Alain Bouchard

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67 clinical centres and hospitals in the USA, Europe, and Israel. High-risk ambulatory patients with New York Heart Association class II-IV symptoms of heart failure and a left ventricular ejection fraction of 0·35 or less due to an ischaemic or non-ischaemic cause were randomly assigned (1:1), via an interactive voice and web-response system, to receive a single intracoronary infusion of 1 × 10(13) DNase-resistant particles of AAV1/SERCA2a or placebo. Randomisation was stratified by country and by 6 min walk test distance. All patients, physicians, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was time to recurrent events, defined as hospital admission because of heart failure or ambulatory treatment for worsening heart failure. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01643330. FINDINGS Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n=127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17·5 months (range 1·8-29·4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0·93, 95% CI 0·53-1·65; p=0·81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes. INTERPRETATION CUPID 2 is the largest gene transfer study done in patients with heart failure so far. Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although we did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, our findings should stimulate further research into the use of gene therapy to treat patients with heart failure and help inform the design of future gene therapy trials. FUNDING Celladon Corporation.

Quantitation of mitral regurgitation by Doppler echocardiography.

The evaluation and care of patients with mitral regurgitation would be facilitated by an easy, reproducible and noninvasive method that could quantitate the hemodynamic burden. In this study, we describe a new Doppler echocardiographic method that measures the regurgitant fraction and we compare it with angiographic and scintigraphic methods. A total of 27 patients with mitral regurgitation were evaluated by echocardiography and either cardiac catheterization or scintigraphy. With two-dimensional echocardiography, diastolic and systolic volumes were measured to derive the left ventricular stroke volume (LVSV). The forward stroke volume (FSV) was obtained from the product of M mode-derived aortic valve area and ascending aortic flow velocity integral assessed by continuous-wave Doppler. Regurgitant fraction was calculated as follows: (LVSV - FSV)/LVSV. Comparisons showed that regurgitant fraction calculated by Doppler echocardiography correlated with regurgitant fraction determined by both cardiac catheterization (r = .82) and by scintigraphy (r = .89). There was, however, an important interobserver variability within each method: 10%, 13%, and 11% for Doppler echocardiography, angiography, and scintigraphy, respectively. In conclusion, Doppler echocardiography can be used to quantitate mitral regurgitation. Serial noninvasive determinations of regurgitant fraction may be useful in the evaluation of therapy and in the follow-up of patients with mitral insufficiency.

Comparison of clinical variables and variables derived from a limited predischarge exercise test as predictors of early and late mortality after myocardial infarction

An exercise test limited to 5 METS or 70% of age-predicted maximal heart rate was performed 1 day before hospital discharge by 225 survivors of acute myocardial infarction, all of whom were subsequently followed up for at least 5 years. The mortality rate was 11.1% during the first year, but averaged only 2.9% per year from the second to fifth year. Over the entire follow-up period, the five variables that predicted mortality by multivariate analysis were QRS score, an exercise-induced ST segment shift, previous infarction, failure to achieve target heart rate or work load and ventricular arrhythmia during the exercise test. Because mortality differed markedly before and after 1 year, Cox regression analyses were performed separately for both of these periods. The factors that were predictive of mortality during the first year were an exercise-induced ST shift (p less than 0.0001, relative risk 7.8), failure to increase systolic blood pressure by 10 mm Hg or more during exercise (p = 0.0039, relative risk 4.3) and angina in hospital 48 hours or longer after admission (p = 0.0046, relative risk 3.4). None of these three variables was predictive of mortality after 1 year. Previous infarction (p = 0.0007), QRS score (p = 0.0042) and ventricular arrhythmia during the exercise test (p = 0.016) were predictive of mortality after the first year. Thus, clinical and exercise test variables are complementary predictors of mortality after myocardial infarction. An abnormal ST segment response during an early limited exercise test and angina in the hospital are common strong predictors of mortality to 1 year, but not thereafter. Late mortality correlates with markers of poor left ventricular function.

