Search

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45 pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF., (© 2023. The Author(s).)

To determine the cardiac and peripheral circulatory responses to changes in afterload with angiotension and vasopressin, we increased mean aortic pressure 25% and 50% above control in splenectomized and ganglion-blocked dogs. We compared these responses to similar mechanical increases in aortic pressure produced by partial balloon occlusion of the descending aorta. With 25% or 50% increases in aortic pressure, angiotensin, vasopressin, and balloon inflation produced no changes in heart rate, right atrial, and mean pulmonary artery pressures. At 25% increase in aortic pressure, cardiac output was maintained with angiotensin and balloon occlusion but decreased with vasopressin. At 50% increase in aortic pressure, cardiac output was maintained with only balloon occlusion and decreased with both angiotensin and vasopressin. Whenever cardiac output fell, central blood volume did not increase as after-load increased. These changes in preload can be explained by alterations in the venous circulation. Vasopressin did not alter venous compliance or unstressed vascular volume but increased resistance to venous return. Angiotensin also increased resistance to venous return but decreased venous compliance and did not change unstressed vascular volume. Balloon occlusion had no effects on these parameters. We conclude that: (a) angiotensin caused significant venoconstriction resulting in maintenance of cardiac output at 25% but not 50% increase in aortic pressure; (b) vasopressin increased the resistance to venous return without venoconstriction; this resulted in a fall in cardiac output even with a 25% increase in aortic pressure; and (c) the effects of the agents on the venous circulation were independent of the mechanical effects of a pressure increase in the arterial circulation.

A retrospective review was conducted to determine the incidence of cardiac catheterization for postinfarction angina, the associated coronary anatomy, and the subsequent clinical course. Over one year, 30 of 178 myocardial infarctions were complicated by postinfarction angina resulting in cardiac catheterization. This was 18% of cardiac catheterizations for evaluation of coronary artery disease. Among the 30 patients, 3 had left main disease, 3 had triple-vessel disease, 11 had double-vessel disease, 11 had single-vessel disease, and 2 had no significant disease. Nine patients had proximal left anterior descending disease without left main disease. In contrast to previous autopsy or surgical series, the extent of coronary artery involvement was less severe and followed a distribution similar to that found in uncomplicated myocardial infarctions. Nevertheless, 17 of the 30 patients underwent revascularization with angioplasty or bypass surgery compared with 41 of 137 without postinfarction angina (p = 0.01). Clinical characteristics of the patients with postinfarction angina did not predict who would ultimately require revascularization. Cardiac catheterization is necessary for management of patients with postinfarction angina, because a majority of them will require revascularization.

