Daniel M. Shindler

Effects of Long-term Enalapril Therapy on Cardiac Structure and Function in Patients With Left Ventricular Dysfunction: Results of the SOLVD Echocardiography Substudy

BACKGROUND Studies of Left Ventricular Dysfunction (SOLVD) demonstrated that enalapril therapy significantly improved the clinical course of patients with left ventricular (LV) dysfunction. The goals of this substudy were to evaluate changes in LV structure and function in SOLVD patients and to test the hypothesis that enalapril inhibits remodeling in patients with LV dysfunction. METHODS AND RESULTS Patients entering both the prevention and treatment arms of SOLVD from 5 of the 23 clinical centers were recruited for this substudy. The 301 patients who participated underwent Doppler-echocardiographic evaluation according to standard protocol before randomization to either enalapril or placebo and again after 4 and 12 months of therapy. Recorded data were analyzed in a blinded fashion at a central core laboratory. Analysis of baseline clinical characteristics showed that patients enrolled in the substudy were generally representative of the SOLVD population, although prevention arm patients were slightly overrepresented in the substudy group (69.8% compared with 61.9% of remaining SOLVD patients). The enalapril group demonstrated significant reductions in the mitral annular E-wave-to-A-wave velocity ratio (due predominantly to a reduction in E-wave velocity), and this response was different from that seen in the placebo group (P = .030). Changes in the E-to-A ratio in the enalapril group correlated significantly with changes in plasma atrial natriuretic peptide (r = .56; P < or = .01). LV end-diastolic and end-systolic volumes increased in placebo but not enalapril-treated patients, and the differences in response between the treatment groups were significant (P = .025 and .019, respectively). LV mass tended to increase in placebo patients and to be reduced in enalapril-treated patients, and the difference in response between the groups was highly significant (P < or = .001). CONCLUSIONS These data demonstrate that enalapril attenuates progressive increases in LV dilatation and hypertrophy in patients with LV dysfunction. The results support the possibility that the favorable effects of enalapril reported in the SOLVD trials were related to inhibition of LV remodeling.

Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy∗∗

OBJECTIVES To assess the relation of left ventricular (LV) and left atrial (LA) dimensions, ejection fraction (EF) and LV mass to subsequent clinical outcome of patients with LV dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry and Trials. BACKGROUND Data are lacking on the relation of LV mass to prognosis in patients with LV dysfunction and on the interaction of LV mass with other measurements of LV size and function as they relate to clinical outcome. METHODS A cohort of 1,172 patients enrolled in the SOLVD Trials (n = 577) and Registry (n = 595) had baseline echocardiographic measurements and follow-up for 1 year. RESULTS After adjusting for age, New York Heart Association (NYHA) functional class, Trial vs. Registry and ischemic etiology, a 1-SD difference in EF was inversely associated with an increased risk of death (risk ratio, 1.62; p = 0.0008) and cardiovascular (CV) hospitalization (risk ratio, 1.59; p = 0.0001). Consequently, the other echo parameters were adjusted for EF in addition to age, NYHA functional class, Trial vs. Registry and ischemic etiology. A 1-SD difference in LV mass was associated with increased risk of death (risk ratio of 1.3, p = 0.012) and CV hospitalization (risk ratio of 1.17, p = 0.018). Similar results were observed with the LA dimension (mortality risk ratio, 1.32; p < 0.02; CV hospitalizations risk ratio, 1.18; p < 0.04). Likewise, LV mass > or =298 g and LA dimension > or =4.17 cm were associated with increased risk of death and CV hospitalization. An end-systolic dimension >5.0 cm was associated with increased mortality only. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% had lower mortality) but not in the group with LV mass <298 g. CONCLUSIONS In patients with LV dysfunction enrolled in the SOLVD Registry and Trials, increasing levels of hypertrophy are associated with adverse events. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% fared better) but not in the group with LV mass <298 g. These data support the development and use of drugs that can inhibit hypertrophy or alter its characteristics.

