Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension

Abstract

Background: Diseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[(18)F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.

Methods: Cardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD+NOH or PAF (PD+NOH/PAF group, N=13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N=15), and in normal control subjects (N=5).

Results: The innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD+NOH/PAF group. For similar heart rate responses, the PD+NOH/PAF group required less isoproterenol (p<0.01) and had lower plasma isoproterenol levels (p<0.01) than did the MSA group.

Conclusions: Among patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.

Figures

Figure 1

Systolic (SBP; panel A) and diastolic (DBP; panel B) blood pressure (BP) at baseline (BL) and during tyramine (TYR) infusion in patients with cardiac sympathetic denervation (DEN; white bars), in patients with normal cardiac innervation (INN; black bars), and in healthy controls (CON; dashed bars). *p

Figure 2

Preejection period index (PEPI; panel A) and systolic time ratio index (STRI) defined as ratio of PEPI to left ventricular ejection time index (panel B) at baseline (BL) and during tyramine (TYR) infusion in patients with cardiac sympathetic denervation (DEN; white bars), in patients with normal cardiac innervation (INN; black bars) and in healthy controls (CON; dashed bars). *p

Figure 3

Correlations between myocardial 6-[18F] fluorodopamine-derived radioactivity in the interventricular septum subtracted by the radioactivity in the chamber and PEPI decrement (deltaPEPI; panel A) as well as between the former and STRI decrement (deltaSTRI; panel B) in response to TYR infusion in patients with cardiac sympathetic denervation (white circles), in patients with normal cardiac innervation (black circles), and in healthy controls (black squares).

Figure 4

Plasma levels of dihydroxyphenylglycol (DHPG; panel A) and norepinephrine (NE; panel B) at baseline (BL) and during tyramine (TYR) infusion in patients with cardiac sympathetic denervation (DEN; white bars), in patients with normal cardiac innervation (INN; black bars), and in healthy controls (CON; dashed bars). *p

Figure 5

Concentration of isoproterenol (ISO) in plasma (left y-axis), ISO infusion rate (right y-axis), at ISO criterion dose i.e. approximately 25 beats per minute increase from baseline in patients with cardiac sympathetic denervation (DEN; white bars) and in patients with normal cardiac innervation (INN; black bars). **p