Robert Zelis

A Comparison of Regional Blood Flow and Oxygen Utilization During Dynamic Forearm Exercise in Normal Subjects and Patients with Congestive Heart Failure

Patients with severe congestive heart failure (CHF) have been found to have a diminished response to the metabolic arteriolar dilator stimulus of ischemia. In order to evaluate a more physiologic stimulus and the possible metabolic consequences of this vascular abnormality, 22 normal subjects (N) and seven patients with severe CHF performed rhythmic forearm exercise by squeezing a rubber bulb to 25, 50, or 100 mm Hg for 5 sec, four times/min, for 5 min. During the last half of the 10 sec relaxation phases, forearm blood flow (FBF) was measured plethysmographically. Not only was FBF reduced at rest in CHF (CHF:2.00 ± 0.31; N: 3.10 ± 0.27 ml/min·100 ml, P < 0.02) but it was reduced at each level of exercise as well (CHF: 4.05 ± 0.71, 5.57 ± 0.71, 6.68 ± 3.09; N: 7.10 ± 0.76, 11.15 ± 1.24, 20.32 ± 1.93 ml/min·100 ml, P < 0.01). Forearm oxygen extraction, calculated from brachial venous and systemic arterial blood, was consistently increased in CHF and was sufficient to maintain a normal forearm oxygen consumption at rest (CHF: 0.14 ± 0.04; N: 0.12 ± 0.01 ml O2/min · 100 ml, P < 0.5). During exercise the calculated index of oxygen consumption was reduced at all levels of exercise (CHF: 0.30 ± 0.04, 0.48 ± 0.09, 0.54 ± 0.14; N: 0.51 ± 0.05, 0.89 ± 0.08, 1.63 ± 0.13 ml O2/min · 100 ml, P < 0.01). These differences persisted despite alpha-adrenergic blockade with phentolamine and suppression of skin flow in N by epinephrine iontophoresis. Therefore, at comparable levels of dynamic forearm exercise patients with CHF have an inadequate arteriolar dilation and their augmented oxygen extraction is not sufficient to prevent them from shifting more completely to anaerobic metabolism.

Quantification of the contractile state of the intact human heart: Maximal velocity of contractile element shortening determined by the instantaneous relation between the rate of pressure rise and pressure in the left ventricle during isovolumic systole

Abstract A new and easily applicable means based on force-velocity principles within the framework of muscle mechanics is presented for quantification of ventricular contractility, independent of loading, in conscious patients. In the intact heart during isovolumic contraction, alterations in ventricular geometry are small, and thus contractile element velocity (VCE) can be assumed to equal series elastic elongation. It was therefore considered in this study that VCE during isovolumic portion of ejecting beats could be determined entirely from isovolumic pressure (IP) and its rate of rise ( dP dt ) without requiring knowledge of tension; this provided the rational basis for accurate calculation of instantaneous isovolumic VCE in the spherical or ellipsoidal ventricle as ( dP dt )/( K × IP ) , where K is series elastic constant of 32 per muscle length (ML) at body temperature. Further, it was recognized that VCE at the ordinate is identical when derived from pressure-velocity or tension-velocity curves, and since the left ventricular pressure-velocity relation can be defined precisely, construction of the isovolumic IP to VCE curve and extrapolation to zero load allowed determination of maximal VCE (vmax), the independent numerical measure of contractility. High fidelity left ventricular pressures and corresponding dP dt were continuously recorded in 23 studies in 8 conscious patients without valvular regurgitation or ventricular segmental disease. Increasing contractility by leg exercise raised VMAX from 1.19 to 1.58 ML/sec and by isoproterenol to 2.03 ML/sec (P dP dt during isovolumic systole affords a new, practical, sensitive and valid means of quantifying left ventricular contractility Without influence of preload and afterload from beat to beat in individual patients. In addition, since VMAX is expressed in terms of muscle units and is free of variables of left ventricular loading and wall thickness, this method permits specific comparison of inotropic state among different patients.

