A visualization analysis of hotspots and frontiers of cardiovascular diseases with frailty.

Cardiovascular diseases (CVD) and frailty are common health problems among the elderly. This research aims to investigate the hotspots and frontiers of the field of CVD with frailty. Data of publications between 2000 and 2021 were collected from the Web of Science Core Collection (WoSCC) and CiteSpace was used for analyzing the hotspots and frontiers of cardiovascular diseases with frailty research from high-impact countries/regions, institutions, authors, cited references, cited journals, high-frequency keywords, and burst keywords. The results showed that the USA, England, and Canada were the leading countries/regions in research on CVD with frailty. Other countries/regions and regions lagged behind these developed countries/regions. There is a need to establish cooperation between developed countries/regions and developing countries/regions. Research hotspots focused on frailty in the elderly with CVD, exercise intervention, assessment for CVD patients with frailty, quality of life, and common diseases related to CVD with frailty. The frontier fields include care and intervention of CVD patients with frailty, social frailty, and validation of CVD with frailty.

Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk.

GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.

Epinephrine is required for normal cardiovascular responses to stress in the phenylethanolamine N-methyltransferase knockout mouse.

BACKGROUND: Epinephrine (EPI) is an important neurotransmitter and hormone. Its role in regulating cardiovascular function at rest and with stress is unclear, however. METHODS AND RESULTS: An epinephrine-deficient mouse model was generated in which the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase was knocked out (KO). Blood pressure and heart rate were monitored by telemetry at rest and during graded treadmill exercise. Cardiac structure and function were evaluated by echocardiography in mice under 1 of 2 conditions: unstressed and lightly anesthetized or restrained and awake. In KO mice, resting cardiovascular function, including blood pressure, heart rate, and cardiac output, was the same as that in wild-type mice, and the basal norepinephrine plasma level was normal. However, inhibition of sympathetic innervation with the ganglion blocker hexamethonium caused a 54% smaller decrease in blood pressure in KO mice, and treadmill exercise caused an 11% higher increase in blood pressure, both suggesting impaired vasodilation in KO mice. Interestingly, phenylethanolamine N-methyltransferase KO did not change the heart rate response to ganglionic blockade and exercise. By echocardiography, KO mice had an increased ratio of left ventricular posterior wall thickness to internal dimensions but did not have cardiac hypertrophy, suggesting concentric remodeling in the KO heart. Finally, in restrained, awake KO mice, heart rate and ejection fraction remained normal, but cardiac output was significantly reduced because of diminished end-diastolic volume. CONCLUSION: Our data suggest that epinephrine is required for normal blood pressure and cardiac filling responses to stress but is not required for tachycardia during stress or normal cardiovascular function at rest.

Cardiovascular responses to electrical stimulation of sympathetic nerves in the pithed mouse.

The pithed rat model has been used extensively to study peripheral cardiovascular responses to electrical stimulation of the sympathetic nervous system, as pithing eliminates central and reflex effects. However, since the transgenic mouse has become a standard and economical model organism, an electrically stimulated pithed mouse would facilitate a variety of studies. We have developed surgical techniques, drug doses and stimulation parameters for an electrically stimulated pithed mouse to study peripheral sympathetic nerve effects on blood pressure. Similar to the pithed rat, the pithed mouse showed voltage and frequency-dependent blood pressure responses to a pulsed train of electrical stimuli. In addition, alpha-adrenergic stimulation with phenylephrine gave a marked systolic pressor response, while the beta2 agonist salbutamol lowered diastolic blood pressure. Furthermore, pithed transgenic mice unable to synthesize catecholamines in adrenergic cells displayed smaller pressor responses than pithed control mice. In summary, the electrically stimulated pithed mouse can be used to study peripheral effects of the sympathetic system on cardiovascular dynamics unencumbered by central responses.

Literature review and pilot studies of the effect of QT correction formulas on reported beta2-agonist-induced QTc prolongation.