To study the effects of an inotropic agent, milrinone, on the entire cardiovascular system, we developed an intact dog model to assess the responses of the heart, arterial and venous circulations. At a dose that increased left ventricular dP/dt by 30% (P less than .001) from 2033 +/- 133 to 2688 +/- 140 mm Hg/sec, milrinone caused a decrease (P less than .001) in mean aortic pressure from 88.4 +/- 3.5 to 73.1 +/- 3.0 mm Hg and cardiac output from 148.0 +/- 14.6 to 134.5 +/- 13.9 ml/kg/min. Heart rate increased (P less than .01) from 124 +/- 8 to 135 +/- 8 beats/min. Systemic vascular resistance did not change. Right atrial pressure and left ventricular end-diastolic pressure decreased (P less than .01). Total blood volume did not change but central blood volume decreased (P less than .01) from 26.1 +/- 0.9 to 22.3 +/- 0.5 ml/kg. After milrinone administration, mean circulatory filling pressure decreased (P less than .01) by 30% from 7.4 +/- 0.4 to 5.0 +/- 0.2 mm Hg. Vascular or venous compliance increased (P less than .05) slightly from 1.96 +/- 0.4 to 2.20 +/- 0.1 ml/mm Hg/kg. This was accompanied by an increase (P less than .01) in unstressed vascular blood volume of 3.3 +/- 0.6 ml/kg. Arterial compliance also increased (P less than .05). In summary, milrinone produces an increase in inotropy, arterial vasodilatation and venodilatation as evidenced by the increased venous compliance and unstressed vascular volume.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether changes in the venous circulation were responsible for preload-afterload mismatch with angiotensin, we examined the changes in the heart and the peripheral circulation in six splenectomized dogs after ganglion blockade during an angiotensin infusion to increase mean aortic pressure 25 and then 50%. The peripheral circulation was evaluated by measuring mean circulatory filling pressure (MCFP), arterial compliance, and venous compliance. A 25% increase in mean aortic pressure increased MCFP from 6.2 +/- 0.3 to 7.6 +/- 0.3 mmHg (P less than 0.001) but did not change cardiac output, heart rate, or stroke volume. Systemic vascular resistance increased (P less than 0.01) from 0.50 +/- 0.02 to 0.59 +/- 0.03 mmHg X min X kg X ml-1. Arterial and venous compliances decreased (P less than 0.01) from 0.08 +/- 0.03 to 0.06 +/- 0.03 ml X mmHg-1 X kg-1 and from 2.1 +/- 0.1 to 1.6 +/- 0.1 ml X mmHg-1 X kg-1, respectively. A 50% elevation in mean aortic pressure increased MCFP from 7.1 +/- 0.4 to 9.5 +/- 0.9 mmHg (P less than 0.001) but did not change heart rate. At this level of aortic pressure, cardiac output and stroke volume decreased (P less than 0.01) 12 and 19%, respectively, whereas systemic vascular resistance increased (P less than 0.001) from 0.48 +/- 0.03 to 0.83 +/- 0.05 mmHg X min X kg X ml-1. Arterial and venous compliances decreased (P less than 0.01) from 0.08 +/- 0.01 to 0.05 +/- 0.01 ml X mmHg-1 X kg-1 and from 2.1 +/- 0.1 to 1.4 +/- 0.1 ml X mmHg-1 X kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cocaine on the heart and peripheral circulation were examined in seven mongrel dogs. Hemodynamic variables, in addition to data on ventricular relaxation, mean circulatory filling pressure and arterial compliance, were measured during an intravenous infusion (0.5 mg/kg per min) of cocaine. Holter monitor recordings (6 h) and coronary arteriograms were also obtained. Cocaine increased (p less than 0.01) mean aortic pressure from 72 +/- 5 to 92 +/- 5, left ventricular systolic pressure from 102 +/- 3 to 121 +/- 5, left ventricular end-diastolic pressure from 4.9 +/- 1.3 to 8.2 +/- 1.4 and mean circulatory filling pressure from 7.9 +/- 0.4 to 10.9 +/- 0.5 mm Hg. Cardiac index and stroke volume decreased (p less than 0.01) from 166 +/- 17 to 125 +/- 8 ml/min per kg and from 44 +/- 4 to 29 +/- 3 ml, respectively. Ejection fraction decreased (p less than 0.01) from 61 +/- 1 to 49 +/- 3%. Heart rate, first derivative of left ventricular pressure (dP/dt) and right atrial, mean pulmonary artery and pulmonary artery wedge pressures did not change. The result was a 58% increase in systemic vascular resistance and a 32% decrease in arterial compliance. The pressure gradient for venous return did not change, but resistance to venous return increased 42%. Cocaine prolonged (p less than 0.05) the half-time of left ventricular isovolumic relaxation from 13.4 +/- 0.8 to 16.4 +/- 0.8 ms and the time constant of left ventricular isovolumic relaxation from 19.3 +/- 1.2 to 23.6 +/- 1.1 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

