Gabriella Malfatto

Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy

We studied heart rate variability in 49 uncomplicated diabetics (27 with insulin therapy; 22 with oral hypoglycemic agents) and in 40 age-matched controls. An automatic autoregressive algorithm was used to compute the power spectral density (PSD) of beat by beat RR variability derived from the surface ECG. The PSD contains two major components (a low frequency approximately 0.1 Hz (LF) and a high frequency, respiratory linked, approximately 0.25 Hz (HF] that provide, respectively, quantitative markers of sympathetic and vagal modulatory activities and of their balance. As compared to controls, in diabetics, besides a reduced RR variance at rest (2722 +/- 300 and 1436 +/- 241 ms2, respectively), we observed during passive tilt an altered response of spectral indices of sympathetic activation and vagal withdrawal, suggestive of a complex modification in the neural control activities. In addition, we compared this approach to the commonly used clinical tests score, and observed that the latter provides overall results similar to those obtained with spectral changes induced by tilt (r = 0.42; P less than 0.01). Of potential clinical importance is that the data obtained with spectral analysis appear more thoroughly quantifiable and do not require the active collaboration of the patients.

Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome

OBJECTIVES We evaluated the diagnostic and prognostic value of morphologic abnormalities of the T wave (mainly notched or biphasic T waves) in patients affected by the idiopathic long QT syndrome. BACKGROUND In the long QT syndrome, these abnormalities in T wave morphology are often observed and are of uncertain significance. METHODS The T wave abnormalities in the electrocardiogram (ECG) of 53 patients with the long QT syndrome and 53 control subjects of similar age and gender were analyzed, and their association with major cardiac events was defined. RESULTS Notched or biphasic T waves were defined according to morphologic criteria. They were present in 33 (62%) of 53 patients with the long QT syndrome and in 8 (15%) of 53 control subjects (p < 0.001). Moreover, among patients with the long QT syndrome they were much more frequent in symptomatic (history of syncope or cardiac arrest) than in asymptomatic subjects (30 [81%] of 37 vs. 3 [19%] of 16, p < 0.001). The same distribution was observed within families with the long QT syndrome, in which symptomatic members had more pronounced T wave abnormalities than did their asymptomatic siblings or parents. In symptomatic patients, the occurrence of T wave abnormalities was independent of the length of repolarization (corrected QT). These T wave abnormalities were associated with the presence of a specific pattern of abnormal left ventricular wall motion. CONCLUSIONS This study has quantified an ECG pattern typical of the long QT syndrome and provides the first evidence that morphologic analysis of T wave abnormalities may contribute to the diagnosis of the long QT syndrome and the identification of patients at higher risk for syncope or cardiac arrest.

Effects of Cardiac Rehabilitation and Beta-Blocker Therapy on Heart Rate Variability After First Acute Myocardial Infarction

After acute myocardial infarction (AMI), rehabilitation with physical training increases parasympathetic tone. It is unknown whether such a favorable effect of exercise on the sympathovagal balance interacts with effects of other widespread therapies, such as beta blockers. In 53 patients after a first, uncomplicated AMI, we studied the combined short- and long-term influence on heart rate variability (HRV) of rehabilitation and beta blockade. Patients were divided into 3 groups: group 1 (n = 19) underwent rehabilitation with physical training; group 2 (n = 20) was taking beta blockers and underwent rehabilitation; group 3 (n = 14) was taking beta blockers and did not enter the rehabilitation program for logistic reasons. Patients were similar as to age, site of infarction, ejection fraction, left ventricular diameter, and baseline stress test duration. Measures of HRV (obtained from a 15-minute resting electrocardiogram) were the standard deviation of the mean RR interval (RRSD), the mean squared successive differences (MSSD), the percent of RR intervals differing >50 ms from the preceding one (pNN50), the low-(LF) and high-(HF) frequency components of the autoregressive power spectrum of the RR intervals and their ratio (LF/HF). Four weeks after AMI, there was less sympathetic predominance in groups 2 and 3 (i.e., patients taking beta blockers [p <0.05]). Rehabilitation modified HRV in groups 1 and 2 (p <0.05), with signs of increased parasympathetic tone (group 1: MSSD +25%, pNN50 +69%, LF/HF -40%; group 2: MSSD +41%, pNN50 +48%, LF/HF -39%). These changes persisted in the long term. In group 3, HRV was unchanged over time. Hence, after AMI, the effects of rehabilitation and beta blockers on HRV are not redundant: their association induces a more favorable sympathovagal balance, accelerating the recovery of a normal autonomic profile.

