Tomaso Gnecchi-Ruscone

Coronary Heart Disease in Smokers Vitamin C Restores Coronary Microcirculatory Function

BackgroundCoronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. Methods and ResultsWe used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects (P <0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects. ConclusionsThe present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.

Measuring regularity by means of a corrected conditional entropy in sympathetic outflow

Abstract. A new method for measuring the regularity of a process over short data sequences is reported. This method is based on the definition of a new function (the corrected conditional entropy) and on the extraction of its minimum. This value is taken as an index in the information domain quantifying the regularity of the process. The corrected conditional entropy is designed to decrease in relation to the regularity of the process (like other estimates of the entropy rate), but it is able to increase when no robust statistic can be performed as a result of a limited amount of available samples. As a consequence of the minimisation procedure, the proposed index is obtained without an a-priori definition of the pattern length (i.e. of the embedding dimension of the reconstructed phase space). The method is validated on simulations and applied to beat- to-beat sequences of the sympathetic discharge obtained from decerebrate artificially ventilated cats. At control, regular, both quasiperiodic and periodic (locked to ventilation) dynamics are observed. During the sympathetic activation induced by inferior vena cava occlusion, the presence of phase-locked patterns and the increase in regularity of the sympathetic discharge evidence an augmented coupling between the sympathetic discharge and ventilation. The reduction of complexity of the neural control obtained by spinalization decreases the regularity in the sympathetic outflow, thus pointing to a weaker coupling between the sympathetic discharge and ventilation.

Temporal asymmetries of short-term heart period variability are linked to autonomic regulation

We exploit time reversibility analysis, checking the invariance of statistical features of a series after time reversal, to detect temporal asymmetries of short-term heart period variability series. Reversibility indexes were extracted from 22 healthy fetuses between 16th to 40th wk of gestation and from 17 healthy humans (aged 21 to 54, median=28) during graded head-up tilt with table inclination angles randomly selected inside the set {15, 30, 45, 60, 75, 90}. Irreversibility analysis showed that nonlinear dynamics observed in short-term heart period variability are mostly due to asymmetric patterns characterized by bradycardic runs shorter than tachycardic ones. These temporal asymmetries were 1) more likely over short temporal scales than over longer, dominant ones; 2) more frequent during the late period of pregnancy (from 25th to 40th week of gestation); 3) significantly present in healthy humans at rest in supine position; 4) more numerous during 75 and 90 degrees head-up tilt. Results suggest that asymmetric patterns observable in short-term heart period variability might be the result of a fully developed autonomic regulation and that an important shift of the sympathovagal balance toward sympathetic predominance (and vagal withdrawal) can increase their presence.

Insulin resistance in patients with cardiac hypertrophy

OBJECTIVE Animal studies suggest that left ventricular hypertrophy might be associated with insulin resistance and alterations in glucose transporters. We have previously demonstrated myocardial insulin resistance in patients with post-ischemic heart failure. The aim was to investigate whether myocardial insulin resistance could be demonstrated in human cardiac hypertrophy in the absence of hypertension, diabetes and coronary artery disease. METHODS Eleven normotensive nondiabetic patients with cardiac hypertrophy due to aortic stenosis and angiographically normal coronary arteries were compared to 11 normal volunteers. Myocardial glucose uptake (MGU) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose during fasting (low insulinemia) or during euglycemic-hyperinsulinemic clamp (physiologic hyperinsulinemia). Myocardial biopsies were obtained in order to investigate changes in insulin-independent (GLUT-1) and insulin-dependent (GLUT-4) glucose transporters. RESULTS During fasting, plasma insulin (7 +/- 1 vs. 6 +/- 1 mU/l) and MGU (0.12 +/- 0.05 vs. 0.11 +/- 0.04 mumol/min/g) were comparable in patients and controls. By contrast, during clamp, MGU was markedly reduced in patients (0.48 +/- 0.02 vs. 0.70 +/- 0.03 mumol/min/g, p < 0.01) despite similar plasma insulin levels (95 +/- 6 vs. 79 +/- 6 mU/l). A decreased GLUT-4/GLUT-1 ratio was shown by Western blot analysis in patients. CONCLUSIONS Insulin resistance seems to be a feature of the hypertrophied heart even in the absence of hypertension, coronary artery disease and diabetes and may be explained, at least in part, by abnormalities in glucose transporters.

