Joseph A. Franciosa

Relation between hemodynamic and ventilatory responses in determining exercise capacity in severe congestive heart failure

The cause of exercise intolerance in congestive heart failure is unclear. Hemodynamic and ventilatory responses were measured during symptomatic maximal upright bicycle exercise in 28 patients with chronic severe left ventricular failure who achieved a maximal oxygen uptake of only 12 +/- 4 ml/min/kg (+/- standard deviation). All patients reached anaerobic metabolism as the respiratory exchange ratio rose and arterial pH fell significantly. Pulmonary capillary wedge pressure increased from 20 +/- 10 mm Hg at rest to 38 +/- 9 mm Hg at peak exercise and cardiac index increased from 2.51 +/- 0.73 to 4.54 +/- 1.65 liters/min/m2 (both p less than 0.001). Systemic vascular resistance decreased, but pulmonary vascular resistance did not change during exercise. Despite the marked pulmonary venous hypertension at peak exercise, blood gases were unchanged (PaO2, 96 +/- 15 mm Hg; PaCO2, 35 +/- 7 mm Hg). Systemic arterial oxygen content increased from 16 +/- 2 to 17 +/- 2 vol% (p less than 0.01). Changes in pulmonary capillary wedge pressure did not correlate with changes in arterial oxygen content. Results were similar whether patients were limited by dyspnea or fatigue. Thus, exercise intolerance in patients with severe left ventricular failure is associated with marked elevation of pulmonary capillary wedge pressure and anaerobic metabolism without hypoxemia or altered carbon dioxide tension. These findings suggest that exercise ability in congestive heart failure is more dependent on cardiac output than on ventilatory consequences of pulmonary congestion.

Pulmonary versus systemic hemodynamics in determining exercise capacity of patients with chronic left ventricular failure

Right, but not left ventricular ejection fraction correlates with exercise capacity in patients with left ventricular failure, suggesting an important role of the pulmonary circulation. Hemodynamics were measured at rest and during bicycle exercise to symptomatic maximum in 41 patients with chronic left ventricular failure. Maximal oxygen consumption averaged only 12.8 +/- 5.2 ml/min/kg. Pulmonary wedge pressure rose from 21.9 +/- 8.2 to 35.9 +/- 9.3 mm Hg during exercise, while pulmonary arterial mean pressure rose from 31.8 +/- 10.9 to 50.4 +/- 12.9 mm Hg (both p less than 0.0001). Resting cardiac index and resting systemic arterial mean pressure did not correlate with maximal oxygen consumption (r = 0.23 and 0.20, respectively), which, however, did correlate with pulmonary wedge pressure (r = -0.54, p less than 0.001), pulmonary arterial mean pressure (r = -0.49, p less than 0.01), and total pulmonary resistance (r = -0.43, p less than 0.01). Maximal oxygen consumption did not correlate with resting systemic vascular resistance (r = -0.20) or resting pulmonary vascular resistance (r = -0.26). During exercise, total pulmonary resistance remained unchanged at 6.5 +/- 3.8 U while systemic vascular resistance fell significantly. The relation between total pulmonary resistance and exercise capacity and the failure of total pulmonary resistance to fall during exercise suggest that afterload on the right ventricle may be an important determinant of exercise capacity in patients with chronic left ventricular failure.

Effects of vasodilators on pulmonary hemodynamics and gas exchange in left ventricular failure

Abstract Nitroprusside (NP) has been shown to improve left ventricular function in patients with congestive heart failure, but despite an increased cardiac output and decreased pulmonary capillary pressure, arterial oxygen tension (P a O 2 ) may fall. In order to determine the mechanism of this hypoxemia, and to determine if similar effects occur with non-parenteral vasodilators, hemodynamic, respiratory, and blood gas responses to NP, hydralazine (H), and hydralazine combined with isiosorbide dinitrate (H+N) were studied in 10 patients with left ventricular failure. At the dosages used, all three drug regimens increased cardiac output equivalently, but pulmonary vascular responses differed. NP and H+N decreased mean pulmonary artery pressure, pulmonary wedge pressure, and pulmonary arteriolar resistance, while H did not. NP decreased P a O 2 by 10.4 mm. Hg (p a O 2 . Arteriolar-alveolar oxygen gradient increased with NP (150 ± 39 per cent, p a O 2 . Changes in arteriolar-alveolar oxygen gradient correlate with the changes in pulmonary arteriolar resistance. Thus vasodilators which have prominent pulmonary vascular effects can decrease P a O 2 in patients with congestive heart failure, and this effect is most likely due to increasing ventilation-perfusion inequities.