Clinical use of sodium nitroprusside in chronic ischemic heart disease. Effects on peripheral vascular resistance and venous tone and on ventricular volume, pump and mechanical performance.

Although hemodynamic benefit has been shown with sodium nitroprusside (NP) in acute coronary pump failure, complete understanding of the mechanisms of action of the agent on the cardiocirculation and its value in chronic ventricular dysfunction are lacking. This investigation evaluates the effects of NP on the systemic and regional arterial and venous beds and on cardiac dynamics, ventricular volumes, contractile state and myocardial energetics in long-standing congestive heart failure. Twelve patients with chronic coronary pump dysfunction received NP infusion to lower systolic pressure to 95-105 mm Hg. Left ventricular (LV) function was assessed directly by angiographic volumes and high fidelity pressure, and peripheral circulatory dynamics were determined simultaneously by forearm arterial and venous plethysmography. NP reduced mean arterial pressure (MAP) from 88.2 to 73.4 mm Hg (P < 0.05) and significantly (P < 0.05) enhanced the variables of LV performance: LV end-diastolic pressure (EDP) diminished from 18.5 to 9.9 mm Hg; ejection fraction rose from 0.47 to 0.55; percent of LV segmental shortening increased; and isovolumic and ejection indices of contractility improved. Concomitantly, NP reduced the indices of myocardial oxygen demands of ventricular tension time index and LVED volume index. These salutary effects on LV performance and energetics occurred secondary to peripheral arterial and venous dilation (P < 0.05) produced by NP: total systemic vascular resistance was lowered from 1590 to 1310 dynes sec cm-5; forearm vascular resistance diminished from 46 to 37 mm Hg/ml/100 gm/min; and forearm venous tone fell from 14.2 to 10.1 mm Hg/cc. Depressed stroke index (SI) and cardiac index (CI) increased (P < 0.05) with NP, despite the fall in LVEDP, when ventricular filling pressures with the agent were at levels slightly above normal. Dextran infusion given with NP to restore LVEDP to moderately elevated values increased SI and CI (P < 0.05) when NP alone produced no change in stroke output. Thus, the peripheral vasodilator properties of nitroprusside improve LV function by reducing impedance to ventricular ejection, while MVO2 is diminished by decreasing LV preload and afterload through relaxing actions on both systemic arterial and venous smooth muscle. These LV unloading effects of nitroprusside in chronic congestive heart failure are most beneficial in patients with marked pump dysfunction and greatly elevated LVEDP and peripheral vascular resistance.

Abnormalities in the regional circulations accompanying congestive heart failure

In congestive heart failure, patients appear to have alimited ability to dilate their resistance vessels in skeletal muscle in response to a metabolic stimulus. This is true whether the metabolic stimulus is ischemia, dynamic, or static exercise. The mechanism for this limited arteriolar capacity is at least twofold; an increased sodium content of the vessels as well as an increased tissue pressure which is seen in edematous states. This can be considered a positive compensatory mechanism in that it helps to maintain systemic arterial pressure during exercise when the cardiac output fails to increase normally. If the resistance vessels were to dilate normally, then in the face of a limited cardiac output, exercise syncope would be expected to occur...

Electrocardiographic and Cineangiographic Correlations in Assessment of the Location, Nature and Extent of Abnormal Left Ventricular Segmental Contraction in Coronary Artery Disease

