Peter M. Okin

Angiogenesis Gene Therapy Phase I Assessment of Direct Intramyocardial Administration of an Adenovirus Vector Expressing VEGF121 cDNA to Individuals With Clinically Significant Severe Coronary Artery Disease

BACKGROUND Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Albuminuria and Cardiovascular Risk in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study

Context Microalbuminuria is a known risk factor for cardiovascular disease. Contribution In this large prospective study of hypertensive patients with left ventricular hypertrophy, increasing microalbuminuria was associated with increasing risks for cardiovascular disease. Risks continuously increased without evidence of a threshold or plateau level. Implications Microalbuminuria assessment in hypertensive patients may improve cardiovascular risk stratification. Cautions The study was based on data collected during a randomized, controlled trial of antihypertensive therapy. Albuminuria was measured as the albumincreatinine ratio in a single spot urine collection. Other than for the study drug received, the authors did not adjust for treatments received during the trial. The Editors Microalbuminuria was first associated with essential hypertension in nondiabetic individuals by Parving and colleagues (1), and subsequent studies (2, 3) confirmed the association. Albuminuria is an independent risk factor for cardiovascular disease and increased all-cause mortality in relatively unselected (4, 5) or general (6-8) populations, postmenopausal women (9), older people (10, 11), diabetic patients (12, 13), hypertensive patients with or without concomitant diabetes (8, 14, 15), and people with known high risk for cardiovascular disease (16). Left ventricular hypertrophy is an independent predictor of adverse prognosis (17-19) and is related to albumin excretion independent of age, blood pressure, diabetes, race, serum creatinine level, or smoking; these associations suggest parallel cardiac damage and increased renal albumin excretion rate (20). Other studies suggest that albuminuria at levels well below traditional partition values is a risk factor for coronary vascular disease in patients with and without diabetes (16, 21), indicating that the relation between albuminuria and cardiovascular risk from other populations cannot be directly applied to nondiabetic hypertensive patients. More precise information about the relation between albuminuria and cardiovascular risk would not only help clinicians better estimate the patients absolute risk but also strengthen the decision to initiate antihypertensive treatment, since current guidelines consider not only blood pressure but also target organ damage (for example, albuminuria) (22). We conducted a prospective study to determine the albuminuria level at which cardiovascular morbidity and mortality are increased in a large group of hypertensive patients with left ventricular hypertrophy. In a predefined protocol, we hypothesized that no unique albuminuria threshold predicts increased cardiovascular risk but rather that increasing albuminuria is associated with a graded increase in risk. We anticipated that in hypertensive patients with left ventricular hypertrophy, any threshold identified would be much lower than the threshold traditionally defined in diabetic populations. Methods Patients Participants in our study were outpatients between 55 and 80 years of age. They were recruited from a mix of general and hospital practices and had previously untreated or treated stage II or III hypertension with electrocardiographically confirmed left ventricular hypertrophy (measured according to the product of QRS duration multiplied by Cornell voltage or according to SokolowLyon voltage). The patients were randomly assigned to receive double-blind therapy with losartan or atenolol in the Losartan Intervention For Endpoint reduction (LIFE) study (23, 24). Study Design The hypotheses of the current study were prespecified as part of the LIFE protocol. Inclusion criteria were a mean trough sitting systolic blood pressure of 160 to 200 mm Hg or a diastolic blood pressure of 95 to 115 mm Hg after 1 and 2 weeks of single-blind placebo treatment and no other antihypertensive medication at the time of randomization. Exclusion criteria were myocardial infarction or stroke within 6 months, current congestive heart failure or previously known left ventricular ejection fraction less than 0.40, and renal insufficiency (serum creatinine level >160 mmol/L [>1.8 mg/dL]). We excluded patients who had a condition that the treating physician believed required treatment with losartan or another angiotensin II-receptor blocker, atenolol or another -blocker, hydrochlorothiazide, or angiotensin-converting enzyme inhibitors. Patients gave informed consent under protocols approved by the ethics committees of the participating institutions. End Points and Adjudication This study of the 8206 LIFE participants who had baseline albuminuria determinations (>90% of the entire sample) is based on analysis of a primary composite end point (n = 971): the first occurrence of cardiovascular death, fatal or