J Mayet

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.

BACKGROUND Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING Cytokinetics Inc.

Left Ventricular Hypertrophy and QT Dispersion in Hypertension

The interlead variation in QT length on a standard electrocardiograph reflects regional repolarization differences in the heart. To investigate the association between this interlead variation (QT dispersion) and left ventricular hypertrophy, we subjected 100 untreated subjects to 12-lead electrocardiography and echocardiography. Additionally, 24 previously untreated subjects underwent a 6-month treatment study with ramipril and felodipine. In the cross-sectional part of the study, QT dispersion corrected for heart rate (QTc dispersion) was significantly correlated with left ventricular mass index (r = .30, P < .01), systolic pressure (r = .30, P < .01), the ratio of peak flow velocity of the early filling wave to peak flow velocity of the atrial wave (E/A ratio) (r = -.22, P = .02), isovolumic relaxation time (r = .31, P < .01), and age (r = .21, P < .04). In the treatment part of the study, lead-adjusted QTc dispersion decreased from 24 to 19 milliseconds after treatment, and after a subsequent 2 weeks of drug washout remained at 19 milliseconds (P < .01). The changes in left ventricular mass index at these stages were 144, 121, and 124 g/m2 (P < .01). Systolic pressure decreased from 175 to 144 mm Hg and increased again to 164 mm Hg after drug washout (P < .01). The E/A ratio (0.97, 1.02, and 1.02; P = 69) and isovolumic relaxation time (111, 112, and 112; P = .97) remained unchanged through the three assessment points. In conclusion, QT dispersion is increased in association with an increased left ventricular mass index in hypertensive individuals. Antihypertensive therapy with ramipril and felodipine reduced both parameters. If an increased QT dispersion is a predictor of sudden death in this group of individuals, then the importance of its reduction is evident.

A Randomized Controlled Trial of Catheter Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure (The CAMTAF Trial)

Background—Restoring sinus rhythm in patients with heart failure (HF) and atrial fibrillation (AF) may improve left ventricular (LV) function and HF symptoms. We sought to compare the effect of a catheter ablation strategy with that of a medical rate control strategy in patients with persistent AF and HF. Methods and Results—Patients with persistent AF, symptomatic HF, and LV ejection fraction <50% were randomized to catheter ablation or medical rate control. The primary end-point was the difference between groups in LV ejection fraction at 6 months. Baseline LV ejection fraction was 32±8% in the ablation group and 34±12% in the medical group. Twenty-six patients underwent catheter ablation, and 24 patients were rate controlled. Freedom from AF was achieved in 21/26 (81%) at 6 months off antiarrhythmic drugs. LV ejection fraction at 6 months in the ablation group was 40±12% compared with 31±13% in the rate control group (P=0.015). Ablation was associated with better peak oxygen consumption (22±6 versus 18±6 mL/kg per minute; P=0.014) and Minnesota living with HF questionnaire score (24±22 versus 47±22; P=0.001) compared with rate control. Conclusions—Catheter ablation is effective in restoring sinus rhythm in selected patients with persistent AF and HF, and can improve LV function, functional capacity, and HF symptoms compared with rate control. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01411371

Racial differences in cardiac structure and function in essential hypertension

Abstract Objective: To assess racial differences in cardiac structure and function in patients presenting with previously untreated hypertension. Design - Untreated black patients with hypertension were compared with untreated white patients matched for age and sex. Both groups had similar body mass indices, blood pressures, and reported duration of hypertension. Setting: Cardiovascular risk factor clinic for outpatients. Subjects: 36 men and 22 women with untreated essential hypertension. Main outcome measures: Variables of heart structure and function on cross sectional and Doppler echocardiography. Results: The black patients had a significantly greater interventricular septal thickness (mean 1.23 (95% confidence interval 1.14 to 1.33) v 1.09 (1.02 to 1.16) cm; P=0.02) and posterior wall thickness (mean 1.14 (1.07 to 1.22) v 0.96 (0.88 to 1.03) cm; P=0.001) than the white patients although left ventricular internal diameter was not significantly different (mean 4.90 (4.68 to 5.12) v 4.82 (4.64 to 5.01) cm; P=0.59). This resulted in a significantly greater left ventricular mass index (mean 151 (137 to 164) v 120 (107 to 133) g/m2; P=0.001) and relative wall thickness (mean 0.47 (0.43 to 0.51) v 0.40 (0.37 to 0.42) cm; P=0.004) in the black patients. Comparison of Doppler measures of left ventricular diastolic function showed a significantly longer isovolumic relaxation time in black patients (mean 107 (98 to 116) v 92 (83 to 101) ms; P=0.02) compared with white patients, although peak early to atrial filling ratios were similar in both groups (mean 1.14 (0.95 to 1.32) v 1.04 (0.94 to 1.15); P=0.37). Conclusion: Among previously untreated hypertensive patients, black subjects compared with white subjects have significantly higher left ventricular mass index and relative wall thickness, as well as more impairment of left ventricular function during diastole.