To define total vascular capacitance, we used acetylcholine to arrest the heart and measured mean circulatory filling pressure (MCFP) during controlled hemorrhage and volume loading in 12 splenectomized dogs after ganglion blockade with hexamethonium. We also examined the gross pathological and histological changes in the lungs. Controlled hemorrhage (n = 12) of 5 and 10 ml/kg decreased MCFP from 6.8 +/- 0.1 to 4.9 +/- 0.3 and 3.6 +/- 0.2 mmHg, respectively. Volume loading of 5 (n = 8) and 10 ml/kg (n = 4) increased MCFP to 9.3 +/- 0.2 and 12.1 +/- 0.1 mmHg, respectively. At MCFPs below 5 mmHg, the pressure (P)-volume (V) relationship was not linear [(P = P0ekV, where k is slope of ln (MCFP) vs. V, k = 0.061, R2 = 0.998]. At MCFPs between 5 and 12 mmHg, the pressure-volume relationship was linear (slope = 0.479 mmHg.ml-1.kg-1, R2 = 0.992) and total vascular compliance was 2.09 ml.mmHg-1.kg-1. There were no changes in heart rate, cardiac output, right atrial, pulmonary artery, and pulmonary artery wedge pressures when values at base line were compared with those measured 15 min after each arrest. There were no changes in arterial gas measurements or acid-base balance, and there was no evidence of atelectasis or interstitial or intra-alveolar edema. We conclude that the total body pressure-volume relationship in the presence of ganglion blockade had a nonlinear configuration. The use of acetylcholine to arrest the heart, four times with hexamethonium in reflex-blocked animals, did not result in changes in hemodynamics or pulmonary function.

To determine the effect of an anteroseptal myocardial infarction on right ventricular systolic and diastolic function, we studied 12 pigs before and 1 h after left anterior descending coronary artery occlusion. Total arterial occlusion was achieved by the percutaneous, transcatheter placement of a 1 mm Teflon plug into the mid portion of the artery. The resulting infarction involved 28 (SEM 3)% of the left ventricular wall, in the anterior and septal regions. A small rim of the right ventricular free wall adjacent to the septum and the right ventricular apex were also affected. End diastolic pressures in both ventricles rose significantly: left ventricular from 12(1) to 20(2) mm Hg and right ventricular from 8(1) to 10(1) mm Hg. Right ventricular peak systolic pressure increased from 29(2) to 35(2) mm Hg while left ventricular peak systolic pressure did not change. One hour after infarction the half time of isovolumic relaxation of the right ventricle was prolonged from 6.9(0.5) to 8.7(0.4) ms. Ejection fraction in both ventricles was depressed: from 46(1) to 34(2)% in the right ventricle and from 69(3) to 49(3) in the left ventricle. There was no change in either right or left ventricular dP/dt. These data suggest that right ventricular systolic and diastolic dysfunction occurs as the result of an anteroseptal myocardial infarction in pigs.

The cardiovascular system of hypothyroid, normal, and hyperthyroid rats was studied by evaluation of the peripheral venous circulation and left ventricular (LV) systolic and diastolic performance in rats. Cardiac index (CI) and CI during a volume load were measured in open-chest rats. When compared with control, hypothyroid rats showed a decrease in heart rate, aortic pressure, LV systolic pressure, first derivative for LV pressure (LV dP/dt), CI, and CI during a volume load. LV pressure-volume relation was shifted to the right, muscle stiffness was unchanged, and LV relaxation was prolonged. There was a decrease in mean circulatory filling pressure (MCFP) to 6.3 +/- 0.2 from 7.6 +/- 0.2 mmHg in control rats. This was associated with an 11% decrease in unstressed vascular volume and 12% decrease in total blood volume but no change in venous compliance. In hyperthyroid rats there was an increase in heart rate, LV systolic pressure, LV dP/dt, CI, and CI during a volume load. LV chamber stiffness was increased, but muscle stiffness and LV relaxation were unchanged. There was an increase in MCFP to 9.5 +/- 0.3 mmHg and a decrease in venous compliance to 2.65 +/- 0.12 compared with 3.20 +/- 0.09 ml.mmHg-1.kg-1 in control rats. Unstressed vascular volume and total blood volume were unchanged. In conclusion, hyperthyroid rats have augmented LV systolic function and altered diastolic function which, combined with changes in the venous circulation, result in increased venous return and thus cardiac output. In hypothyroid rats both LV systolic and diastolic function are altered. When combined with changes of the venous circulation the changes result in a decrease in cardiac output.