as increased atrial duration from baseline or prior pacemaker setting with minimal atrial truncation). Left ventricular (LV) systolic ejection time and velocity time integral (VTI) at fixed and optimal AV delay was also tested in 13 patients. Rate adaptive AV delay was then programmed according to the optimal AV delay at the highest HR tested and patients were followed for 1 month to assess change in NYHA class and Quality of Life Score as assessed by Minnesota Living with Heart Failure Questionnaire.Results81 AV delays were evaluated at different atrial pacing rates. Optimal AV delay decreased as atrial paced HR increased (201 ms at 60 bpm, 187 ms at 70 bpm, 146 ms at 80 bpm and 123 ms at 90 bpm (ANOVA F-statistic = 15, p = 0.0010). Diastolic filling time (P < 0.001 vs. fixed AV delay), mitral inflow VTI (p < 0.05 vs fixed AV delay) and systolic ejection time (p < 0.02 vs. fixed AV delay) improved by 14%, 5% and 4% respectively at optimal versus fixed AV delay at the same HR. NYHA improved from 2.6 ± 0.7 at baseline to 1.7 ± 0.8 (p < 0.01) 1 month post optimization. Physical component of Quality of Life Score improved from 32 ± 17 at baseline to 25 ± 12 (p < 0.05) at follow up.ConclusionsIncreased heart rate by atrial pacing in patients with Biv pacing causes compromise in diastolic filling time which can be improved by AV delay shortening. Aggressive AV delay shortening was required at heart rates in physiologic range to achieve optimal diastolic filling and was associated with an increase in LV ejection time during optimization. Functional class improved at 1 month post optimization using aggressive AV delay shortening algorithm derived from echo-guidance at the time of Biv pacemaker optimization.

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study

Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. Cytokinetics Inc.

At the Source: Treating Heart Failure by Altering Muscle Motor Function

### Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure Malik et al Science . 2011;331:1439–1443. A new study in Science provides proof of the principle for directly modulating the cardiac muscle's motor, myosin, as a therapeutic target in heart failure. The human and economic tolls from heart failure (HF) are significant in both developed and undeveloped countries.1–3 Although HF can take many forms,4,5 it is most commonly associated with decreased cardiac contractility and is, therefore, referred to as systolic HF (sHF).6 Current therapeutic strategies rely on blocking neurohormonal activation by inhibiting associated pathways or by receptor blockade using either β-adrenergic or aldosterone blockers.7,8 Alternatively, some therapies are directed at increasing cardiac contractility in an effort to restore sufficient blood flow, usually by activating second messenger signaling pathways that increase cardiomyocyte calcium levels and augment sarcomere contraction.9 Both strategies suffer from a lack of specificity in that they target proteins upstream of the actual contractile events that underlie force production. Affecting important signaling pathways or receptor-ligand interactions can impact cellular function and perturb homeostasis in ways unrelated to the contractile apparatus, leading to undesirable side effects, such as hypotension, tachycardia, and even arrhythmias that can lead to sudden death.10 Recognizing the significant limitations of current therapeutic modalities, Malik and co-workers have directed their efforts at directly modulating cardiac contractility by tuning motor function at the source, the myosin heavy chain. The cardiac myosin heavy chains are encoded by two genes, MYH6 , which encodes α myosin heavy chain, and MYH7 , which encodes β myosin heavy chain, the latter being the predominant isoform in human ventricle. Although having greater than 90% amino acid homology, the two proteins differ significantly at the biochemical level. In comparison with α myosin, β myosin is relatively more efficient in force production as a function of energy consumption, with …

Assessment of Systolic Ejection Time as a Hemodynamic Marker of Incipient Bradycardic Vasovagal Syncope. A Pilot Study