nonfatal stroke, and fatal or nonfatal myocardial infarction. Additional end points were all-cause mortality (n = 703) and the first occurrence of each component of the composite end point, regardless of whether it was preceded by another component of the primary end point: 383 cardiovascular deaths, 479 strokes, and 344 myocardial infarctions. In the nondiabetic subgroup there were 755 composite end points, including 292 cardiovascular deaths, 379 fatal and nonfatal strokes, 261 fatal and nonfatal myocardial infarctions, and 554 all-cause deaths. Investigators reported all end points; source data were verified by independent monitors and were adjudicated by an independent committee on the basis of definitions provided in a predefined end point manual (24). Patients and the investigators reported the prevalences of coronary, cerebral, or peripheral vascular disease and smoking habits. Diabetes was defined according to investigator report and plasma glucose level. The Framingham risk score (25) was estimated from baseline blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking status, glucose level, and level of left ventricular hypertrophy on electrocardiography (ECG). Renal Evaluation On the same day, a spot urine sample was collected as the first morning voiding and the serum creatinine level was measured. Urine albumin concentration was determined by standard methods (26) using a turbidometric method (Hitachi 717 analyzer, Hoffmann-La Roche Ltd., Basel, Switzerland) (27) on a single urine specimen. Both serum and urine levels of creatinine were analyzed by using the Jaff reaction without deproteinizing and then quantified by a photometric method using the same analyzer. The ratio of urine albumin (in mg/L) to creatinine concentration (UACR) (in mmol/L) provided a composite measure (in mg/mmol) of renal glomerular capillary permeability that adjusted for urine dilution (28). To derive U.S. measures of UACR (mg/g), UACR in mg/mmoL is multiplied by 8.84. Statistical Analysis We used SPSS software, version 11.0.1 (SPSS, Inc., Chicago, Illinois), for statistical analyses. The study sample as a whole and the nondiabetic patients were divided into UACR deciles; diabetic patients were divided into UACR quintiles. We used Cox proportional-hazards models to compare hazard ratios among groups and to evaluate the contributions of differences in the degree of left ventricular hypertrophy (both Cornell voltage duration product and SokolowLyon voltage as continuous variables), the Framingham risk score (25), and treatment allocation (losartan or atenolol) as covariates. To express the increase in risk per increase in UACR as a continuous variable, we log-transformed UACR. We used a Cox model in the test for trend and used the decile group as a continuous variable. Hazard ratios from the decile groups were then used to estimate the best-fitting curve (SPSS curve estimation function). Two-tailed P values less than 0.05 were considered statistically significant. Role of the Funding Source The funding source had no role in the design, analysis, and reporting of the study or in the decision to submit the manuscript for publication. Results Patient Characteristics Descriptive data for the LIFE study sample (23) and relations of microalbuminuria and macroalbuminuria to cardiovascular risk factors have been reported elsewhere (20). Of the 9193 patients participating in the LIFE study, 8206 had the baseline UACR measurements necessary for inclusion in the present study. The mean age (SD) was 66 7 years; 54% of patients were women, and 92% were white. Thirteen percent had diabetes, 13.5% had coronary heart disease, and 7.7% had had a stroke. The mean arterial blood pressure (SD) was 174 14/98 9 mm Hg, the mean serum creatinine level (SD) was 87 20 mmol/L, and the median UACR was 1.28 mg/mmol. Additional baseline characteristics of patients with albuminuria are described elsewhere (20). To stratify risk in hypertensive patients with albuminuria and left ventricular hypertrophy, patients were divided into UACR deciles, with 814 to 821 patients in each group. Patients were followed for a median of 4.8 years and a total of 39 122 patient-years. End point rates were 24.8 per 1000 patient-years of follow-up for the composite endpoint, 9.4 for cardiovascular mortality, 17.6 for all-cause mortality, 11.9 for stroke, and 8.5 for myocardial infarction. Age; sex; race; body mass index; blood pressure; level of left ventricular hypertrophy on ECG; Framingham risk score; prevalence of known diabetes, coronary heart disease, or peripheral vascular disease; and smoking habits did not differ between the patients who provided a urine sample and the 987 patients who did not. The prevalence of history of cerebral vascular disease (13.2% vs. 10.5%; P = 0.029) and mean serum creatinine level (90.0 vs. 86.7 mmol/L; P = 0.001) were higher in patients who did not provide a urine sample than in those who did. When we considered differences in left ventricular mass on ECG, Framingham risk score, and study treatment, patients without a urine sample had a 52% higher all-cause mortality rate (95% CI, 23% to 87%); the rates of t