Sympathetic modulation of the relation between ventricular repolarization and cycle length.

Sympathetic influences on ventricular repolarization are not yet fully elucidated, despite their relevance to arrhythmogenesis. The sympathetic control of repolarization, measured from an endocardial monophasic action potential duration (APD) and from the QT interval, was investigated in 24 anesthetized cats. The effects of right and left stellectomy and of subsequent bilateral stellectomy or beta-blockade on the relation between APD (or QT) and cycle length (CL) at steady state, and on the kinetics of adaptation of APD to a sudden change in cycle length were studied separately. Steady-state APD/CL (or QT/CL) relations were obtained by atrial pacing at different cycle lengths. The kinetics of APD adaptation were evaluated for a sudden decrease of approximately 100 msec in pacing cycle length. The steady-state APD/CL (QT/CL) relation was fitted by the hyperbolic function APD = CL/[(a. CL) + b]. From this, two parameters were computed: 1) 1/a, that is, APD (QT) extrapolated at infinite cycle length (APDmax or QTmax) and 2) the cycle length at which 50% of the total change in APD (or QT) occurred (CL50 = b/a). Right stellectomy reduced APDmax and CL50, an effect reversed by subsequent left stellectomy or beta-blockade (propranolol, 0.5 mg/kg). Left stellectomy prolonged APDmax and CL50. Bilateral stellectomy, in both groups, caused a further increase in these variables. Results were similar for the QT/CL relation. The adaptation kinetics of APD to cycle length was described by the sum of two exponentials. The first time constant (tau fast, about three beats) was unchanged by any intervention; the second (tau slow) was shortened by right stellectomy and prolonged by left stellectomy. The further removal of the remaining stellate ganglion had the same effect in both groups, that is, an increase in tau slow. Thus, sympathetic innervation modulates both the steady-state dependence on cycle length and the kinetics of adaptation to sudden rate changes of ventricular repolarization. The effects of sympathetic influence are asymmetrical. Right stellectomy shortens APDmax and QTmax, reduces CL50, and accelerates APD adaptation to a new steady state. Because these effects are reversed by beta-blockade or left stellectomy, they are likely to be due to a reflexly enhanced sympathetic outflow to the ventricles through the left-sided nerves.

Recovery of cardiac autonomic responsiveness with low‐intensity physical training in patients with chronic heart failure

A gradual worsening of autonomic control of cardiovascular function accompanies the progression of heart failure. Exercise training modulates autonomic balance, and may affect the prognosis of the disease.

Individual patient meta-analysis of exercise training effects on systemic brain natriuretic peptide expression in heart failure.

