Relationships between sympathetic markers and heart rate thresholds for cardiovascular risk in chronic heart failure.

BACKGROUND: Results of recent clinical trials have shown that in heart failure (HF) heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk. No information is available on whether the sympathetic nervous system is differently activated in HF patients displaying resting HR values above or below this cutoff. METHODS: In 103 HF patients aged 62.7 ± 0.9 (mean ± SEM) years and in 62 heathy controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in different groups according to their resting clinic and 24-h HR values. RESULTS: In HF progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and NE. HR cutoff values adopted in large scale clinical trials for determining cardiovascular risk, i.e., 70 beats/minute, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for NE. In HF both MSNA and NE were significantly related to clinic (r = 0.92, P < 0.0001 and r = 0.81, P < 0.0001, respectively) and 24-h (r = 0.91, P < 0.0001 and r = 0.79, P < 0.0001, respectively) HR. The behavior of sympathetic markers described in HF was specific for this clinical condition, being not observed in healthy controls. CONCLUSIONS: Both clinic and 24-h HR values greater than 70 beats/minute are associated with an increased sympathetic activation, which parallels for magnitude the HR elevations. These findings support the relevance of using in the therapeutic approach to HF drugs exerting sympathomoderating properties.

Elevated resting heart rate as independent in-hospital prognostic marker in COVID-19.

BACKGROUND: Scarce and non-homogeneous data are available on the prognostic value of clinic heart rate (HR) in coronavirus disease 2019 (COVID-19). METHODS: The present study evaluated in 389 patients hospitalized for COVID-19 the in-hospital prognostic value of resting HR, assessed over different time periods, i.e., at hospital admission, during initial 3 days and 7 days of hospitalization. RESULTS: Results show that assessment of this hemodynamic variable during hospitalization provides information on the clinical outcome of the patients, greater HR values being associated with a worse inhospital prognosis. The prognostic value of elevated HR during COVID-19: 1) was independent on other confounders such as age, gender, comorbidities and fever, 2) appeared to be strengthened by repeated measurements of HR during the initial 3/7 days of hospitalization, and 3) was detectable in patients in which the therapeutic intervention did not include drugs, such as beta-blockers, calcium antagonists, digoxin, ivabradine and antiarrhythmic compounds known to interfere with HR. CONCLUSIONS: Heart rate may represent an important marker of a patient's outcome in COVID-19.

Transient effects of carotid baroreflex stimulation via the neck chamber device on central venous pressure.

We examined in 11 young subjects (age 29.7±3.6 years, mean±SEM) whether carotid baroreceptor stimulation via the neck chamber device may affect central venous pressure (CVP), thus potentially involving other reflexogenic areas in the examined responses. Application of progressively greater neck chamber subatmospheric pressures caused a progressive lengthening in RR interval, which reached a peak at the maximal value of negative neck chamber pressure applied. This was accompanied by significant and progressively greater reduction in CVP values when the data were calculated considering the early changes occurring within the first 2 seconds of the stimulus. There was a weak correlation between the early changes in CVP and the RR interval responses when all stimuli were pooled together (r = 0.32, P < .05). The results of the present study suggest that the neck chamber technique employed to assess carotid baroreceptor-heart rate sensitivity can transiently affect via the CVP reduction cardiopulmonary receptors activity, which may participate at the integrated reflex responses.

Sympathetic Overactivation in Patients With Essential Hypertension and Hepatic Iron Overload.

Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly (P<0.02 at least) greater in HT+ than in patients with hypertension without iron overload and normotensive subjects both when expressed as bursts incidence over time (41.8±1.4 versus 31.5±1.4 and 23.6±0.9 bursts/min) and as bursts corrected for heart rate (55.3±1.8 versus 42.3±1.2 and 31.7±1.2 bursts/100 heartbeats). In HT+, low-frequency systolic blood pressure variability was significantly reduced. In HT+, but not in the other 2 groups, muscle sympathetic nerve traffic was significantly related to serum ferritin (r=0.51, P<0.03), transferrin saturation (r=0.47, P<0.03), and hepatic iron load (r=0.76, P<0.0001, magnetic resonance imaging), as well as to homeostatic model assessment index values (r=0.46, P<0.05). These data provide the first evidence that in HT+ elevated serum ferritin is associated with a hyperadrenergic state of greater magnitude than the one seen in patients with hypertension without iron overload. They also show that the potentiation of the sympathetic activation detected in HT+ is related to elevated serum ferritin and to the associated metabolic alterations, possibly participating in the increased cardiovascular risk characterizing iron overload.

Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction.