Relation of ventricular size and function to heart failure status and ventricular dysrhythmia in patients with severe left ventricular dysfunction

Patients with severe left ventricular (LV) dysfunction may or may not have overt heart failure and ventricular dysrhythmia. To study factors behind this variability, we examined a subset of 311 patients from the Studies of Left Ventricular Dysfunction-95 with a history of moderate heart failure (treatment trial) and 216 with no failure (prevention trial), all with ejection fractions <0.35. Echocardiographic variables were compared between trials and also correlated with dysrhythmia in 258 patients, and with neurohormones in 199 patients. Compared with prevention patients, treatment patients had larger LV end-diastolic diameter, end-systolic volume, sphericity index, and ratio of early to late diastolic filling velocity by Doppler (E/A ratio), lower LV ejection fraction and atrial contribution to ventricular filling, and similar LV mass, end-diastolic volume, and estimates of systolic wall stress. With prevention and treatment patients combined, the prevalence of abnormally elevated atrial natriuretic peptide was 92% in the highest tertile of E/A ratio compared with 55% in the lower tertiles (p=0.006). Across tertiles of LV end-diastolic volume, there was an increase in the prevalence of nonsustained ventricular tachycardia (24%, 45%, and 45%; p=0.007) and premature ventricular complexes >10/hour (48%, 62%, and 80%; p<0.001). Thus, in severe LV dysfunction, ventricular filling indexes suggestive of high filling pressures, along with larger and more spherical ventricles, are particularly common in patients with overt heart failure, thus suggesting that diastolic properties and the degree of ventricular remodeling affect clinical status. Once ejection fraction is significantly reduced, the prevalence of ventricular dysrhythmia correlates with LV size rather than systolic function. This observation lends support to previous experimental findings on the role of myocardial stretch and scar in the genesis of dysrhythmia.

Diabetes mellitus in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry☆

OBJECTIVES We sought to examine the role of diabetes mellitus in cardiogenic shock (CS) complicating acute myocardial infarction (AMI) in the SHOCK Trial Registry. BACKGROUND The characteristics, outcomes and optimal treatment of diabetic patients with CS complicating AMI have not been well described. METHODS Baseline characteristics, clinical and hemodynamic measures, treatment variables, shock etiologies and comorbid conditions were compared for 379 diabetic and 784 nondiabetic patients. Logistic regression was used to examine the association between diabetes and in-hospital mortality, after adjustment for baseline differences. RESULTS Diabetics were less likely than nondiabetics to undergo thrombolysis (28% vs. 37%; p = 0.002) or attempted revascularization (40% vs. 49%; p = 0.008). The survival benefit for diabetics selected for percutaneous or surgical revascularization (55% vs. 19% without revascularization) was similar to that for nondiabetics (59% vs. 25%). Overall unadjusted in-hospital mortality was significantly higher for diabetics (67% vs. 58%; p = 0.007), but diabetes was only a borderline predictor of mortality after adjustment for baseline and treatment differences (odds ratio for death, 1.36; 95% confidence interval, 1.00 to 1.84; p = 0.051). CONCLUSIONS Diabetics with CS complicating AMI have a higher-risk profile at baseline, but after adjustment, diabetics have an in-hospital survival rate that is only marginally lower than that of nondiabetics. Diabetics who undergo revascularization derive a survival benefit similar to that of nondiabetics.

A Pharmacokinetic—Pharmacodynamic Model of d‐Sotalol Q‐Tc Prolongation During Intravenous Administration to Healthy Subjects

