Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.

We did four experiments to determine whether the lateral hypothalamus-perifornical (LH/PF) region is the source of neuronal cell bodies responsible for producing the cardiovascular (CV) responses associated with emotion or the defense reaction. Of particular concern was whether the paraventricular nucleus (PVN) plays a role in the generation of these CV responses. Mapping the hypothalamus with electrical stimulation showed that the CV pattern of responses was never produced by stimulating the PVN and was invariably produced by stimulating the LH/PF region. Complete electrolytic destruction of the PVN and subsequent axonal degeneration did not change the CV pattern of responses elicited by LH/PF stimulation, whereas any encroachment of the lesion on the LH/PF region decreased the magnitude of the CV responses. Injection of the neuroexcitotoxin ibotenic acid (Ibo) into the PVN did not affect responses to LH/PF stimulation, whereas Ibo injection into the LH/PF region eliminated or severely attenuated the CV responses. Retrograde labeling of cells from the thoracic cord and the ventrolateral reticular formation revealed a scattered group of cells in the LH/PF region that may be the cells controlling the CV responses. These results point directly to the LH/PF region as the source of the cell bodies responsible for the autonomic responses associated with emotion or defense reactions.

Blood pressure, heart rate, oxygen consumption, and blood flow to the renal and hind-limb vasculatures were measured in healthy, unanesthetized baboons (Papio cynocephalus) in a controlled environment. Appropriate behavioral techniques were applied to allow the reproducible elicitation of a conditional emotional response (CER). Section of renal nerves and autonomic pharmacologic interventions were used to determine the mechanisms for the cardiovascular responses accompanying the CER. The resistance changes in the renal and hind-limb vascular beds were generated by rapid, neurally mediated vasoconstriction of the renal vasculature and by a slower acting, circulating vasoactive agent, most probably epinephrine, which causes a delayed second constriction in the renal bed and a net dilation in the hind limbs.

Bilateral carotid occlusion was performed in seven baboons during dynamic leg exercise, static arm exercise, feeding, rest, and sleep. The baroreceptor reflex effects on blood pressure, heart rate and interval, renal blood flow, and terminal aortic blood flow were determined during each behavior. The carotid sinus baroreflex increase in blood pressure and heart rate was greatest during sleep and least during exercise. The hindlimb and renal vasomotor responses followed different patterns. The baroreceptor reflex sensitivity for renal vasoconstriction was greatest during rest and least during sleep. The reflex sensitivity in the hindlimb was unaltered by behavior. Thus behavior modifies baroreceptor reflex responses in the heart and peripheral circulation in different patterns.

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