Background: Brain natriuretic peptide (BNP) predicts exercise performance and exercise training may modulate BNP and its N-terminal portion (NT-pro-BNP), we therefore conducted an individual patient analysis of exercise training effects on BNP and NT-pro-BNP. Aims: To use an individual patient meta-analysis to relate changes in BNP, NT-pro-BNP, and peak VO2; to link these changes to volume parameters of exercise training programmes (intensity etc.); and to identify patient characteristics likely to lead to greater improvements in BNP, NT-pro-BNP, and peak VO2. Design: Individual patient meta-analysis. Methods: A systematic search was conducted of Medline (Ovid), Embase.com, Cochrane Central Register of Controlled Trials, and CINAHL (until July 2008) to identify randomized controlled trials of aerobic and/or resistance exercise training in systolic heart failure patients measuring BNP and/or NT-pro-BNP. Primary outcome measures were change in BNP, NT-pro-BNP, and peak VO2. Subanalyses were conducted to identify (1) patient groups that benefit most and (2) exercise programme parameters enhancing favourable changes in primary outcome measures. Results: Ten randomized controlled studies measuring BNP or NT-pro-BNP met eligibility criteria, authors provided individual patient data for 565 patients (313 exercise and 252 controls). Exercise training had favourable effects on BNP (−28.3%, p < 0.0001), NT-pro-BNP (−37.4%, p = < 0.0001), and peak VO2 (17.8%, p < 0.0001). The analysis showed a significant change in primary outcome measures; moreover, change in BNP (r = −0.31, p < 0.0001) and NT-pro-BNP (r = −0.22, p < 0.0001) were correlated with peak VO2 change. Conclusion: Exercise training has favourable effects on BNP, NT-pro-BNP, and peak VO2 in heart failure patients and BNP/NT-pro-BNP changes were correlated with peak VO2 changes.

Improvement in Left Ventricular Diastolic Stiffness Induced by Physical Training in Patients With Dilated Cardiomyopathy

BACKGROUND Diastolic dysfunction in long-term heart failure is accompanied by abnormal neurohormonal control and ventricular stiffness. The diastolic phase is determined by a balance between pressure gradients and intrinsic ventricular wall properties: according to a mathematical model, the latter (ie, left ventricular [LV] elastance, K(LV)) may be calculated by the formula: K(LV) = (70/[DT-20])(2) mm Hg/mL, where DT is the transmitral Doppler deceleration time. METHODS AND RESULTS In 54 patients with chronic systolic heart failure (39 men, 15 women; age 65 +/- 10 years; New York Heart Association [NYHA], 2.3 +/- 0.9; ejection fraction [EF], 32% +/- 5%), we analyzed the relationship between K(LV) and an index of neurohormonal derangement (levels of brain natriuretic peptide [BNP]), and investigated whether 3 months of physical training could modulate diastolic operating stiffness. Patients were randomized to physical training (n = 27) or to a control group (n = 27). Before and after training, patients underwent Doppler echocardiogram and cardiopulmonary stress test. At baseline, ventricular stiffness was related to BNP levels (P < .01). Training improved NYHA class, exercise performance, and estimated pulmonary pressure. BNP was reduced. Ventricular volumes, mean blood pressure, and EF remained unchanged. A 27% reduction of elastance was observed (K(LV), 0.111 +/- 0.044 from 0.195 +/- 0.089 mm Hg/mL; P < .01), whose magnitude was related to changes in BNP (P < .05) and to K(LV) at baseline (P < .01). No changes in K(LV) were observed in controls after 3 months (0.192 +/- 0.115 from 0.195 +/- 0.121 mm Hg/mL). CONCLUSIONS In heart failure, left ventricular diastolic stiffness is related to neurohormonal derangement and is modified by physical training. This improvement in LV compliance could result from a combination of hemodynamic improvement and regression of the fibrotic process.

Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance, and one-year survival.

Abstract: The role of repeated infusions of Levosimendan (LEVO) in patients with chronic advanced heart failure is still unclear. Thirty-three patients with chronic heart failure presenting clinical deterioration were randomized 2:1 to receive monthly infusions of LEVO (n = 22) or Furosemide (Controls, n = 11). At the first drugs administration, noninvasive hemodynamic evaluation was performed; before and after each infusion, we assessed NYHA class, systolic and diastolic function, functional mitral regurgitation, and brain natriuretic peptide (BNP) levels. Noninvasive hemodynamic in the LEVO group showed vasodilation and decrease in thoracic conductance (index of pulmonary congestion), whereas in Controls, only a reduced thoracic conductance was observed. In the LEVO group, systolic and diastolic function, ventricular volumes, severity of mitral regurgitation, and BNP levels improved over time from baseline and persisted 4 weeks after the last infusion (P < 0.01). In Controls, no change developed over time in cardiac function and BNP levels. In LEVO-treated patients, 1-year mortality tended to be lower than in those treated with Furosemide. In conclusion, serial LEVO infusions in advanced heart failure improved ventricular performance and favorably modulated neurohormonal activation. Multicenter randomized studies are warranted to test the effect of LEVO on long-term outcome.