BACKGROUND: Drugs that stimulate the beta2-adrenergic receptor have been reported to prolong the QT interval corrected for heart rate (QTc interval), a potential mechanism for cardiac toxicity. OBJECTIVE: This study evaluated whether beta2-adrenergic agonist drugs prolong the QTc interval when different correction formulas for the effect of heart rate are used. METHODS: Healthy subjects of both sexes aged 19 to 33 years were recruited with advertisements. In pilot studies, subjects took a preparation containing the beta2-agonist ephedrine, or they participated in a postural study of the effect of endogenous beta-agonists. The study-drug group took 3 pills of the ephedra preparation per day for 2 days and then 6 pills per day for the next 2 days. Electrocardiograms (ECGs) were recorded before and at 1, 3, and 82 hours after the first study-drug dose and both before and after standing in the standing-up group. QT intervals obtained by automatic measurement were corrected for heart rate with 3 formulas: Bazett (QTc[B]), Framingham (QTc[F]), and Fridericia (QTc[Fr]). For the literature review, PubMed was searched using the search terms beta2-agonist drugs, QT, QTc, EKG, ECG, or electrocardiogram for studies that reported prolongation of the QTc by beta2-agonist drugs. We analyzed the method by which 11 different studies corrected QT interval for heart rate after the use of formoterol, salmeterol, terbutaline, salbutamol, and fenoterol. RESULTS: The ephedra study included 20 healthy subjects (35% men; mean [SD] age, 25 [4] years). Two hours after the last dose, QTc[B] had increased significantly from baseline by 19 ms (P=0.02). QTc[F] and QTc[Fr] did not change significantly. In the postural study, 19 healthy subjects (68% men; mean [SD] age, 32 [8] years) stood up and QTc[B] increased by a mean (SD) of 8 (15) ms (P=0.03). In these subjects, the QTc[B]/RR regression slope was significantly different from 0 (r=0.60, P=0.002), and the Bazett formula did not eliminate the dependence of QTc on heart rate. However, QTc[F] and QTc[Fr] did not change significantly, meaning that these formulas eliminated the dependence of QTc on heart rate. Eleven publications reported prolongation of QTc[B] by 5 beta2-adrenergic agonists for asthma. The change in QTc[B] interval from these publications was still dependent on the change in heart rate (r=0.63, P=0.004), but this dependence was eliminated after using QTc[F] and QTc[Fr]. The increase in QTc[B] would have been up to 30 ms less if QTc[F] or QTc[Fr] had been reported instead. CONCLUSIONS: The Bazett correction is the one typically reported by computerized ECG machines and the medical literature. This review suggests that QTc[B] may overestimate QTc when heart rate increases. Because the beta2-adrenergic agonist drugs increase heart rate, a systematic bias may have implicated these drugs in prolongation of cardiac repolarization. Prospective, large studies with a placebo and active control group are needed to evaluate the effect of beta2 agonists on QTc using formulas other than Bazett.

Location, development, control, and function of extraadrenal phenylethanolamine N-methyltransferase.

Phenylethanolamine N-methyltransferase (PNMT) methylates norepinephrine (NE) to form epinephrine (E). It is present in a high concentration in the adrenal medula but occurs in many other tissues throughout the body. In the brain stem and retina PNMT is present in specific neurons. Cardiac PNMT develops early in the fetal heart and is found in relatively high levels in the adult left atrium. Intrinsic cardiac adrenergic cells are distributed throughout the adult myocardium and contain all the enzymes necessary for E synthesis. The PNMT gene promoter region contains a glucocorticoid response element; however, the initial development of brain and cardiac fetal PNMT is glucocorticoid independent. Rat fetal heart PNMT peaks at embryonic day 11 and becomes sensitive to glucocorticoid induction by day 12. PNMT-containing cells are concentrated in the atrioventricular canal and interventricular septum during cardiac development, areas important in the development of the cardiac conduction system. In the adult rat, cardiac PNMT is inducible by glucocorticoids and synthesizes E. Glucocorticoids are essential for development of the high levels of PNMT in the adrenal, but are less important outside the adrenal. The PNMT gene contains 3 exons and 2 introns. Adrenal PNMT mRNA exists as a single type, but in the heart PNMT mRNA is present as both an intronless and an intron-containing type. In some cardiac tissues, glucocorticoids decrease levels of intron-containing PNMT mRNA and increase intronless PNMT mRNA and PNMT activity. Studies in adrenalectomized animals suggest that extraadrenal PNMT increases blood pressure, blood glucose, and lymphocyte cytokine production. PNMT may also play a role in the regulation of fetal heart rate prior to development of the adrenal medulla.

Human autonomic activity and its response to acute oxygen supplement after high altitude acclimatization.

It is well established that after acclimatization at high altitude, many sympathetic pathways are hyperactive yet heart rate (HR) remains unchanged. In this study, we attempted to determine if this unchanged heart rate is due to compensatory mechanisms such as changes in parasympathetic activity or levels of receptors for autonomic neurotransmitters. We also examined the role played by hypoxia in these autonomic adaptations to high altitude. Three experiments were carried out on five healthy lowlanders both at sea level (SL) and after 2 weeks of acclimatization at 3800 m (Post-Ac) with: (a) placebo (control); (b) acute beta-adrenergic receptor blockade by propranolol (PRO), or (c) acute parasympathetic receptor blockade by glycopyrrolate (GLY). Compared with SL control values, post-Ac venous norepinephrine (NE) and dopamine increased by 96% (p < 0.001) and 55% (p < 0.05), but epinephrine and HR did not change. PRO resulted in a smaller decrease in HR (bpm) Post-Ac than at SL (15 +/- 6 vs. 21 +/- 6, p < 0.05), while GLY caused a greater increase in HR Post-Ac than at SL (59 +/- 8 vs. 45 +/- 6, p < 0.05). Breathing oxygen at SL concentration while at altitude did not decrease NE, or alter the effect of PRO on HR, but reduced the chronotropic effect of GLY by 14% (p < 0.05). These results suggest that after acclimatization to altitude, increased parasympathetic neurotransmitter release and decreased beta-adenoreceptor activity account for the unchanged HR despite enhanced sympathetic activity. Acute oxygen replacement rapidly counteracted the parasympathetic, but not sympathetic hyperactivity that occurs at high altitude.