Detection of markers of incipient syncope in patients with vasovagal syncope (VVS), without prodromal symptom, is still an open issue. The aim of this study was to assess the behavior of heart rate (HR) and ejection time, expressed as the percentage of the corresponding cardiac cycle (ET%), in patients with bradycardic VVS with a view to providing an alarm before the event. In 33 patients with syncope and positive tilt testing and in 33 control patients, we collected beat-to-beat data on HR, ET%, stroke volume (SV), and blood pressure (BP). The trends of HR and ET% were analyzed. A set of combined changes of HR and ET% were tested in order to select the most appropriate algorithm for detecting the incipient syncope within the 3 minutes preceding the event. In patients with positive tilt testing, BP significantly decreased at 3 minutes before and at the time of syncope (P < 0.0001). HR slowly rose at 3 minutes before syncope and then suddenly decreased at the time of syncope (P < 0.0001). The correlation between SV and ET% was r = 0.79 (P < 0.0001). SV and ET% significantly decreased throughout tilt testing (P < 0.0001). The selected setting for the algorithm provided sensitivity of 97% and specificity of 73%. The theoretical alarm was generated at least 9 and 5 seconds before syncope, respectively, in 76% and 85% of the subjects. The combined trends in HR and ET% may provide a marker of incipient bradycardic VVS in the majority of patients.

Percutaneous Balloon Aortic Valvuloplasty for Severe Aortic Stenosis: Haemodynamic Evaluation by Echocardiography

the continuity equation usingVTImeasurements. Dimensionless index (DI) was defined by LVOTVTI/AVVTI. Mean LVOT flow rate was determined by stroke volume divided by systolic ejection time. Results: A 109 patients (43% f) had LGAS (MG 31± 7mmHg) and 142 (57%) had HGAS (MG 55± 13mmHg, p< 0.001). Age, height and body weight were similar in the two groups. There were no differences in heart rate or systolic or diastolic blood pressure taken at the time of echocardiography. In comparison with HGAS, patients with LGAS had larger AVA (0.797± 0.114 vs 0.713± 0.148 cm2, p< 0.001) and higherDI (0.25± 0.06 vs 0.20± 0.04, p< 0.001), but lower LV stroke volume (71± 14 vs 85± 20ml, p< 0.001) and lower LVOT flow rate (220± 36 vs 255± 58ml/s, p< 0.001). Conclusions: In this consecutive series of patients with severe AS and preserved LVEF, LGAS was highly prevalent. Whilst LGAS patients have slightly larger AVA in comparison with HGAS, they also have smaller LV stroke volumes and lower transvalvular flow rates. This suggests that LGAS is a real phenomenonwith thepathophysiology partly explained by “less brisk” LV systolic function. doi:10.1016/j.hlc.2011.05.459

Novel Use of Intra-arterial Doppler in the Assessment of Pulmonary Artery Flow Velocities—Observations Before and After Therapy for Pulmonary Arterial Hypertension

Background: Intra-arterial Doppler is a novel technique which enables accurate assessment of blood flow haemodynamics. We evaluated the feasibility of using intra-arterial Doppler for insights into the pulmonary artery flow velocity profile in patients with pulmonary arterial hypertension (PAH), and determined the changes in the flow velocity profile following pulmonary vasodilator therapy. Methods: Intra-arterial Doppler was performed in the pulmonary arteries of seven subjects with PAH before and after six months of Bosentan therapy. The following Doppler derived parameters weremeasured: acceleration time (AcT), systolic ejection time (ET), ratio of acceleration time to systolic ejection time (AcT/ET), systolic velocity time integral (sVTI), diastolic velocity time integral (dVTI) and total velocity time integral (tVTI). Relationships between Doppler parameters and clinical response to Bosentan therapy were analysed. Results: At baseline, all PAH patients displayed a standardised pharmacological treatment and computer assisted, intensified follow-up and treatment titration). Methods: VIPER-BP is a multicentre, open-label, randomisedcontrolled trial inGPclinics throughoutAustralia comparing usual GP management with an intensive BP management strategy using three forms of valsartanbased therapy. The primary endpoint is individualised BP control at six months. Results: During recruitment 2334 patients initially screened. Of these, 2131 (91%) commenced a 28 day valsartan 80mg “run-in” phase. Subsequently, 310 patients achieved their individualBP target (15%)whilst 81patients (5.2%) were rescue randomised. Overall, 1555 patients were randomised to usual care (n= 519) or the VIPER-BP Intervention (n= 1036): comprising 948men (62%) and 607 women (aged 59± 12 vs. 60± 12 years, respectively) and 1004 patients (65%) previously treated for hypertension. Individual BP targets (systolic/diastolic BP) were as follows; 125/75mmHg (18%withproteinuria), 130/80mmHg (55% with diabetes or CVD) and 140/90mmHg (27%). Mean BP at randomisation was 149± 17/88± 11mmHg with similar BP profiles for men and women, respectively (149± 16/88± 11 versus 149± 17/87± 10mmHg). Conclusion:With study completion in August 2011, the VIPER-BP Study will provide invaluable insights into the most effective means to optimise BP levels (on an individualised basis) in the primary care setting.