Presence of vasomotor and respiratory rhythms in the discharge of single medullary neurons involved in the regulation of cardiovascular system

We analyzed the discharges of 77 single neurons located in the rostral ventrolateral medulla (RVLM, n = 25), caudal ventrolateral medulla (CVLM, n = 18), lateral tegmental field (LTF, n = 19) and caudal raphe nuclei (n = 15). These recordings were made from 36 vagotomized and sinoaortic denervated cats that were either decerebrate (n = 27) or anesthetized with urethane (n = 9) and from 3 decerebrate cats with intact sinoartic and vagal nerves. These neurons were classified as sympathetic-related (n = 61) if spike triggered averaging showed that their naturally occurring discharges were correlated to either the cardiac related (2-6 Hz) or a faster (10 Hz) oscillation in inferior cardiac sympathetic nerve discharge. Neurons were classified as sympathetic-unrelated (n = 16) if they lacked these characteristics. We used autoregressive spectral techniques to detect additional slower oscillations hidden in the variability of neuronal discharge and possibly correlated to the oscillations of systolic arterial pressure (SAP). This analysis revealed the existence of a low frequency (LF) oscillation (0.12 +/- 0.02 Hz) in the discharges of 36 sympathetic-related and 9 sympathetic-unrelated neurons. In relation to 35 neurons in 21 animals there was also an LF component in SAP variability. In 29 instances the LF neuronal discharges and SAP variabilities were significantly correlated. In addition, there was a high frequency (HF) oscillation (0.34 +/- 0.06 Hz) in the discharges of 59 medullary neurons. In 56 cases the HF in neuronal discharge variability cohered to that in SAP variability. These data are the first to demonstrate the existence of an LF component in the discharges of individual medullary neurons, at least some of which were likely to be involved in the regulation of the cardiovascular system. Since these oscillations were evident in cats with section of sinoaortic and vagal nerves, they likely reflect central rhythmogenic properties.

Complexity and Nonlinearity in Short-Term Heart Period Variability: Comparison of Methods Based on Local Nonlinear Prediction

This paper evaluates the paradigm that proposes to quantify short-term complexity and detect nonlinear dynamics by exploiting local nonlinear prediction. Local nonlinear prediction methods are classified according to how they judge similarity among patterns of L samples (i.e., according to different definitions of the cells utilized to discretize the phase space) and examined in connection with different types of surrogate data: 1) phase-randomized or Fourier transform based, FT; 2) amplitude-adjusted FT, AAFT; 3) iteratively-refined AAFT, IAAFT, preserving distribution IAAFT-1; 4) IAAFT preserving power spectrum, IAAFT-2. The methods were applied on ad-hoc simulations and on a large database of short heart period variability series (~300 cardiac beats) recorded in healthy young subjects during experimental conditions inducing a sympathetic activation (head-up tilt, infusion of nitroprusside, or handgrip), a parasympathetic activation (low dose administration of atropine or infusion of phenylephrine), a complete parasympathetic blockade (high dose administration of atropine), or during controlled respiration at different breathing rates. As to complexity analysis we found that: 1) although complexity indexes derived from different methods were different in terms of absolute values, changes due to experimental conditions were consistently detected; 2) complexity was significantly decreased by all the experimental conditions provoking a sympathetic activation and by controlled respiration at slow breathing rates. As to detection of nonlinearities we found that: 1) IAAFT-1 and IAAFT-2 surrogates performed similarly in all protocols; 2) FT and IAAFT surrogates detected about the same percentage of nonlinear dynamics in all protocols; 3) AAFT surrogates were inappropriate with all the methods and should be dismissed in future applications; 4) methods based on overlapping cells with variable size were characterized by a larger rate of false detections of nonlinear dynamics; 5) short-term heart period variability at rest was mostly linear; 6) controlled respiration at slow breathing rates increased nonlinear components, while the separate activation of the two branches of the autonomic nervous system (i.e., sympathetic or parasympathetic) was ineffective at this regard

Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation.

OBJECTIVES The purpose of this study was to investigate the role of ivabradine in the treatment of symptomatic inappropriate sinus tachycardia using a double-blind, placebo-controlled, crossover design. BACKGROUND Due to its I(f) blocking properties, ivabradine can selectively attenuate the high discharge rate from sinus node cells, causing inappropriate sinus tachycardia. METHODS Twenty-one patients were randomized to receive placebo (n=10) or ivabradine 5 mg twice daily (n=11) for 6 weeks. After a washout period, patients crossed over for an additional 6 weeks. Each patient underwent symptom evaluation and heart rate assessment at the start and finish of each phase. RESULTS After taking ivabradine, patients reported elimination of >70% of symptoms (relative risk: 0.25; 95% CI: 0.18 to 0.34; p<0.001), with 47% of them experiencing complete elimination. These effects were associated with a significant reduction of heart rate at rest (from 88±11 beats/min to 76±11 beats/min, p=0.011), on standing (from 108±12 beats/min to 92±11 beats/min, p<0.0001), during 24 h (from 88±5 beats/min to 77±9 beats/min, p=0.001), and during effort (from 176±17 beats/min to 158±16 beats/min, p=0.001). Ivabradine administration was also associated with a significant increase in exercise performance. No cardiovascular side effects were observed in any patients while taking ivabradine. CONCLUSIONS In this cohort, ivabradine significantly improved symptoms associated with inappropriate sinus tachycardia and completely eliminated them in approximately half of the patients. These findings suggest that ivabradine may be an important agent for improving symptoms in patients with inappropriate sinus tachycardia.