Cardiac consequences of renal transplantation: Changes in left ventricular morphology and function

To characterize changes in left ventricular morphology and function associated with renal transplantation, noninvasive cardiac evaluations were performed in 41 adults at the time of surgery and at follow-up. At the time of transplantation, 36 patients had undergone hemodialysis through a fistula for 2.3 +/- 2.5 years (mean +/- SD); their hematocrit level was 26 +/- 6% and systolic blood pressure was 151 +/- 19 mm Hg. Perioperatively, left ventricular hypertrophy was present in 93% of patients by echocardiography, but in only 37% by electrocardiography. Abnormal left ventricular diastolic function was present in 67% of patients and indicated a high risk for perioperative pulmonary edema. At follow-up (1.5 +/- 1.4 years), mean hematocrit level increased to 39 +/- 7%, systolic blood pressure decreased to 132 +/- 14 mm Hg and spontaneous closure of the fistula occurred in 13 patients. Left ventricular mass by echocardiography decreased from 237 +/- 66 to 182 +/- 47 g (p less than 0.001), a decrease of 23%. Left ventricular volumes and cardiac index also decreased significantly, reflecting the rapid resolution of a pretransplant high output state. Despite proportionate regression of left ventricular hypertrophy within months of transplantation, diastolic function did not improve. The significant regression of left ventricular hypertrophy that occurs after renal transplantation may help explain the improved cardiovascular survival of patients with a renal transplant over that of patients on long-term dialysis.

Left ventricular mass and volume/mass ratio determined by two-dimensional echocardiography in normal adults.

This study prospectively defined the range of left ventricular mass and volume/mass ratio determined by two-dimensional echocardiography in 84 normal adults. A modified Simpsons rule algorithm was used to calculate ventricular volumes from orthogonal two and four chamber apical views. An algorithm based on a model of the left ventricle as a truncated ellipsoid was used to calculate ventricular mass. Like left ventricular volumes, left ventricular mass values were larger in normal men than in women (mean 148 versus 108 g, p less than 0.001) and remained larger after correction for body surface area. Volume/mass ratios, however, were constant at end-diastole (0.80) and end-systole (0.26). The influence of age and heart rate on all variables in this normal group was minimal, and no correction for these variables was necessary. The definition of normal mass, volume and volume/mass ratios by two-dimensional echocardiography will facilitate the noninvasive, quantitative diagnosis of left ventricular hypertrophy and help clarify the relation between hypertrophy and systolic wall stress.

Measurement of left ventricular stroke volume using continuous wave Doppler echocardiography of the ascending aorta and M-mode echocardiography of the aortic valve.

A number of reports have described different Doppler echocardiographic methods to calculate left ventricular stroke volume and cardiac output, but the clinical application of the noninvasive measurements of cardiac function remains in the early stages of development. This slow dissemination may be partly explained by the varying success of these ultrasound methods in determining accurate left ventricular stroke volume. The purpose of this study was to improve the simplicity and accuracy of Doppler stroke volume determination so that it could be more easily applied to patient management. Stroke volume was measured using the product of the integral of aortic velocity obtained by continuous wave Doppler technique and the M-mode tracing of the aortic valve, validating the data against cardiac output obtained by thermodilution technique in 41 patients (r = 0.95, SEE = 7 cc). Intra- and interobserver variability was between 9 and 11%. The results of different sampling sites and the temporal relation between Doppler and thermodilution measurements were also studied. Analysis of 21 patients who had M-mode and two-dimensional echocardiographic studies of the aortic root revealed that the method using M-mode measurement of aortic valve area was most accurate in determining left ventricular stroke volume (r = 0.94, SEE = 10 cc), stroke volume being overestimated when area measurements of the ascending aorta were used. In conclusion, maximal ascending aortic velocity determined by continuous wave Doppler echocardiography with M-mode measurement of aortic valve area can be used to calculate left ventricular stroke volume and cardiac output. The simplicity and practicality of this method should enhance the clinical application of Doppler echocardiography as a noninvasive monitoring technique.

Magnetic resonance imaging in pulmonary arterial hypertension

Magnetic resonance imaging (MRI) was used to examine the right ventricle and pulmonary arteries in 17 patients with pulmonary artery (PA) hypertension documented by cardiac catheterization. The study population consisted of 7 patients with primary pulmonary hypertension, 7 with Eisenmengers syndrome and 3 with pulmonary hypertension secondary to lung disease. The MRI studies of patients were compared with those of 10 normal volunteers. Multislice gated transaxial images encompassed the right ventricle and central pulmonary arteries, showing the severity of right ventricular (RV) hypertrophy in proportion to the elevation of PA pressure and reversal of septal curvature when PA pressure approximated systemic pressure. End-diastolic RV wall thickness and mean pulmonary pressure correlated well (r = 0.79). MRI showed enlargement of PAs in all patients with PA hypertension. A magnetic resonance signal was present in the PAs throughout the cardiac cycle in patients with severe PA hypertension (more than 90 mm Hg) and was absent during systole in normal subjects. A signal within the PAs in systole is consistent with decreased flow velocity in patients with severe PA hypertension. MRI was useful in detecting each of the congenital anatomic defects in patients with Eisenmengers syndrome. This study indicates the potential of MRI for evaluating the severity of PA hypertension by providing direct measurements of RV wall thickness and PA diameter and by detecting abnormal intraluminal signal intensity during the cardiac cycle.