Improvement of Cardiac Function by a Cardiac Myosin Activator in Conscious Dogs With Systolic Heart Failure

Therapy for chronic systolic heart failure (sHF) has improved over the past 2 decades, but the armamentarium of drugs is limited and consequently sHF remains a leading cause of death and disability. In this investigation, we examined the effects of a novel cardiac myosin activator, omecamtiv mecarbil (formerly CK-1827452) in 2 different models of heart failure. Two different models of sHF were used: (1) pacing-induced sHF after myocardial infarction (MI-sHF) and (2) pacing-induced sHF after 1 year of chronic pressure overload left ventricular hypertrophy (LVH-sHF). Omecamtiv mecarbil increased systolic function in sHF dogs, chronically instrumented to measure LV pressure, wall thickness, and cardiac output. Omecamtiv mecarbil, infused for 24 hours, induced a sustained increase without desensitization (P<0.05) in wall thickening (25+/-6.2%), stroke volume (44+/-6.5%) and cardiac output (22+/-2.8%), and decreased heart rate (15+/-3.0%). The major differences between the effect of omecamtiv mecarbil on cardiac function and the effect induced by a catecholamine, for example, dobutamine, is that omecamtiv mecarbil did not increase LV dP/dt but rather increased LV systolic ejection time by 26+/-2.9% in sHF. Another key difference is that myocardial O(2) consumption (MVO(2)), which increases with catecholamines, was not significantly affected by omecamtiv mecarbil. These results demonstrate that chronic infusion of the cardiac myosin activator, omecamtiv mecarbil, improves LV function in sHF without the limitations of progressive desensitization and increased MVO(2.) This unique profile may provide a new therapeutic approach for patients with sHF.

Cardiovascular Effects of Torcetrapib in Conscious and Pentobarbital-anesthetized Dogs

Torcetrapib is a cholesteryl ester transfer protein inhibitor with an undesired response of increasing arterial pressure in humans. Pressor responses to torcetrapib have been demonstrated in multiple preclinical species. However, these studies have not related plasma concentrations to observed effects. Our purpose was to 1) characterize the cardiovascular responses of torcetrapib in conscious and anesthetized dogs with measured plasma concentrations; and 2) characterize the hemodynamic effects contributing to hypertension using comprehensively instrumented anesthetized dogs. Torcetrapib was dosed orally (3, 30 mg/kg) and intravenously (0.01, 0.33, 0.1 mg/kg) in conscious and anesthetized dogs, respectively. Mean arterial pressure and heart rate were monitored in both models; additional parameters were measured in anesthetized dogs. Plasma drug concentrations were assessed in both models. In conscious and anesthetized dogs, torcetrapib increased mean arterial pressure 25 and 18 mm Hg and heart rate 35 and 21 beats/min, at 2.94 and 3.99 microg/mL, respectively. In anesthetized dogs, torcetrapib increased pulmonary arterial pressure, both systemic and pulmonary hypertension driven by increases in vascular resistance. The compound increased rate pressure product and myocardial contractility while decreasing time to systolic pressure recovery and ejection time. Thus, torcetrapib-induced pressor responses are mediated by systemic and pulmonary vasoconstriction and are associated with increased myocardial oxygen consumption and positive inotropy.