The relationship between the resting electrocardiogram and left ventricular contractile pattern, as documented by angiography, was evaluated in 123 patients with coronary artery disease who underwent left ventriculography. Dyssynergy was present in 73/77 (95%) patients with pathologic Q waves on ECG recordings in contrast to 11/46 ( 24%; P < 0.01) without Q waves. The location of Q waves correlated well with the site of abnormal ventricular motion: antero-apical dyssynergy in 40/40 (100%) patients with anterior myocardial infarction (MI) and infero-apical dyssynergy in 25/28 (89%) with inferior MI. Four contraction patterns were defined: 1) normal motion-39 patients (35 without Q waves, four with inferior or posterior Q waves); 2) segmental hypokinesis-37 patients (six without Q, 31 with Q); 3) segmental akinesis-26 patients (four without Q, 22 with Q); and 4) localized dyskinesis-aneurysm in 21 patients (only one without Q, 20 with Q). The presence of ST elevation and T wave inversion (ST↑ - T↓) along with Q waves were associated with dyskinesis or akinesis in 18/19 (95%) patients. The Q wave location reflected the type of dyssynergy: 32/40 (80%) patients with anterior MI had akinesis or dyskinesis, while 18/28 (64%) patients with inferior MI exhibited hypokinesis. Lateral extension of the Q wave in an anterior MI was related to the dyssynergy type (average V lead: 4.9 in dyskinesis and 3.3 in hypokinesis; P < 0.05) and extent (dyssynergy area /LV silhouette: 31% with Q to V3 and 58% to V5 or V6; P < 0.05). Dyssynergy area was larger in isolated anterior than inferior MI (42% and 23% of LV perimeter; P < 0.05) and largest in the anterior-inferior MI (68%; P < 0.05). Dyssynergy was more extensive with Q and ST↑-T↓ than with Q alone (48% and 33% LV perimeter; P < 0.05). Thus, specific QRS and ST-T wave alterations, when monitoring coronary disease, accurately predict characteristics of LV dyssynergy: Q identifies its presence and location and Q with ST↑-T↓ estimates its nature and extent.

Diminished Forearm Arteriolar Dilator Capacity Produced by Mineralocorticoid-Induced Salt Retention in Man Implications Concerning Congestive Heart Failure and Vascular Stiffness

The mechanism of the increased stiffness of peripheral vessels in patients with congestive heart failure (CHF) is unknown. It was considered that an increased sodium (Na+) content of peripheral vessels, shown in experimental CHF, might lead to diminished arteriolar dilator capacity. Thus, Na+ retention was induced in six normal volunteers by the daily oral administration of 0.2 mg of fludrocortisone acetate (F) and 10 g NaCl for 1 week. This induced a weight increase of 3.1 lb and increased serum Na+ and decreased serum potassium concentrations (P < 0.02). The peak reactive hyperemia blood flow (RHBF) was measured plethysmographically in the forearm before and after treatment. Upon restoration of the circulation after 1, 5, and 10 min of ischemia the peak RHBF was 21.8, 33.1, and 34.9 ml/min/100 ml before administration of F and NaCl but was reduced to 19.6 (P > 0.2), 28.6 (P < 0.02), and 24.4 (P < 0.02) ml/min/100 ml by treatment. Thus, steroid-induced salt retention leads to diminished vascular compliance. Furthermore, it is suggested that increased vascular Na+ content is causally related to the vascular stiffness abnormality characterostic of CHF.

Current concepts and treatment of digitalis toxicity.

Abstract Digitalis toxicity is among the most common adverse drug reactions, and may cause arrhythmias and conduction disturbances in as many as 1 of 5 patients. Particularly responsible are the electrophysiologic properties of digitalis in increasing the automaticity of subsidiary pacemakers, reducing the refractory period and prolonging conduction velocity in the atria and ventricles, and delaying conduction in the atrioventricular (A-V) node. Underlying these electrophysiologic effects are digitalis-influenced alterations of cardiac cell transmembrane movements of sodium and potassium; the induction of ectopic impulses due to increased automaticity appears to be caused by inhibition of the activity of the sodium-potassium membrane adenosine triphosphatase (ATPase) pump. Digitalis can provoke every type of cardiac arrhythmia, and no specific disorder of rhythm can be considered absolutely pathognomonic of digitalis toxicity. The factors that predispose to digitalis toxicity, as well as the onset and duration of action of the agent, must be taken into account. Potassium has relatively little influence on the toxic and the contractile actions of digitalis when the cation is administered after the glycoside has been taken up by the myocardium. In contrast, alterations in serum potassium effected before treatment with digitalis may have drastic effects on the electrophysiologic and contractile actions of the glycoside; hyperkalemia reduces the binding of digitalis to the myocardium. Diphenylhydantoin, lidocaine and propranolol are effective in terminating digitalisprovoked tachyarrhythmias, usually without inducing or worsening A-V block. Atrial or ventricular pacing to achieve electrical overdrive of the ectopic focus may be used if standard measures fail. In complete heart block, potassium should not be administered; atropine and electrical pacing should be used.