Noninvasive assessment of cardiomyopathy in normotensive diabetic patients between 20 and 50 years old

PURPOSE To further the understanding of diabetic heart disease, we tested the hypothesis that an asymptomatic group of normotensive diabetic patients between 20 and 50 years old had a restrictive cardiomyopathy independent of clinically significant coronary artery disease. PATIENTS AND METHODS Quantitative two-dimensional echocardiography and stress myocardial perfusion scintigraphy were performed to detect and characterize the cardiac abnormalities in this study group comprising 88 patients with rigorously classified diabetes and 65 volunteer control subjects. RESULTS Diabetic patients were shown to have a mildly reduced left ventricular end-diastolic volume index: 50.1 +/- 8.2 and 52.1 +/- 14.7 mL/m2 for patients with type I and type II diabetes, respectively, versus 58.9 +/- 11.7 mL/m2 for control subjects. The left ventricular diastolic filling was also impaired in diabetic patients as reflected by a lower atrial emptying index: 0.73 +/- 0.24 and 0.76 +/- 0.3 for type I and type II diabetics, respectively, compared with 1.14 +/- 0.24 for control subjects. Exercise tolerance was normal in subjects with type I diabetes and slightly reduced in subjects with type II diabetes. Only one patient developed regional ischemia on thallium exercise testing. CONCLUSION Using a comprehensive, noninvasive approach, we have shown that asymptomatic normotensive patients with type I or type II diabetes who were between 20 and 50 years old had a restrictive cardiomyopathy characterized by mildly reduced left ventricular end-diastolic volume and altered left ventricular compliance independent of critical coronary artery disease.

Accuracy and reproducibility of clinically acquired two-dimensional echocardiographic mass measurements☆

Left ventricular mass (LVM) measurements made by the truncated ellipsoid algorithm from clinical two-dimensional echocardiograms (2DE) were compared to autopsy weights in 37 patients. All six 2DE instruments were calibrated with an ultrasound phantom to standardize LVM measurements. Measurements were made by an experienced echocardiographer (LVME) and by an echocardiographer (LVMN) newly trained in LVM measurement from clinical 2DE tapes of patients with LV weights later confirmed at autopsy. LVME (r = 0.91, SEE +/- 41 gm) were more accurate than LVMN for all 2DE, but LVMN equalled LVME in accuracy for technically good 2DE. Interobserver variability was 36 gm, or 17% of LVM for all 2DE, and fell to 27 gm, or 12% of LVM for technically good 2DE. Segmental wall motion abnormalities and time from 2DE to death did not influence measurement accuracy significantly. LVM measurements by the 2DE truncated ellipsoid formula are accurate and reproducible in patients with normal and abnormal hearts.

Value of color Doppler estimation of regurgitant volume in patients with chronic aortic insufficiency

We studied 16 patients with chronic aortic insufficiency to compare a method for measuring regurgitant volume with color Doppler flow mapping to stroke count ratio determined by radionuclide ventriculography and to ventricular volumes assessed by two-dimensional echocardiography. A real-time color flow map of the left ventricular was obtained from an apical two- and five-chamber view and the maximal mosaic pattern of diastolic turbulent flow was planimetered as a reflection of the maximal regurgitant volume using biplane Simpsons rule. The maximal Doppler regurgitant volume evaluated by color Doppler flow mapping correlated with the stroke count ratio measured by scintigraphy (r = 0.86, SEE = 11 cc). There were significant relationships between maximal regurgitant volume measured by color Doppler and echocardiographic left ventricular end-diastolic volume (r = 0.88), left ventricular end-systolic volume (r = 0.77), and left ventricular mass (r = 0.71). Patients with larger regurgitant volumes tended to have a larger left ventricular end-diastolic volume-to-mass ratio (r = 0.56). Thus maximal aortic regurgitant volume can be estimated noninvasively with color Doppler flow mapping. The measurement appears to relate to left ventricular morphologic changes occurring in this condition and it may prove to be useful in assessing patients with chronic aortic insufficiency and in determining their long-term management.