AIM: Although abnormalities in reflex sympathetic neural function represent a hallmark of heart failure, no information is available on the neuroadrenergic and baroreflex function in heart failure with preserved, midrange and reduced ejection fraction. The current study was designed to assess muscle sympathetic nerve traffic (MSNA) and baroreflex function in the clinical classes of heart failure defined by the new European Society of Cardiology/American College of Cardiology Foundation/American Heart Association guidelines. METHODS: In 32 treated heart failure patients aged 69.3 ±â€Š1.1 (mean ±â€ŠSEM) classified according to new heart failure guidelines, we measured MSNA (microneurography), spontaneous baroreflex sensitivity and venous plasma norepinephrine (HPLC). Fourteen age-matched healthy individuals represented the control group. RESULTS: MSNA was progressively and significantly increased from controls to heart failure conditions characterized by preserved, midrange and reduced ejection fraction (40.4 ±â€Š2.5, 55.6 ±â€Š2.1, 70.4 ±â€Š3 and 78.6 ±â€Š2.6 bursts/100 heart beats, P < 0.01). In contrast, plasma norepinephrine was significantly increased in heart failure with reduced ejection fraction only. Baroreflex sensitivity was significantly reduced in the latter two clinical conditions and almost unaltered in heart failure with preserved ejection fraction. There was an inverse relationship between different markers of adrenergic activity (MSNA, heart rate and plasma norepinephrine), left ventricular ejection fraction and baroreflex function. Brain natriuretic peptides were directly and significantly related to MSNA and plasma norepinephrine. CONCLUSION: Thus clinical categories of heart failure patients defined by the new European Society of Cardiology/American College of Cardiology Foundation/American Heart Association classification share as a common pathophysiological link the marked overactivity of the sympathetic nervous system, whose magnitude is significantly and strongly related to the impairment of the left ventricular ejection fraction. A baroreflex dysfunction accompanies in the more severe heart failure state the neuroadrenergic activation.

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension.

BACKGROUND AND OBJECTIVES: The plasma concentration of the endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) associates with sympathetic activity in patients with CKD, but the driver of this association is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this longitudinal study (follow-up: 2 weeks-6 months), repeated measurements over time of muscle sympathetic nerve activity corrected (MSNAC), plasma levels of ADMA and symmetric dimethylarginine (SDMA), and BP and heart rate were performed in 14 patients with drug-resistant hypertension who underwent bilateral renal denervation (enrolled in 2013 and followed-up until February 2014). Stability of ADMA, SDMA, BP, and MSNAC over time (6 months) was assessed in two historical control groups of patients maintained on stable antihypertensive treatment. RESULTS: Time-integrated changes in MSNAC after renal denervation ranged from -40.6% to 10% (average, -15.1%), and these changes were strongly associated with the corresponding changes in plasma ADMA (r= 0.62, P=0.02) and SDMA (r=0.72, P=0.004). Changes in MSNAC went along with simultaneous changes in standardized systolic (r=0.65, P=0.01) and diastolic BP (r=0.61, P=0.02). In the historical control groups, no change in ADMA, SDMA, BP, and MSNAC levels was recorded during a 6-month follow-up. CONCLUSIONS: In patients with resistant hypertension, changes in sympathetic activity after renal denervation associate with simultaneous changes in plasma levels of the two major endogenous methylarginines, ADMA and SDMA. These observations are compatible with the hypothesis that the sympathetic nervous system exerts an important role in modulating circulating levels of ADMA and SDMA in this condition.

Blood pressure responses to renal denervation precede and are independent of the sympathetic and baroreflex effects.

It is still largely unknown whether the neuroadrenergic responses to renal denervation (RD) are involved in its blood pressure (BP)-lowering effects and represent predictors of the BP responses to RD. In 15 treated true resistant hypertensives, we measured before and 15 days, 1, 3, and 6 months after RD clinic, ambulatory and beat-to-beat BP. Measurements included muscle sympathetic nerve traffic (MSNA), spontaneous baroreflex-MSNA sensitivity, and various humoral and metabolic variables. Twelve treated hypertensives served as controls. BP, which was unaffected 15 days after RD, showed a significant decrease during the remaining follow-up period. MSNA and baroreflex did not change at 15-day and 1-month follow-up and showed, respectively, a decrease and a specular increase at 3 and 6 months after RD. No relationship, however, was detected between baseline MSNA and baroreflex, MSNA changes and BP changes. At the 6-month follow-up, the MSNA reduction was similar for magnitude in patients displaying a BP reduction greater or lower the median value. Similarly, the BP reduction detected 6 months after RD was similar in patients displaying a MSNA reduction greater or lower median value. No significant BP and MSNA changes were detected in the control group. Thus, the BP reduction associated with RD seems to precede the MSNA changes and not to display a temporal, qualitative, and quantitative relationship with the MSNA and baroreflex effects. Given the small sample size of the present study further investigations are warranted to confirm the present findings.

Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension.