An apolipoprotein preferentially enriched in cholesteryl ester-rich very low density lipoproteins☆

Abstract One of the plasma apolipoproteins, rich in arginine and predominantly alpha-helical in conformation, is preferentially enriched in cholesteryl ester-rich very low density lipoproteins. The incidence of plasma lipoproteins that are enriched in the arginine-rich apolipoprotein appears to be a function of genetic, hormonal, and dietary factors and is high in hypothyroidism and type III hyperlipoproteinemia and in rabbits fed excess cholesterol. This apolipoprotein appears to be one of several involved primarily in the transport and metabolism of cholesteryl esters and/or cholesterol.

Indirect assessment of myocardial oxygen consumption in the evaluation of mechanisms and therapy of angina pectoris

Abstract Exercise testing, applied in a systematic, standardized manner, is a more reliable means of assessing angina pectoris than clinical evaluation. In utilizing exercise testing to determine functional impairment In angina, it is essential to distinguish between external stress, or the load on the skeletal muscles, and internal or cardiac stress. This distinction is critical to meaningful evaluation of angina since the performance of the heart is of primary concern in this syndrome. Evaluation of external exercise capacity alone is limited as a measure of cardiac performance since the relationship between external function and cardiac performance may not be direct. A readily applicable approach to determination of cardiac functional capacity in angina is afforded by indirect assessment of myocardial oxygen consumption (MVO 2 ). This is achieved through derived indexes of heart rate and blood pressure, two major determinants of MVO 2 , usually in the form of the product of heart rate × systolic blood pressure × systolic ejection period (triple product) or the product of the first two variables (double product). Although these indexes do not encompass all the major determinants of MVO 2 , they demonstrate a constancy at the point of angina in each individual that is consistent with the occurrence of this syndrome at a peak, critical threshold of MVO 2 above which regional myocardial perfusion cannot rise. Utilization of indirect indexes of MVO 2 allows evaluation of the mechanisms of action of a variety of conditions and therapeutic interventions in angina. Thus, enhanced perfusion of ischemic myocardium is suggested by augmentation of the triple product when angina occurs during exercise, as observed after successful aortocoronary bypass graft surgery. Medical therapy of angina acts through a fundamentally different mechanism demonstrated by reduction in the triple product at given levels of exercise with no increase at the point of angina, thus indicating a major effect on the circulatory response to the physical stress. Indirect indexes of MVO 2 are thus useful in interpreting mechanisms and evaluating therapy of angina but they must be applied with appropriate caution because of their inherent limitations.

Alterations of hemodynamics and myocardial mechanics in patients with congestive heart failure: Pathophysiologic mechanisms and assessment of cardiac function and ventricular contractility

HE FUNDAMENTAL PHYSIOLOGIC DERANGEMENTS, the disturbed events comprising cardiac contraction, the altered modulation of cardiovascular function, and the role of compensatory mechanisms in patients with congestive heart failure have been the subject of intense interest and investigation for many years. In the past, considerable attention has been focused on the clinical manifestations of heart failure and the hemodynamic alterations characteristic of this common pathologic condition. More recently, following the development of a multiplicity of improved technics and their application to experimental biologic systems and patients, a great body of new information has been provided which has permitted important advances in our understanding of the pathophysiology of congestive heart failure. Therefore, it is desirable at this time to examine certain of these findings, methods of evaluation, and current concepts concerning the mechanisms and regulation of contraction of the failing heart in man. This work begins with consideration of the principal determinants governing the performance of the intact ventricle and progresses to interpretation of the experimental data which form the basis for the conclusion that, of these major determinants, the fundamental abnormality in congestive heart failure