Electrocardiographic identification of increased left ventricular mass by simple voltage-duration products☆

OBJECTIVES This study was conducted to validate the hypothesis that the product of QRS voltage and duration, as an approximation of the time-voltage area of the QRS complex, can improve the electrocardiographic (ECG) detection of echocardiographically determined left ventricular hypertrophy and to further assess the relative contribution of QRS duration to the ECG detection of hypertrophy. BACKGROUND The ECG identification of left ventricular hypertrophy has been limited by the poor sensitivity of standard voltage criteria alone. However, increases in left ventricular mass can be more accurately related to increases in the time-voltage area of the QRS complex than to changes in QRS voltage or duration alone. METHODS Standard 12-lead ECGs and echocardiograms were obtained for 389 patients, including 116 patients with left ventricular hypertrophy. Simple voltage-duration products were calculated by multiplying Cornell voltage by QRS duration (Cornell product) and the 12-lead sum of voltage by QRS duration (12-lead product). RESULTS In a stepwise logistic regression model that also included Cornell voltage, Sokolow-Lyon voltage, age and gender, QRS duration remained a highly significant predictor of the presence of left ventricular hypertrophy (chi-square 26.9, p < 0.0001). At a matched specificity of 96%, each voltage-duration product significantly improved sensitivity for the detection of left ventricular hypertrophy compared with simple voltage criteria alone (Cornell product 37% vs. Cornell voltage 28%, p < 0.02, and 12-lead product 50% vs. 12-lead voltage 43%, p < 0.005). Sensitivities of both the Cornell product and the 12-lead product were significantly greater than the 27% sensitivity of QRS duration alone (p < 0.01 vs. p < 0.001), the 20% sensitivity of a Romhilt-Estes point score > 4 (p < 0.001) and the 33% sensitivity of the best-fit logistic regression model in this cohort (p < 0.05 vs. p < 0.001). CONCLUSIONS QRS duration is an independent ECG predictor of the presence of left ventricular hypertrophy, and the simple product of either Cornell voltage or 12-lead voltage and QRS duration significantly improves identification of left ventricular hypertrophy relative to other ECG criteria that use QRS duration and voltages in linear combinations.

Electrocardiographic Detection of Left Ventricular Hypertrophy by the Simple QRS Voltage-Duration Product

OBJECTIVES The object of this study was to assess the hypothesis that the product of QRS voltage and duration, as an approximation of the time-voltage integral of the QRS complex, can improve the electrocardiographic (ECG) identification of left ventricular hypertrophy. BACKGROUND Electrocardiographic identification of left ventricular hypertrophy has been limited by the poor sensitivity of standard voltage criteria. However, increases in left ventricular mass can be more closely related to increases in the time-voltage integral of the summed left ventricular dipole than to changes in voltage or QRS duration alone. METHODS Antemortem ECGs were compared with left ventricular mass at autopsy in 220 patients. There were 95 patients with left ventricular hypertrophy, defined by left ventricular mass index > 118 g/m2 in men and > 104 g/m2 in women. The voltage-duration product was calculated as the product of QRS duration and Cornell voltage (Cornell product) and the 12-lead sum of QRS voltage (12-lead product). RESULTS At partitions with a matched specificity of 95%, each voltage-duration product significantly improved sensitivity for the detection of left ventricular hypertrophy when compared with simple voltage criteria alone (Cornell product 51% [48 of 95] vs. Cornell voltage 36% [34 of 95], p < 0.005 and 12-lead product 45% [43 of 95] vs. 12-lead voltage 31% [30 of 95], p < 0.001). Sensitivity of both the Cornell product and 12-lead product was significantly greater than that found for QRS duration alone (28%, 27 of 95, p < 0.005) and the Romhilt-Estes point score (27%, 26 of 95, p < 0.005), and compared favorably with the sensitivity of the complex Cornell multivariate score (44%, 42 of 95, p = NS). Comparison of receiver operating characteristic curves demonstrated that improved performance of the voltage-duration products for the detection of left ventricular hypertrophy was independent of test partition selection. In addition, test performance of the voltage-duration products was not significantly affected by the presence or absence of a bundle branch block. CONCLUSIONS These data suggest that the simple product of either Cornell or 12-lead voltage and QRS duration can identify left ventricular hypertrophy more accurately than can voltage or QRS duration criteria alone and may approach or exceed the performance of more complex multiple regression analyses.