BACKGROUND: An increase in sympathetic drive to the heart and the peripheral circulation characterizes mild and severe essential hypertension. However, it remains unsettled whether sympathetic cardiovascular influences are potentiated in true resistant hypertension (RHT). METHODS: In 32 RHT patients treated with 4.6 ± 0.3 drugs (mean ± SEM) and aged 58.6 ± 2.1 years, 35 non-resistant treated hypertensives (HT) and 19 normotensive controls (NT), all age-matched with RHT, we measured clinic, 24-hour ambulatory and beat-to-beat blood pressures (BP), heart rate (HR, EKG), muscle sympathetic nerve traffic (MSNA, microneurography) and spontaneous baroreflex MSNA-sensitivity. RESULTS: BP values were markedly greater in RHT patients than in NT and HT (172.2 ± 1.7/100.7 ± 1.2 vs 132.1 ± 1.3/82.1 ± 0.9 and 135.5 ± 1.2/83.6 ± 0.9 mmHg, P < 0.01). This was paralleled by a significant and marked increase in MSNA (87.8 ± 2.0 vs 46.8 ± 2.6 and 59.3 ± 1.7 and bursts/100 heartbeats, P < 0.01). In multiple regression analysis the MSNA increase observed in RHT was significantly related to hemodynamic, hormonal and metabolic variables. It was also significantly related to plasma aldosterone values as well as spontaneous baroreflex MSNA-sensitivity, which were the variables that at the multivariate analysis were more closely related to the adrenergic activation of RHT after adjustment for confounders, including antihypertensive treatment (r(2)partial=0.04405 and r(2)partial=0.00878, P<0.05 for both). CONCLUSIONS: These data represent the first evidence that RHT is a state of marked adrenergic overdrive, greater for magnitude than that detectable in HT. They also suggest that impaired baroreflex mechanisms, along with hemodynamic and neurohumoral factors, may be responsible for the phenomenon.

Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction.

The sympathetic overdrive that characterizes essential hypertension is potentiated when left ventricular hypertrophy or congestive heart failure is detected. No information exists, however, on whether this is the case also for left ventricular diastolic dysfunction. In 17 untreated hypertensive subjects with left ventricular diastolic dysfunction (age: 47.7+/-2.9 years, mean+/-SEM), we measured sympathetic nerve traffic (microneurography), heart rate (ECG), and beat-to-beat arterial blood pressure (Finapres) at rest and during baroreceptor deactivation and stimulation. Data were compared with those collected in 20 age-matched normotensive and 20 hypertensive subjects without a diastolic function impairment. Muscle sympathetic nerve traffic values were markedly and significantly greater in the 2 hypertensive groups than in the normotensive one (55.3+/-1.2 and 71.2+/-1.6 versus 41.7+/-1.0 bursts per 100 heartbeats, respectively; P<0.01 for both). For a similar blood pressure elevation, however, the sympathetic nerve traffic increase was significantly greater in patients with than without left ventricular diastolic dysfunction (+28.9%; P<0.05). In the population as a whole, muscle sympathetic nerve traffic was significantly and inversely related to various echocardiographic indices of diastolic function. Although baroreflex-heart rate control was significantly attenuated in the 2 hypertensive groups, baroreflex-sympathetic modulation was impaired only in those with diastolic dysfunction. These data provide the first evidence that, in hypertension, activation of the sympathetic nervous system may contribute not only at the blood pressure elevation but also at the development of left ventricular diastolic dysfunction. The sympathetic overactivity, which is likely to be related to the baroreflex impairment, may account for the increased cardiovascular risk characterizing diastolic dysfunction.

Different patterns of interleukin-6 and von Willebrand factor antigen changes after coronary stenting in unstable versus stable angina.

BACKGROUND: Inflammation plays an important role in the pathogenesis of acute coronary syndromes. The purpose of our study was to evaluate the time course and the clinical relevance of inflammatory markers in patients with unstable angina undergoing successful coronary stent implantation. METHODS: Fifty-six patients (33 with unstable and 23 with stable angina) scheduled for single vessel coronary angioplasty followed by successful stent implantation were studied. Blood samples for measurements of interleukin-6 (IL-6) and von Willebrand factor antigen (vWf) were taken immediately before coronary angioplasty and 24 hours and 1 month after the procedure. Patients were clinically examined 1 month after the procedure. RESULTS: The mean levels of IL-6 before stenting were significaNtly higher in unstable than in stable angina patients (p = 0.002), whereas baseline values of vWf showed no difference between the two groups. In unstable angina, serum levels of IL-6 and of vWf did not change 24 hours after stent implantation, but significantly decreased 1 month after the procedure (p = 0.005 and p = 0.0015 respectively). In stable patients, serum levels of IL-6, but not of vWf, increased 24 hours after the procedure and returned to baseline levels 1 month after stent implantation (p = 0.046). CONCLUSIONS: In unstable angina, successful treatment of the culprit lesion by coronary stenting results in a significant decrease in the serum levels of IL-6 and of vWf 1 month after the procedure, suggesting that, in this clinical condition, elevated levels of these parameters correlate with the instability of the atheromatous plaque and that their decrease after successful stent implantation is the result of plaque stabilization.