Blood pressure variability in obstructive sleep apnea: role of sympathetic nervous activity and effect of continuous positive airway pressure.

BACKGROUND: Many studies support a link between obstructive sleep apnea (OSA), increased blood pressure (BP) and/or BP variability, and sympathetic nervous system (SNS) activity. We assessed the relationship between SNS activity and 24-h BP variability in patients with OSA, and the effect of continuous positive airway pressure (CPAP) on BP variability. DESIGN: Forty-one patients with a respiratory disturbance index (RDI) > 15 were randomized into CPAP or CPAP placebo groups for a 1-week trial. METHODS: Ambulatory BP, 24-h urine norepinephrine (NE) and polysomnography were measured prior to treatment and after 1 and 7 days of treatment. RESULTS: Neither RDI nor 24-h urine NE levels were related to 24-h mean BP levels. While RDI was associated only with night-time BP variability, daytime urine NE levels were associated with both night-time and daytime BP variability. After treatment, the BP variability decreased significantly but equally in both active and placebo CPAP groups. CONCLUSIONS: Obstructive sleep apnea is more related to BP variability than BP. Sympathetic nervous activity, as inferred from daytime urine NE, is related to changes in BP variability in OSA patients. BP variability is not specifically affected by CPAP.

Endogenous epinephrine protects against obesity induced insulin resistance.

Epinephrine (E) is a hormone released from the adrenal medulla in response to low blood sugar and other stresses. E and related ß2-adrenergic agonists are used to treat asthma, but a side effect is high blood sugar. C57BL/6 mice prone to overfeeding induced type II diabetes had the PNMT gene knocked out to prevent E synthesis. These E deficient mice were very similar to control animals on a 14% fat diet. On a 40.6% fat diet they gained 20 to 33% more weight than control animals and increased their blood glucose response to a glucose tolerance test because they became resistant to insulin. Although the short term effect of ß2-agonists such as E is to raise blood glucose, some long acting ß2-agonists improve muscle glucose uptake. Endogenous E protects against overfeeding induced diabetes. Since adrenal E release can be impaired with aging and diabetes, endogenous E may help prevent adult onset diabetes.

Impaired chronotropic response to exercise in mice lacking catecholamines in adrenergic cells.

To define the in vivo role of adrenergic catecholamines (CAs), we generated a mouse model whereby tyrosine hydroxylase (TH) was knocked out (KO) in phenylethanolamine N-methyltransferase-expressing cells. These adrenergic specific TH-KO mice were viable and grossly normal. Their resting heart rate and blood pressure, as monitored by telemetry, were unchanged. However, when challenged with treadmill exercise, their chronotropic responses were significantly reduced by 14% compared to wild-type mice. Thus, our data suggest that adrenergic CA is required for normal chronotropic responses to stress, but not required for prenatal and postnatal development or normal cardiovascular function at rest.

Epinephrine regulation of hemodynamics in catecholamine knockouts and the pithed mouse.

Phenylethanolamine N-methyltransferase (PNMT) catalyzes synthesis of epinephrine (E) and is present in the brain, heart, and adrenal. E is a neurotransmitter and important hormone; however, its role in regulating cardiovascular dynamics is still unclear. We generated an E-deficient mouse model by knocking out the PNMT gene. The PNMT KO mouse had normal resting blood pressure, while treadmill exercise caused hypertension, suggesting an impaired response to stress in the absence of the stress hormone E. As PNMT occurs at a lower concentration in many extra-adrenal tissues including the brain, we set up a pithed mouse model to study the peripheral effects of E on cardiovascular dynamics, using pithing to eliminate central and reflex effects. The pithed mouse requires different surgical techniques and stimulation voltages than rats, and showed voltage- and frequency-dependent blood pressure responses to electrical stimuli. Stimulation with the alpha-adrenergic agonist phenylephrine gave a marked systolic pressor response, while the beta2 agonist salbutamol lowered diastolic blood pressure. The pithed PNMT KO mouse had an exaggerated blood pressure response to salbutamol, suggesting beta2 receptor supersensitivity. A targeted KO of tyrosine hydroxylase in PNMT-producing cells produced a mouse deficient in catecholamines in the adrenal. These targeted KO mice displayed significantly smaller pressor responses than pithed control mice. We find that E release during stress prevents an excessive increase in blood pressure.

Interactive effects of common beta2-adrenoceptor haplotypes and age on susceptibility to hypertension and receptor function.

Few studies have examined to what extent genetic variants of the beta2-adrenoceptor (ADRB2) are involved in the development of hypertension with age, although beta2-adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; n=610) and African American (AA; n=420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithm-based methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (P=0.01). Haplotype 1 was associated with protection against hypertension in young (< or =50 years of age) but not in old (>50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91; P=0.02). This age-specific effect was further supported by the observations that young subjects carrying > or =1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (P<0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%; P<0.05) and decreased heart rate (7%; P<0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.