Antihypertensive and Hemodynamic Properties of the New Beta Adrenergic Blocking Agent Timolol

The antihypertensive activity of timolol, a new beta adrenergic blocking agent, was assessed in hypertensive patients. In hospitalized patients timolol, 5 mg orally every 8 hr for one week, resulted in a significant although mild reduction of blood pressure with diastolic pressure falling from a mean of 101 mm Hg to 91 mm Hg. Heart rate and cardiac output fell while total peripheral resistance increased. The Valsalva response, the reflex tachycardia following inhalation of amyl nitrite and the cardiovascular responses to infusion of isoproterenol were significantly inhibited. Timolol also was compared to propranolol in a randomized double-blind outpatient trial. The antihypertensive and bradycrotic effects of the two drugs were similar. Heart rate was reduced 18% by both drugs (P < 0.05). Supine diastolic pressure fell 9% (P < 0.05). Unlike the short term effects of timolol, and in contrast to propranolol, cardiac output did not remain reduced after five weeks of continuous treatment with timolol. It is concluded that timolol merits further investigation as an antihypertensive agent.

Effect of hydralazine on renal failure in patients with congestive heart failure.

SUMMARYHydralazine is known to improve cardiac function in patients with congestive heart failure (CHF), but its effects on renal function in CHF are less clear. Sodium retention is known to occur with longterm use of hydralazine to treat hypertension; if this occurs in patients with CHF it could be deleterious. Therefore, in a metabolic unit we studied renal effects of hydralazine in patients with stable class III or IV CHF. In a single-blind study, the patients were given placebo twice daily for 3 days (period P-1), 100 mg of oral hydralazine twice daily for 3 days (period P-H), and placebo for 3 more days (period P-2). The average 24-hour creatinine clearance was 69.7 ± 7.7 ml/min (mean ± SEM) in P-1, increased to 76.3 ± 9.0 ml/min with hydralazine (p < 0.01) and fell again when hydralazine was stopped (P-2) to 68.5 ± 7.8 ml/min (p < 0.02). Though the slight improvement in sodium excretion was not statistically significant (60.2 ± 12.1 mEq in P-1, 64.5 ± 12.4 mEq in P-H, 52.3 ± 7.7 mEq in P-2), serum osmolality decreased from 288 ± 1.8 mosM in P-1 to 283 ± 1.9 mosM in P-H (p < 0.02) and rose to 286 ± 1.9 mosM in P-2 (NS). During the three periods, serum sodium, chloride, potassium, carbon dioxide, blood urea nitrogen, creatinine and glucose were unchanged, as were weight and urine volume. Systolic blood pressure was 109.6 ± 3.6 mm Hg in P-1, 110.1 ± 3.9 mm Hg in P-H (NS), and 114.2 ± 5.0 mm Hg in P-2 (p < 0.05). Diastolic blood pressure, heart rate and respirations were unchanged. Thus, we found no evidence of sodium or water retention during hydralazine administration in patients with CHF, and renal function was actually improved, as evidenced by the increased creatinine clearance.