Ethnic Differences in the identification of left ventricular hypertrophy in the hypertensive patient

Left ventricular hypertrophy (LVH) is more prevalent in black than white hypertensives, but this difference is greater when identified by electrocardiography (ECG) than by echocardiography. We evaluated the proposal that current ECG criteria for LVH are less specific, and therefore, less useful, in blacks than whites. In a retrospective cross-sectional study, 408 subjects (271 white, 137 black) referred to a hypertension clinic for assessment of hypertension underwent measurement of blood pressure, ECG voltages (Sokolow-Lyon and Cornell sex-specific), and echocardiographic left ventricular mass index (LVMI). Black subjects had greater ECG voltages than whites, even when closely matched for LVMI. In black subjects, current ECG criteria were twice as sensitive as in whites (Sokolow-Lyon: 44.9% v 22.5%, P = .003. Cornell: 30.4% v 15.7%, P = .03). They were less specific in blacks using the Sokolow-Lyon criteria (73.5% v 86.8%, P = .02) but this failed to reach significance using the Cornell criteria (83.8% v 91.8%, P = .07). When voltage criteria were adjusted to give matched sensitivities and specificities, respectively, differences in specificity and sensitivity were no longer apparent. Receiver operating characteristic curve analyses confirmed no significant differences in overall performance of either ECG criteria between blacks and whites. In conclusion, ECG detection of LVH is insensitive in both ethnic groups. Sensitivity is higher in blacks due to higher LVMI in those with LVH. Apparent differences in specificity are due to ethnic differences in ECG voltages that are unrelated to differences in LVMI. When these differences are taken into account, there are no overall differences in test accuracy. However, given the prognostic importance of the detection of LVH, currently accepted ECG voltage criteria for the detection of LVH remain of equal or greater value in black hypertensives compared with whites.

Stress echocardiography for the diagnosis and risk stratification of patients with suspected or known coronary artery disease: a critical appraisal. Supported by the British Society of Echocardiography

Stress echocardiography today has matured into a robust and reliable technique not only for the diagnosis of suspected coronary artery disease (CAD) but also for the accurate risk stratification of patients with suspected and established CAD. This is mainly because of rapid advances in image acquisition, digital display, and the development of harmonic and contrast imaging. Stress echocardiography today is also utilised in patients with heart failure both for assessing the cause of heart failure and determining the extent of hibernating myocardium. With advances in myocardial perfusion imaging, stress echocardiography now allows simultaneous assessment of myocardial function and perfusion. Tissue Doppler imaging allows quantitation of wall motion. Ready availability and reliability makes stress echocardiography a cost effective technique for the assessment of CAD.

Selection and optimisation of biventricular pacing: the role of echocardiography

The quantification of ventricular dyssynchrony is a key factor in identifying patients with severe heart failure who may benefit from cardiac resynchronisation with biventricular pacing (BVP). Echocardiographic techniques appear to offer superior sensitivity and specificity than the ECG in selecting these patients. This paper reviews the scope of current echocardiographic techniques for guiding both patient selection and optimisation of device programming following implantation.