Device-Guided Paced Breathing in the Home Setting Effects on Exercise Capacity, Pulmonary and Ventricular Function in Patients With Chronic Heart Failure: A Pilot Study

Background— Regular slow breathing is known to improve autonomic cardiac regulation and reduce chemoreflex sensitivity in heart failure. We explored the acceptability and usefulness of a device for paced slow breathing at the home setting. Methods and Results— In this open pilot study, 24 patients with chronic heart failure (61% males, mean age, 64±9 years; New York Heart Association class, 2.81±0.01) were randomized to a control group receiving conventional treatment (n=12) or to a group receiving conventional treatment and device-guided paced breathing (n=12). Groups were comparable for age, therapies, and clinical characteristics. They were evaluated at baseline and again after 10 weeks by Doppler echocardiography, pulmonary function, cardiopulmonary stress test, and quality of life (Minnesota Quality of Life questionnaire). The treatment group was instructed to use the equipment for 18 minutes twice daily. The device is a computerized box connected to a belt-type respiration sensor and to headphones; it generates musical tones (based on the user’s breathing rate and inspiration ratio), which guide the user to progressively and effortlessly slow his or her breathing rate <10 breaths/min. The treatment group showed high compliance to the device (90% of the prescribed sessions were completed). Blinded analysis of data demonstrated increased ejection fraction and decreased estimated pulmonary pressure in the echocardiograms of the treated group versus controls and favorable changes in New York Heart Association class, Ve/Vco2, FEV1, and a quality of life measure, as well (all P <0.05). Conclusions— This pilot investigation demonstrates that device-guided paced breathing at home is feasible and results in an improvement in clinically relevant parameters for patients with heart failure and systolic dysfunction. Received February 12, 2008; accepted July 23, 2008.Background—Regular slow breathing is known to improve autonomic cardiac regulation and reduce chemoreflex sensitivity in heart failure. We explored the acceptability and usefulness of a device for paced slow breathing at the home setting. Methods and Results—In this open pilot study, 24 patients with chronic heart failure (61% males, mean age, 64±9 years; New York Heart Association class, 2.81±0.01) were randomized to a control group receiving conventional treatment (n=12) or to a group receiving conventional treatment and device-guided paced breathing (n=12). Groups were comparable for age, therapies, and clinical characteristics. They were evaluated at baseline and again after 10 weeks by Doppler echocardiography, pulmonary function, cardiopulmonary stress test, and quality of life (Minnesota Quality of Life questionnaire). The treatment group was instructed to use the equipment for 18 minutes twice daily. The device is a computerized box connected to a belt-type respiration sensor and to headphones; it generates musical tones (based on the user’s breathing rate and inspiration ratio), which guide the user to progressively and effortlessly slow his or her breathing rate <10 breaths/min. The treatment group showed high compliance to the device (90% of the prescribed sessions were completed). Blinded analysis of data demonstrated increased ejection fraction and decreased estimated pulmonary pressure in the echocardiograms of the treated group versus controls and favorable changes in New York Heart Association class, Ve/Vco2, FEV1, and a quality of life measure, as well (all P<0.05). Conclusions—This pilot investigation demonstrates that device-guided paced breathing at home is feasible and results in an improvement in clinically relevant parameters for patients with heart failure and systolic dysfunction.

Different baseline sympathovagal balance and cardiac autonomic responsiveness in ischemic and non-ischemic congestive heart failure

A profound autonomic unbalance is present in heart failure: its correlation with the etiology of the disease has never been investigated.