Comparison of a new beta adrenergic blocker (MK 950) and propranolol in man

The effects of oral doses of MK 950 and propranolol on heart rate in the sitting and standing positions were measured in 6 volunteers. Although the response to beta blockade is related to the initial heart rate and to the log of the dose of the drug, multiple regression analysis made it possible to separate these interactions. In a dose of 2.5 mg. orally, MK 950 reduced heart rate to the same degree as did 20 mg. of propranolol. The regression lines relating dose to response of the heart rate was steeper for MK 950 than for propranolol. There was a fall of about 20 per cent in heart rate and cardiac output after 5 mg. of MK 950, with little change in stroke volume or blood pressure. MK 950 blocked the response to isoproterenol infusion in doses up to 8 µg per minute and reduced the heart rate response to tilting and amylnitrite inhalation and the pressure overshoot in Valsalva maneuver.

Significance of hypotension preceding fatal ventricular tachyarrhythmias in post-coronary obstruction sudden death

While sudden death after acute myocardial infarction or ischemia most commonly occurs in the first few minutes, usually from tachyarrhythmias, little is known of associated hemodynamics. We monitored hemodynamics for 15 minutes following coronary embolization with mercury in 31 awake dogs. In 17 nonsurvivors, mean arterial pressure (MAP) fell 7 mm Hg at 15 seconds, 15 mm Hg by 45 seconds, 27 mm Hg at 120 seconds, and continued falling until ventricular fibrillation (VF) occurred. In contrast, in 14 survivors, MAP was unchanged at 15 seconds, fell 8 mm Hg at 45 seconds, 15 mm Hg at 120 seconds, and than returned toward control. The decline in MAP was significantly greater and earlier in nonsurvivors. Heart rate increased at 15 seconds in nonsurvivors (21 bpm) but not until 75 seconds in survivors (33 bpm). Cardiac output fell significantly only in nonsurvivors. Ventricular ectopics (greater than 5 beats/15 sec) first appeared after hemodynamic changes in both groups; at 68 seconds in survivors and at 45 seconds in non survivors. While such ectopy persisted at the same frequency thereafter in both groups, VF occurred only in the more hypotensive dogs at 177 seconds. In a second series of 26 dogs, hypotension was randomly treated by intra-aortic balloon. All nine nonhypotensive dogs survived, whereas five of six untreated hypotensive dogs died compared to 2 of 11 treated ones (p less than 0.02). We conclude that significant hemodynamic changes precede ectopy, and VF and sudden coronary death occurs usually after persistence of hypotension.

Isosorbide dinitrate and exercise performance in patients with congestive heart failure

Nitrates are widely used for the management of congestive heart failure (CHF), as well as angina pectoris. In both situations, nitrates significantly increase exercise capacity. The mechanism of this beneficial effect is unclear, especially in CHF. Isosorbide dinitrate reduces pulmonary capillary wedge pressure (PCWP) after a first dose. The improvement in exercise capacity is not apparent in the short term but is evident after long-term nitrate administration. Nitrates do not affect hemodynamics at maximal exercise but do reduce PCWP during submaximal exercise in patients with CHF. This observation, in addition to increased oxygen extraction at peak exercise during nitrate administration, suggests a training like peripheral effect of nitrates in CHF. Lowering of PCWP by nitrates may be important, since vasodilators that do not reduce PCWP also do not improve exercise capacity in CHF. How PCWP influences exercise performance in CHF is unknown, but the mechanism may relate to effects of PCWP on pulmonary hemodynamics more than on ventilation and blood oxygenation.

Effect of Systemic Vasoconstriction on Left Ventricular Function: Implications Regarding Hypertension and Heart Failure

A high impedance to left ventricular ejection (aortic input impedance) is a hallmark of hypertension. Cardiac output and stroke volume remain normal, despite this increased impedance, and arterial pressure therefore rises. The ability of the left ventricle to withstand this increased impedance is probably dependent on both acute and chronic compensatory mechanisms. The acute response probably involves primarily an increase in end-diastolic fiber length (Frank-Starling mechanism) that allows the left ventricle to maintain its stroke volume against a higher outflow resistance. The more chronic response involves myocardial hypertrophy, which tends to restore left ventricular wall stress to normal despite the increased systolic pressure [1]. At a later stage ventricular dilation supervenes, wall stress rises again, and heart failure may develop.