Cardiovascular Manifestations and Complications of Pheochromocytomas and Paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare neuro-endocrine tumors. The catecholamine surge causes paroxysmal or chronic secondary hypertension. PPGLs may present as hypertensive- or PPGL-crisis with severe life-threatening cardiac and cerebrovascular complications. PPGLs-induced cardiac manifestations have been reported with diagnoses as PPGLs-induced electrocardiogram (ECG) changes “mimicking acute myocardial infarction”, arrhythmias, myocarditis, acute coronary syndrome, dilated cardiomyopathy, and lately as takotsubo syndrome. Critical analysis of these reports reveals that most of these cardiac manifestations have certain features in common. They have a dramatic clinical presentation and are reversible if the disease is treated with appropriate medical therapy and surgical resection of the PPGL tumor. They may have the same repolarization ECG changes irrespective of the clinical cardiac diagnosis, usually associated with mild to moderate elevations of myocardial biomarkers as troponins and normal coronary arteries. The histopathological findings are usually focal or multifocal in the form hypercontracted sarcomeres and contraction band necrosis (myofibrillar degeneration) with subsequent secondary mononuclear cell infiltration. Evidences argue the PPGL caused surge of catecholamines triggers hyperactivation of the sympathetic nervous system with cardiac sympathetic nerve terminal disruption with norepinephrine spillover causing the cardiac complications. A comprehensive review of various reported cardiovascular manifestations and complications of PPGLs are presented.

Mechanisms of postspaceflight orthostatic hypotension: low α1-adrenergic receptor responses before flight and central autonomic dysregulation postflight

Although all astronauts experience symptoms of orthostatic intolerance after short-duration spaceflight, only ∼20% actually experience presyncope during upright posture on landing day. The presyncopal group is characterized by low vascular resistance before and after flight and low norepinephrine release during orthostatic stress on landing day. Our purpose was to determine the mechanisms of the differences between presyncopal and nonpresyncopal groups. We studied 23 astronauts 10 days before launch, on landing day, and 3 days after landing. We measured pressor responses to phenylephrine injections; norepinephrine release with tyramine injections; plasma volumes; resting plasma levels of chromogranin A (a marker of sympathetic nerve terminal release), endothelin, dihydroxyphenylglycol (DHPG, an intracellular metabolite of norepinephrine); and lymphocyte β2-adrenergic receptors. We then measured hemodynamic and neurohumoral responses to upright tilt. Astronauts were separated into two groups according to their ability to complete 10 min of upright tilt on landing day. Compared with astronauts who were not presyncopal on landing day, presyncopal astronauts had 1) significantly smaller pressor responses to phenylephrine both before and after flight; 2) significantly smaller baseline norepinephrine, but significantly greater DHPG levels, on landing day; 3) significantly greater norepinephrine release with tyramine on landing day; and 4) significantly smaller norepinephrine release, but significantly greater epinephrine and arginine vasopressin release, with upright tilt on landing day. These data suggest that the etiology of orthostatic hypotension and presyncope after spaceflight includes low α1-adrenergic receptor responsiveness before flight and a remodeling of the central nervous system during spaceflight such that sympathetic responses to baroreceptor input become impaired.

Renin-angiotensin system inhibition on noradrenergic nerve terminal function in pacing-induced heart failure

Chronic angiotensin-converting enzyme (ACE) inhibition has been shown to improve cardiac sympathetic nerve terminal function in heart failure. To determine whether similar effects could be produced by angiotensin II AT1 receptor blockade, we administered the ACE inhibitor quinapril, angiotensin II AT1 receptor blocker losartan, or both agents together, to rabbits with pacing-induced heart failure. Chronic rapid pacing produced left ventricular dilation and decline of fractional shortening, increased plasma norepinephrine (NE), and caused reductions of myocardial NE uptake activity, NE histofluorescence profile, and tyrosine hydroxylase immunostained profile. Administration of quinapril or losartan retarded the progression of left ventricular dysfunction and attenuated cardiac sympathetic nerve terminal abnormalities in heart failure. Quinapril and losartan together produced greater effects than either agent alone. The effect of renin-angiotensin system inhibition on improvement of left ventricular function and remodeling, however, was not sustained. Our results suggest that the effects of ACE inhibitors are mediated via the reduction of angiotensin II and that angiotensin II plays a pivotal role in modulating cardiac sympathetic nerve terminal function during development of heart failure. The combined effect of ACE inhibition and angiotensin II AT1 receptor blockade on cardiac sympathetic nerve terminal dysfunction may contribute to the beneficial effects on cardiac function in heart failure.

ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure

Cardiac sympathetic nerve terminal dysfunction plays an important role in the downregulation of myocardial β-adrenoceptors in heart failure. To determine whether chronic angiotensin-converting enzyme (ACE) inhibition improved cardiac sympathetic nerve terminal function and hence increased myocardial β-adrenergic responsiveness, we administered ACE inhibitors to dogs with chronic right-sided heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. The RHF animals exhibited fluid retention, elevated right heart filling pressures, blunted inotropic response to isoproterenol, and reduced β-adrenoceptor density. These changes were accompanied by decreases in right ventricular norepinephrine (NE) uptake and neuronal NE histofluorescence and tyrosine hydroxylase immunoreactive profiles. ACE inhibitors had no effect on the production of heart failure but greatly reduced the attenuation of cardiac NE uptake, neuronal NE histofluorescence, and tyrosine hydroxylase immunoreactive profiles. ACE inhibition also improved the inotropic response to isoproterenol and restored myocardial β-adrenoceptor density. The changes probably are caused by reduction of cardiac NE release by ACE inhibition and may contribute to the beneficial effects of ACE inhibitor therapy in patients with chronic heart failure.