Assessment of QT Interval and QT Dispersion for Prediction of All-Cause and Cardiovascular Mortality in American Indians The Strong Heart Study

BACKGROUND Both a prolonged QT interval and increased QT interval dispersion (QTD) have been proposed as surface ECG markers of vulnerability to ventricular arrhythmias and potential predictors of mortality. METHODS AND RESULTS The predictive values of QT prolongation and QTD were assessed in 1839 participants in the Strong Heart Study, a prospective study of cardiovascular disease in American Indians. ECGs were acquired at 250 Hz; QT intervals were measured by computer in all 12 leads and corrected for heart rate (QTc) by use of Bazetts formula. QTD was calculated as the difference between the maximum and minimum QTc. After a mean follow-up of 3.7+/-0.9 years, there were 188 deaths from all causes, including 55 cardiovascular deaths. In univariate Cox analyses, prolonged QTc and increased QTD were significant predictors of all-cause mortality (chi(2)=53.0, P<0.0001; chi(2)=11.3, P=0.0008) and cardiovascular mortality (chi(2)=14.7, P=0.0001; chi(2)=26.5, P<0.0001). In multivariate Cox regression analyses controlling for risk factors, QTc remained a strong predictor of all-cause mortality (chi(2)=16.5, P<0.0001) and a weaker predictor of cardiovascular mortality (chi(2)=5.8, P=0.016); QTD remained a significant predictor of cardiovascular mortality only (chi(2)=12.5, P=0.0004). CONCLUSIONS These findings support the value of computerized measurements of QTc and QTD in noninvasive risk stratification and suggest that these surface ECG variables may reflect different underlying abnormalities of ventricular repolarization.

Regression of Electrocardiographic Left Ventricular Hypertrophy by Losartan Versus Atenolol The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study

Background—Electrocardiographic left ventricular hypertrophy (LVH) predicts cardiovascular morbidity and mortality, and regression of ECG LVH may predict improved prognosis in hypertensive patients. However, uncertainty persists as to how best to regress ECG LVH. Methods and Results—Regression of ECG LVH with losartan versus atenolol therapy was assessed in 9193 hypertensive patients with ECG LVH by Sokolow-Lyon voltage or Cornell voltage-duration product criteria enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Patients had ECGs at study baseline and after 6 months, 1, 2, 3, 4, and 5 years of blinded losartan-based or atenolol-based therapy. After 6 months’ follow-up, adjusting for baseline ECG LVH levels, baseline and in-treatment systolic and diastolic pressures, and for diuretic therapy, losartan-based therapy was associated with greater regression of both Cornell product (adjusted means, −200 versus −69 mm · ms, P <0.001) and Sokolow-Lyon voltage (−2.5 versus −0.7 mm, P <0.001) than was atenolol-based therapy. Greater regression of ECG LVH persisted at each subsequent annual evaluation in the losartan-treated group, with between 140 and 164 mm · ms greater mean reductions in Cornell product and from 1.7 to 2.2 mm greater mean reductions in Sokolow-Lyon voltage (all P <0.001). The effect of losartan was consistent across subgroups defined by gender, age, ethnicity, and diabetes. Conclusions—After adjusting for baseline and in-treatment blood pressure and baseline severity of ECG LVH, losartan-based antihypertensive therapy resulted in greater regression of ECG LVH by Cornell voltage-duration product and Sokolow-Lyon voltage criteria than did atenolol-based therapy. These findings support the value of angiotensin receptor blockade with losartan for reversing ECG LVH.

AHA/ACCF/HRS Recommendations for the Standardization and Interpretation of the Electrocardiogram Part V: Electrocardiogram Changes Associated With Cardiac Chamber Hypertrophy: A Scientific Statement From the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: Endorsed by the International Society for Computerized Electrocardiology

This is the sixth and final section of the project to update electrocardiography (ECG) standards and interpretation. The project was initiated by the Council on Clinical Cardiology of the American Heart Association (AHA). The rationale for the project and the process for its implementation were described in a previous publication.1 The ECG is considered the single most important initial clinical test for diagnosing myocardial ischemia and infarction. Its correct interpretation, particularly in the emergency department, is usually the basis for immediate therapeutic interventions and/or subsequent diagnostic tests. The ECG changes that occur in association with acute ischemia and infarction include peaking of the T waves, referred to as hyperacute T-wave changes, ST-segment elevation and/or depression, changes in the QRS complex, and inverted T waves. The ST-segment changes are produced by the flow of currents, referred to as “injury currents,” that are generated by the voltage gradients across the boundary between the ischemic and nonischemic myocardium during the resting and plateau phases of the ventricular action potential, which correspond to the TQ and ST segments of the ECG.2,3 Current guidelines suggest that when these ST-segment shifts reach

Six-Month Assessment of a Phase I Trial of Angiogenic Gene Therapy for the Treatment of Coronary Artery Disease Using Direct Intramyocardial Administration of an Adenovirus Vector Expressing the VEGF121 cDNA