Ethnic Differences in the Hypertensive Heart and 24-Hour Blood Pressure Profile

Black hypertensive persons have been observed to have a greater degree of left ventricular hypertrophy than white hypertensives. However, previous studies have matched groups for blood pressure (BP) measured in the clinic, and it has been demonstrated that black hypertensives have an attenuated nocturnal BP dip. Clinic BPs may thus underestimate mean 24-hour BP in this group. To investigate whether the differences in left ventricular hypertrophy can be accounted for by the greater mean 24-hour BP in black hypertensives, 92 previously untreated hypertensives were studied with 24-hour ambulatory BP monitoring and echocardiography. The 46 black hypertensives (24 men and 22 women) were matched with the 46 white hypertensives for age, gender, and mean 24-hour BP. Despite similar mean 24-hour BPs (blacks, 142/93 mm Hg; whites, 145/92 mm Hg; P=.53/.66), the black group had a smaller mean nocturnal dip than the white group (blacks, 8/8 mm Hg; whites, 16/13 mm Hg; P<.01). In addition, mean left ventricular mass index (LVMI) was greater (blacks, 130 g/m2; whites, 107 g/m2; P<.001). Mean 24-hour systolic BP was significantly related to LVMI in both groups (blacks, r=.45, P<.01; whites, r=.56, P<.01). However, systolic BP dip correlated inversely with LVMI only in the black group (blacks, r=-.30, P<.04; whites, r=.05, P=.76). In a multiple regression model, LVMI was independently related to both mean daytime BP and mean nocturnal BP dip in black subjects but only to mean daytime BP in white subjects. In conclusion, the increased left ventricular hypertrophy observed in black hypertensives compared with white hypertensives is not accounted for by differences in mean 24-hour BP. However, LVMI in black hypertensives appears to be more dependent on nocturnal BP than that in white hypertensives; this, coupled with the attenuated BP dip in black hypertensives, suggests that the BP profile rather than 24-hour BP may be important in determining the differences in left ventricular hypertrophy.

Real-Time Dynamic Carbon Dioxide Administration: A Novel Treatment Strategy for Stabilization of Periodic Breathing With Potential Application to Central Sleep Apnea

OBJECTIVES This study targeted carbon dioxide (CO(2)) oscillations seen in oscillatory ventilation with dynamic pre-emptive CO(2) administration. BACKGROUND Oscillations in end-tidal CO(2) (et-CO(2)) drive the ventilatory oscillations of periodic breathing (PB) and central sleep apnea in heart failure (HF). METHODS Seven healthy volunteers simulated PB, while undergoing dynamic CO(2) administration delivered by an automated algorithm at different concentrations and phases within the PB cycle. The algorithm was then tested in 7 patients with HF and PB. RESULTS In voluntary PB, the greatest reduction (74%, p < 0.0001) in et-CO(2) oscillations was achieved when dynamic CO(2) was delivered at hyperventilation; when delivered at the opposite phase, the amplitude of et-CO(2) oscillations increased (35%, p = 0.001). In HF patients, oscillations in et-CO(2) were reduced by 43% and ventilatory oscillations by 68% (both p < 0.05). During dynamic CO(2) administration, mean et-CO(2) and ventilation levels remained unchanged. Static CO(2) (2%, constant flow) administration also attenuated spontaneous PB in HF patients (p = 0.02) but increased mean et-CO(2) (p = 0.03) and ventilation (by 45%, p = 0.03). CONCLUSIONS Dynamic CO(2) administration, delivered at an appropriate time during PB, can almost eliminate oscillations in et-CO(2) and ventilation. This dynamic approach might be developed to treat central sleep apnea, as well as minimizing undesirable increases in et-CO(2) and ventilation.

Development of respiratory control instability in heart failure: a novel approach to dissect the pathophysiological mechanisms

Observational data suggest that periodic breathing is more common in subjects with low F  ETCO 2, high apnoeic thresholds or high chemoreflex sensitivity. It is, however, difficult to determine the individual effect of each variable because they are intrinsically related. To distinguish the effect of isolated changes in chemoreflex sensitivity, mean F  ETCO 2 and apnoeic threshold, we employed a modelling approach to break their obligatory in vivo interrelationship. We found that a change in mean CO2 fraction from 0.035 to 0.045 increased loop gain by 70 ± 0.083% (P < 0.0001), irrespective of chemoreflex gain or apnoea threshold. A 100% increase in the chemoreflex gain (from 800 l min−1 (fraction CO2)−1) resulted in an increase in loop gain of 275 ± 6% (P < 0.0001) across a wide range of values of steady state CO2 and apnoea thresholds. Increasing the apnoea threshold F  ETCO 2 from 0.02 to 0.03 had no effect on system stability. Therefore, of the three variables the only two destabilizing factors were high gain and high mean CO2; the apnoea threshold did not independently influence system stability. Although our results support the idea that high chemoreflex gain destabilizes ventilatory control, there are two additional potentially controversial findings. First, it is high (rather than low) mean CO2 that favours instability. Second, high apnoea threshold itself does not create instability. Clinically the apnoea threshold appears important only because of its associations with the true determinants of stability: chemoreflex gain and mean CO2.