The objective of this study was to assess the pharmacokinetics and pharmacodynamics of the dextro (d‐) isomer of sotalol, a class III antiarrhythmic agent, in healthy young men and women after a single intravenous bolus dose. The design was open‐label, randomized, parallel group. Each group (4 men and 4 women) received either 0.5, 1.5, or 3.0 mg/kg d‐sotalol as an intravenous infusion for 2 minutes. Serial measurements of the d‐sotalol plasma concentration and the Q‐Tc interval data were recorded before, during, and for 72 hours after drug administration. The pharmacokinetics of d‐sotalol were found to be well described by a three‐compartment model with linear elimination clearance from the central compartment. There were no significant differences in the elimination clearance or volume of the central compartment between dose levels or between men and women. However, women were found to have a lower steady‐state volume of distribution than men (1.20 L/kg versus 1.43 L/kg). The Q‐Tc versus d‐sotalol plasma concentration data were fitted to a model that assumed a distinct “effect compartment” and sigmoidal Emax response. The baseline Q‐Tc, determined from the fittings, was found to be significantly higher in women (0.40 versus 0.38 seconds). The effect compartment clearance was found to be highly variable, with a median of 12.3 (range, 0.2‐671,300) L/h. There were statistically significant differences in the effect compartment clearance by dose among men and by gender at a dose of 1.5 mg/kg. There were no significant differences detected between dose groups or genders for the d‐sotalol effect site concentration at one half the maximum Q‐Tc prolongation from baseline (EC50), EMAX, (the maximum Q‐Tc prolongation from baseline) or the Hill coefficient. In conclusion, the pharmacokinetics of d‐sotalol after intravenous administration are independent of dose and gender, because the difference between men and women in volume of distribution at steady‐state is not clinically significant. The pharmacodynamics of Q‐Tc prolongation produced by d‐sotalol appear to be independent of dose and gender; however, there is considerable variability in the time course of effects on Q‐Tc between individuals.

Differential Exercise Effects of Captopril and Nadolol in Patients with Essential Hypertension

In a crossover study, 12 patients with mild to moderate hypertension were given placebo, captopril (12.5 to 50 mg three times a day), and nadolol (20 to 160 mg once a day) to control the resting diastolic blood pressure to a nearly identical degree (p < 0.0001) (106.1 ±4 placebo, 89.6 ±8 captopril, 89.8 ±7 nadolol). Both drugs lowered (p < 0.0004) systolic and diastolic blood pressure at rest and during exercise. However, systolic blood pressure lowering during exercise was more pronounced (p < 0.05) with nadolol than with captopril (difference of 6 mmHg, 16 mmHg, and 21 mmHg at 5.0, 7.0, and 9.0 metabolic equivalents (METS) respectively). Heart rate was lower (p < 0.05) at rest and during exercise with nadolol as compared with placebo and with captopril. These data imply different mechanisms of action of the two drugs at rest and during exercise and may help in selection of drug therapy in special patient subsets.

Electrocardiography: Principles and Applications in Sleep Medicine

It is possible to think about cardiac rhythm during sleep in the same way as during wakefulness. Arrhythmias can be separated into two large groups. Those that originate in the sinus node, atria, or atrioventricular node are referred to as supraventricular arrhythmias. Those that originate in the ventricles are classified as ventricular arrhythmias. Arrhythmias can be genetic. There may be underlying structural heart disease. Patients may have an implanted pacemaker. Sustained ventricular arrhythmias require immediate attention. The patient needs to be awakened, and blood pressure and mental status must be determined. If an arrhythmia causes hypotension or if the patient is unarousable, emergency measures may be required.

Electrocardiographic Recognition of Cardiac Arrhythmias

Publisher Summary This chapter discusses electrocardiographic recognition of cardiac arrhythmias. A 24-hour ambulatory electrocardiography (ECG) has made it possible to study cardiac rhythm in both awake and sleeping subjects. For most practical purposes, it is possible to consider cardiac rhythm during sleep in the same way as during wakefulness though the heart rate is slower during sleep. Arrhythmias occur because of disturbances of impulse formation, impulse conduction, or a combination of the two. Arrhythmias can be separated into two large groups: (1) those that originate in the sinus node, atria, or atrioventricular (AV) node, referred to as supraventricular arrhythmias, and (2) those that originate in the ventricles, classified as ventricular arrhythmias. The chapter illustrates a variety of cardiac arrhythmias. The most common rhythm disturbance that may not be abnormal—that is, sinus tachycardia—is an acceleration of the sinus heart rate above 100. In most cases, sinus tachycardia does not exceed 180 beats per minute. Sinus tachycardia is best diagnosed by identifying P waves, determining that they are of normal morphology, subsequently establishing that the PR interval is normal and constant, and finally determining that each QRS complex is preceded by the P wave and each P wave is followed by a normal QRS.