OBJECTIVE To summarize the 6-month follow-up of a cohort of patients with clinically significant coronary artery disease who received direct myocardial injection of an E1-E3- adenovirus (Ad) gene transfer vector (Ad(GV)VEGF121.10) expressing the human vascular endothelial growth factor (VEGF) 121 cDNA to induce therapeutic angiogenesis. BACKGROUND Therapeutic angiogenesis describes a novel approach to the treatment of vascular occlusive disease that uses the administration of growth factors known to induce neovascularization of ischemic tissues. METHODS Direct myocardial injection of Ad(GV)VEGF121.10 into an area of reversible ischemia was carried out in 21 patients as an adjunct to conventional coronary artery bypass grafting (group A, n = 15) or as sole therapy using a minithoracotomy (group B, n = 6). RESULTS No evidence of systemic or cardiac-related adverse events related to vector administration was observed up to 6 months after therapy. Trends toward improvement in angina class and exercise treadmill testing at 6-month follow-up in the sole therapy group suggest the effects of this therapy are persistent for > or =6 months. CONCLUSIONS This study suggests that direct myocardial administration of Ad(GV)VEGF121.10 appears to be well tolerated in patients with clinically significant coronary artery disease. Initiation of phase II evaluation of this therapy appears warranted.

High central pulse pressure is independently associated with adverse cardiovascular outcome the strong heart study.

OBJECTIVES This study was designed to facilitate clinical use of central pulse pressure (PP). We sought to determine a value that might predict adverse outcome and thereby provide a target for assessment of intervention strategies. BACKGROUND We previously documented that central PP more strongly relates to carotid hypertrophy and extent of atherosclerosis and, more importantly, better predicts incident cardiovascular disease (CVD) than brachial PP. METHODS Radial applanation tonometry was performed in the third Strong Heart Study examination to determine central blood pressure. Cox regression analyses were performed using pre-specified covariates and quartiles of central and brachial PP. RESULTS Among 2,405 participants without prevalent CVD, 344 suffered CVD events during 5.6 +/- 1.7 years. Quartiles of central PP (p < 0.001) predicted outcome more strongly than quartiles of brachial PP (p = 0.052). With adjustment for covariates, only the event rate in the fourth quartile of central PP (> or =50 mm Hg) was significantly higher than that in the first quartile (hazard ratio [HR]: 1.69, 95% confidence interval [CI]: 1.20 to 2.39, p = 0.003). Central PP > or =50 mm Hg was related to outcome in both men (HR: 2.06, 95% CI: 1.39 to 3.04, p < 0.001) and women (HR: 2.03, 95% CI: 1.55 to 2.65, p < 0.001); in participants with (HR: 1.84, 95% CI: 1.41 to 2.39, p < 0.001) and without diabetes (HR: 1.91, 95% CI: 1.29 to 2.83, p = 0.001); and in individuals younger (HR: 2.51, 95% CI: 1.59 to 3.95, p < 0.001) and older (HR: 1.53, 95% CI: 1.19 to 1.97, p = 0.001) than the age of 60 years. CONCLUSIONS Central PP > or =50 mm Hg predicts adverse CVD outcome and may serve as a target in intervention strategies if confirmed in other populations and in prospective studies.

Relations of central and brachial blood pressure to left ventricular hypertrophy and geometry: the Strong Heart Study.

Objective We previously demonstrated stronger relations of central vs. brachial blood pressure, particularly pulse pressure, to carotid artery hypertrophy and extent of atherosclerosis. Data regarding the relative impacts of central and brachial pressures on left ventricular hypertrophy and geometry are limited. Methods Echocardiography and radial applanation tonometry were performed in American Indian participants in the 4th Strong Heart Study examination. Left ventricular mass was calculated using an anatomically validated formula and adjusted for height2.7. Brachial blood pressure was measured according to a standardized protocol. Central pressures were derived using a generalized transfer function. Results Of 2585 participants in the analysis, 60% were women, 21% had diabetes and 33% were hypertensive; the mean age was 40 ± 17 years. All blood pressure variables were significantly related to left ventricular absolute and relative wall thicknesses and left ventricular mass index (all P < 0.001), with considerable variation in correlation coefficients (r = 0.135–0.432). Central and brachial systolic pressures were uniformly more strongly related to left ventricular wall thicknesses, diastolic diameter and mass index than their respective pulse pressures (all P < 0.005 by z statistics). Left ventricular relative wall thickness and mass index were more strongly related to central than brachial pressures. Conclusion Left ventricular hypertrophy is more strongly related to systolic pressure than to pulse pressure. Furthermore central pressures are more strongly related than brachial pressures to concentric left ventricular geometry. These data suggest that absolute (systolic) pressure is more important in stimulating left ventricular hypertrophy and remodeling, whereas pulsatile stress (pulse pressure) is more important in causing vascular hypertrophy and atherosclerosis.