RT variability unrelated to heart period and respiration progressively increases during graded head-up tilt

Open-loop linear parametric models were exploited to describe ventricular repolarization duration (VRD) variability during graded head-up tilt. Surface ECG and thoracic movements were recorded in 15 healthy humans (age: 24-54 yr, median: 28 yr; 6 women and 9 men). Tilt table inclinations ranged from 15 to 90 degrees and were varied in steps of 15 degrees . All subjects underwent recordings at every step in random order. Heart period was assessed as the time difference between two consecutive R-wave peaks (RR) and the respiratory signal (R) as the sampling of the thoracic movement signal at the R-wave peaks. VRD was measured automatically as the temporal difference between the R-wave peak and T-wave apex (RT(a)) or T-wave end (RT(e)). The best model decomposed RT variability as due to RR changes (RR-related RT variability) to direct respiratory-related inputs (R-related RT variability) and to unknown rhythmical sources unrelated to RR changes and R (RR-R-unrelated RT variability). Using this model, RT(e) variability was found to be less predictable than RT(a) variability and composed of a smaller fraction of RR-related RT variability and a larger fraction of RR-R-unrelated RT variability. Predictability progressively decreased with tilt table angles, suggesting increased complexity of RT regulation. RT variance progressively increased with tilt table inclination. This increase was characterized by a gradual rise of the amount of RR-R-unrelated RT variability, whereas the amount of RR-related RT variability remained unchanged. These results suggest that the amount of RT variability, complexity of RT dynamics, and amount of RR-R-unrelated RT variability increase with the magnitude of the sympathetic drive directly related to tilt table inclination. We propose the utilization of the amount of RR-R-unrelated RT variability instead of overall RT variability as an indirect measure of autonomic regulation directed to ventricles.

Cardiomyopathy in duchenne, becker, and sarcoglycanopathies: A role for coronary dysfunction?

Dilated cardiomyopathy is a feature of Duchenne and Becker muscular dystrophies and occasionally of sarcoglycanopathies. Its pathogenesis is unknown. Patients with myotonic dystrophy have an impairment of coronary smooth muscle and this could contribute to their cardiomyopathy. We used positron emission tomography (PET) to study myocardial blood flow and coronary vasodilator reserve at baseline and during hyperemia in 7 Duchenne, 8 Becker, and 5 sarcoglycanopathy patients. The study was normal in all Becker patients. In contrast, baseline myocardial blood flow was increased and coronary vasodilator reserve blunted in Duchenne and sarcoglycanopathy patients despite normal hyperemic myocardial blood flow. The reduction of coronary vasodilator reserve was due to an increased baseline myocardial blood flow. In Duchenne dystrophy, but not in sarcoglycanopathies, correction for cardiac workload normalized the coronary vasodilator reserve. In the latter patients, abnormal baseline myocardial blood flow could be due to vascular smooth muscle dysfunction.

Effects of Spinal Section and of Positive-Feedback Excitatory Reflex on Sympathetic and Heart Rate Variability

The sympathetic outflow appears to be capable of displaying a rhythmicity synchronous with cardiovascular Mayer’s waves even after spinal section. To test the hypothesis that spinal sympathetic low frequency (LF) oscillation can be enhanced during sympathetic excitation, we recorded cardiac sympathetic nerve activity (SNA), R-R interval, arterial pressure, and ventilation in 9 unanesthetized decerebrate-vagotomized cats before and after C1 spinal section. LF and high frequency (HF) components were detected in the variability of SNA, R-R interval, and systolic arterial pressure both before and after spinal section. In this latter condition, a significant coherence between LFSNA and LFR-R was present in 5 animals, whereas HFSNA and HFR-R were correlated in 4 animals. During an excitatory sympathetic spinal reflex elicited by aortic constriction, the efferent sympathetic firing was markedly enhanced (from 7±2 to 33±7 spikes/s); concomitantly, the powers of both LFSNA and HFSNA were also increased. Coherence between LFSNA and LFR-R became significant in all cases, whereas HFSNA and HFR-R became correlated in 6 animals. In 3 animals, the reflex sympathetic excitation was no longer elicitable after interrupting a vast contingent of sympathetic afferents by means of thoracic dorsal root section. We report for the first time that LF and HF oscillations are detectable in SNA, R-R interval, and systolic arterial pressure variabilities of decerebrate-vagotomized spinal cats and that an excitatory spinal reflex is capable of increasing the power of both SNA spectral components.