Left Ventricular Ejection Time on Echocardiography Predicts Long-Term Mortality in Light Chain Amyloidosis

Light chain amyloidosis (AL) is associated with high mortality. The aim was to identify echocardiographic parameters that predict AL long-term mortality. Forty-two subjects with biopsy-proven AL (43% were female; aged 61 +/- 12 years) underwent echocardiography and were followed 29 +/- 16 months (median 29.4 months). Standard echocardiographic and clinical parameters and heart failure (HF) class were tested using univariate/multivariable Cox proportional hazard regression analyses to identify markers of mortality. Twenty-three subjects died, with a 1-year mortality of 44%. Univariate predictors of mortality were HF class (P < .001), left ventricular systolic ejection time (ET) (P = .002), alkaline phosphatase (P < .001), and aspartate and alanine aminotransferase (P = .003 each). On multivariable analysis, only HF class (hazard ratio [HR] 4.86; 95% confidence interval [CI], 1.58-14.9; P = .006), ET (10 ms increase; HR 0.87; CI, 0.78-0.97; P = .01), and alkaline phosphatase (10 U/L increase; HR 1.04; CI, 1.01-1.06; P = .01) were prognostic. ET <or= 240 ms had a sensitivity of 61% and a specificity of 90% in predicting 1-year mortality and a sensitivity of 73% and a specificity of 90% in predicting 1-year cardiac mortality. AL amyloidosis was associated with high long-term mortality. Among echocardiographic and clinical parameters, only ET and alkaline phosphatase had incremental value to HF class in predicting mortality. This may be useful to identify high-risk patients.

Perioperative Hemodynamic Monitoring with Transesophageal Doppler Technology

Invasive cardiac output (CO) monitoring, traditionally performed with transpulmonary thermodilution techniques, is usually reserved for high-risk patients because of the inherent risks of these methods. In contrast, transesophageal Doppler (TED) technology offers a safe, quick, and less invasive method for routine measurements of CO. After esophageal insertion and focusing of the probe, the Doppler beam interrogates the descending aortic blood flow. On the basis of the measured frequency shift between the emitted and received ultrasound frequency, blood flow velocity is determined. From this velocity, combined with the simultaneously measured systolic ejection time, CO and other advanced hemodynamic variables can be calculated, including estimations of preload, afterload, and contractility. Numerous studies have validated TED-derived CO against reference methods. Although the agreement of CO values between TED and the reference methods is limited (95% limits of agreement: median 4.2 L/min, interquartile range 3.3-5.0 L/min), TED has been shown to accurately follow changes of CO over time, making it a useful device for trend monitoring. TED can be used to guide perioperative intravascular volume substitution and therapy, with vasoactive or inotropic drugs. Various studies have demonstrated a reduced postoperative morbidity and shorter length of hospital stay in patients managed with TED compared with conventional clinical management, suggesting that it may be a valuable supplement to standard perioperative monitoring. We review not only the technical basis of this method and its clinical application but also its limitations, risks, and contraindications.

Phase II Safety Study Evaluating the Novel Cardiac Myosin Activator, CK-1827452, in Patients with Ischemic Cardiomyopathy and Angina

Introduction: CK-1827452 (CK-452) increases systolic function by directly activating cardiac myosin. In healthy volunteers and stable heart failure (HF) patients, CK-452 infusions resulted in concentration-dependent increases in systolic ejection time (SET), stroke volume, fractional shortening, and left ventricular ejection fraction. Hypothesis: The dose limiting effect of CK-452 is related to excessive prolongation of SET, which can limit diastolic coronary flow and ventricular filling. This study investigated whether symptom-limited exercise capacity in HF patients with ischemic cardiomyopathy and angina was deleteriously affected by CK-452 at pharmacodynamically active concentrations.

A novel approach to improve cardiac performance: cardiac myosin activators

Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise.