Synthesis and Investigation of 2,6-Bis(picrylamino)-3,5-dinitro-pyridine (PYX) and Its Salts.

2,6-Bis(picrylamino)pyridine (1; pre-PYX) and 2,6-bis(picrylamino)-3,5-dinitropyridine (2; PYX) were synthesized using an improved literature method. Compounds 1 and 2 were reinvestigated in detail and the X-ray structures (1: ρ=1.698 g cm(-3) at 173 K; 2: ρ=1.757 g cm(-3) at 298 K) are given. The reactions of 2 with different bases, such as alkali metal hydroxides (sodium, potassium, rubidium, cesium), and N-bases (ammonia, hydrazine, hydroxylamine, guanidinium carbonate, aminoguanidine bicarbonate) are reported, as well as metathesis reactions producing energetic salts. Several energetic compounds were synthesized and characterized for the first time using vibrational (IR, Raman) and multinuclear NMR spectroscopy, mass spectrometry, elemental analysis, and DSC. The crystal structures of four energetic salts were determined using low temperature single-crystal X-ray diffraction. Heats of formation for the metal-free species were calculated using the Gaussian 09 software. Detonation parameters were estimated using the EXPLO5 program. The sensitivities towards impact, friction, and electrostatic discharge were also determined.

Synthesis and Investigation of Advanced Energetic Materials Based on Bispyrazolylmethanes.

Herein we present the preparation and characterization of three new bispyrazolyl-based energetic compounds with great potential as explosive materials. The reaction of sodium 4-amino-3,5-dinitropyrazolate (5) with dimethyl iodide yielded bis(4-amino-3,5-dinitropyrazolyl)methane (6), which is a secondary explosive with high heat resistance (Tdec =310 °C). The oxidation of this compound afforded bis(3,4,5-trinitropyrazolyl)methane (7), which is a combined nitrogen- and oxygen-rich secondary explosive with very high theoretical and estimated experimental detonation performance (Vdet (theor)=9304 m s-1 versus Vdet (exp)=9910 m s-1 ) in the range of that of CL-20. Also, the thermal stability (Tdec =205 °C) and sensitivities of 7 are auspicious. The reaction of 6 with in situ generated nitrous acid yielded the primary explosive bis(4-diazo-5-nitro-3-oxopyrazolyl)methane (8), which showed superior properties to those of currently used diazodinitrophenol (DDNP).

Synthesis, characterisation and crystal structures of two bi-oxadiazole derivatives featuring the trifluoromethyl group.

The synthesis, characterisation, and crystal structure determination of the closely related compounds 3,3'-bi-(5-trifluoromethyl-1,2,4-oxadiazole) and 5,5'-bi-(2-trifluoromethyl-1,3,4-oxadiazole) are reported. These two compounds are known for their bioactivity; however, in this study they serve as model compounds to evaluate the suitability of the heterocyclic oxadiazole ring system for energetic materials when the fluorine atoms in the exocyclic CF3 groups are substituted successively by nitro groups. Quantum chemical calculations for the bi-1,3,4-oxadiazole derivatives with difluoronitromethyl, fluorodinitromethyl, and trinitromethyl groups have been carried out and predict promising energetic performances for both explosive and propulsive applications.

Effect of cardiac resynchronization therapy in patients without left intraventricular dyssynchrony.

AIMS: To evaluate the effects of cardiac resynchronization therapy (CRT) on long-term survival of patients without baseline left ventricular (LV) mechanical dyssynchrony. METHODS AND RESULTS: A total of 290 heart failure patients (age 67 ± 10 years, 77% males) without significant baseline LV dyssynchrony (<60 ms as assessed with tissue Doppler imaging) were treated with CRT. Patients were divided according to the median LV dyssynchrony measured after 48 h of CRT into two groups. All-cause mortality was compared between the subgroups. In addition, the all-cause mortality rates of these subgroups were compared with the all-cause mortality of 290 heart failure patients treated with CRT who showed significant LV dyssynchrony (≥60 ms) at baseline. In the group of patients without significant LV dyssynchrony, median LV dyssynchrony increased from 22 ms (inter-quartile range 16-34 ms) at baseline to 40 ms (24-56 ms) 48 h after CRT. The cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with LV dyssynchrony ≥40 ms 48 h after CRT implantation were significantly higher when compared with patients with LV dyssynchrony <40 ms (10, 17, and 23 vs. 3, 8, and 10%, respectively; log-rank P< 0.001). Finally, the cumulative mortality rates at 1-, 2-, and 3-year follow-up of patients with baseline LV dyssynchrony were 3, 8, and 11%, respectively (log-rank P= 0.375 vs. patients with LV dyssynchrony <40 ms). Induction of LV dyssynchrony after CRT was an independent predictor of mortality (hazard ratio: 1.247; P= 0.009). CONCLUSION: In patients without significant LV dyssynchrony, the induction of LV dyssynchrony after CRT may be related to a less favourable long-term outcome.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure.

AIMS: Periodic breathing with central sleep apnoea (CSA) is common in heart failure patients and is associated with poor quality of life and increased risk of morbidity and mortality. We conducted a prospective, non-randomized, acute study to determine the feasibility of using unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure patients. METHODS AND RESULTS: Thirty-one patients from six centres underwent attempted transvenous lead placement. Of these, 16 qualified to undergo two successive nights of polysomnography-one night with and one night without phrenic nerve stimulation. Comparisons were made between the two nights using the following indices: apnoea-hypopnoea index (AHI), central apnoea index (CAI), obstructive apnoea index (OAI), hypopnoea index, arousal index, and 4% oxygen desaturation index (ODI4%). Patients underwent phrenic nerve stimulation from either the right brachiocephalic vein (n = 8) or the left brachiocephalic or pericardiophrenic vein (n = 8). Therapy period was (mean ± SD) 251 ± 71 min. Stimulation resulted in significant improvement in the AHI [median (inter-quartile range); 45 (39-59) vs. 23 (12-27) events/h, P = 0.002], CAI [27 (11-38) vs. 1 (0-5) events/h, P≤ 0.001], arousal index [32 (20-42) vs. 12 (9-27) events/h, P = 0.001], and ODI4% [31 (22-36) vs. 14 (7-20) events/h, P = 0.002]. No significant changes occurred in the OAI or hypopnoea index. Two adverse events occurred (lead thrombus and episode of ventricular tachycardia), though neither was directly related to phrenic nerve stimulation therapy. CONCLUSION: Unilateral transvenous phrenic nerve stimulation significantly reduces episodes of CSA and restores a more natural breathing pattern in patients with heart failure. This approach may represent a novel therapy for CSA and warrants further study.

Early Heart Rate Recovery after a 6-min Walking Test Predicts Clinical Benefits in Patients after Percutaneous Aortic Valve Implantation.

BACKGROUND: It was hypothesized that the time-appropriate return to a resting heart rate (HR) after cessation of exercise could be a marker for predicting outcomes in patients with heart failure (HF). We aimed to evaluate the prognostic value of HR recovery in functional improvement among adults with severe aortic stenosis undergoing percutaneous aortic valve implantation (TAVI). METHODS: We performed a 6 min walk test (6MWT) in 93 individuals before TAVI and 3 months after the procedure. The change in walking distance was calculated. During the pre-TAVI 6MWT, we analyzed the differences between baseline HR, HR at the end of the test, and HR at the 1st, 2nd, and 3rd minute of recovery. RESULTS: After 3 months, 6MWT distances improved by 39 ± 63 m and reached a total of 322 ± 117 m. Multiple linear regression proved the differences between HR after 2 min of recovery and baseline HR in pre-TAVI after a 6MWT was the only significant predictor of waking distance improvement during follow-up. CONCLUSIONS: Our study suggests that analysis of HR recovery after a 6MWT may be a helpful and easy parameter to assess improvements in exercise capacity after TAVI. This simple method can help to identify patients in whom no significant benefit in functional improvement can be expected despite successful valve implantation.

Alterations in multidirectional myocardial functions in patients with aortic stenosis and preserved ejection fraction: a two-dimensional speckle tracking analysis.

AIMS: To identify changes in multidirectional strain and strain rate (SR) in patients with aortic stenosis (AS). METHODS AND RESULTS: A total of 420 patients (age 66.1 ± 14.5 years, 60.7% men) with aortic sclerosis, mild, moderate, and severe AS with preserved left ventricular (LV) ejection fraction [(EF), ≥50%] were included. Multidirectional strain and SR imaging were performed by two-dimensional speckle tracking. Patients were more likely to be older (P < 0.001) and at a worse New York Heart Association functional class (P < 0.001) with increasing AS severity. There was a progressive stepwise impairment in longitudinal, circumferential, and radial strain and SR with increasing AS severity (all P < 0.001). The myocardial dysfunction appeared to start in the subendocardium with mild AS, to mid-wall dysfunction with moderate AS, and eventually transmural dysfunction with severe AS. Aortic valve area, as a measure of AS severity, was an independent determinant of multidirectional strain and SR on multiple linear regressions. CONCLUSIONS: Patients with AS have evidence of subclinical myocardial dysfunction early in the disease process despite normal LVEF. The myocardial dysfunction appeared to start in the subendocardium and progressed to transmural dysfunction with increasing AS severity. Symptomatic moderate and severe AS patients had more impaired multidirectional myocardial functions compared with asymptomatic patients.

Simultaneous placement of leadless pacemaker and dialysis catheter in patient with exhausted vasculature.

The problem with limited venous access may occur in patients receiving long-term hemodialysis treatment with no possibility of arteriovenous access or in patients with cardiac implantable electronic device-related infection leading to the removal of cardiac implantable electronic device. We present a case report where both situations occur simultaneously. Using recent development in cardiac pacing-leadless cardiac pacemaker-we manage to overcome the vascular access problem. The described case emphasizes the necessity of multispecialty collaboration and gains of new pacing technology in patients who need placement of vascular access for hemodialysis and cardiac implantable electronic device where vascular access is scarce.

Prevalence and characteristics of patients with clinical improvement but not significant left ventricular reverse remodeling after cardiac resynchronization therapy.

BACKGROUND: Although most patients who improve in clinical status after cardiac resynchronization therapy (CRT) also show a significant left ventricular (LV) reverse remodeling, some patients do not show echocardiographic improvement. The aim of the present study was to evaluate the degree of agreement between clinical and echocardiographic response to CRT in a large cohort of heart failure patients, and to evaluate the characteristics of patients with clinical response but without echocardiographic response. METHODS: In 440 consecutive heart failure patients (mean age 66 ± 11 years, 81% men) treated with CRT, agreement between clinical and echocardiographic responses at 6 months of follow-up were evaluated. The combined clinical response was defined as: ≥1-point New York Heart Association functional class improvement or ≥15% increase in 6-minute walk test. Echocardiographic response was defined by a reduction in LV end-systolic volume (LVESV) ≥15%. RESULTS: At 6 months of follow-up, clinical response was observed in 84% (n = 370) of the patients. Significant reduction in LVESV was noted in 63% (n = 276). The majority of patients who improved clinically did show LV reverse remodeling (72%, n = 268). Importantly, 28% (n = 102) of patients who improved clinically did not show significant LV reverse remodeling. The patients with clinical response but without echocardiographic response had more often ischemic heart failure as compared to patients with positive clinical and echocardiographic response (69.6% vs 57.5%; P = .021). Moreover, patients with such discordant responses had more narrow QRS complex (148 ± 31 vs 159 ± 31 milliseconds; P = .004), and showed less LV dyssynchrony than patients with concordant positive responses (90 ± 77 vs 171 ± 105 milliseconds; P < .001). CONCLUSIONS: Although there is a good concordance between echocardiographic and clinical response to CRT, up to 28% of the population experienced clinical response without significant LV reverse remodeling. Subjects with such discrepant responses have more frequently ischemic heart failure and show more narrow QRS complex and less LV dyssynchrony than patients with both clinical and echocardiographic response.

Pathophysiological and clinical relevance of simplified monitoring of nocturnal breathing disorders in heart failure patients.

AIMS: Nocturnal breathing disorders in the form of periodic breathing (PB) are very common in heart failure (HF) patients. There is an increasing interest in simple and affordable tools to screen patients and monitor these disorders at home on a long-term basis. We aimed to assess the pathophysiological and clinical relevance of a simplified method for monitoring of PB suitable to be self-managed by the patient at home. METHODS AND RESULTS: A night-time respiratory recording was performed in 397 optimally treated HF patients (age 60 +/- 11 years, NYHA class 2.4 +/- 0.6, left ventricular ejection fraction 29 +/- 7%) and the duration of PB (PB(Dur)) automatically computed. Patients were followed-up for 1 year and the prognostic value of PB(Dur) evaluated. In 45 patients, we assessed the association between PB(Dur) and severity of oxygen desaturations (number of desaturations >3%). Twenty six of the 397 patients died of cardiac causes. A PB(Dur) > or =2 h was significantly associated with an increased risk of cardiac death after adjustment for major clinical predictors [hazard ratio (95% CI): 3.5 (1.6-7.9), P = 0.002]. The correlation between PB(Dur) and severity of desaturations was 0.94 (P < 0.0001). CONCLUSION: Relevant pathophysiological and clinical information can be obtained from simplified monitoring of breathing disorders managed by the patient. These results provide new perspectives in the investigation of the clinical impact of abnormal breathing in HF patients.

Abnormal indices of autonomic function are no longer predictors of poor outcome in diabetic patients without neuropathy but with coexisting coronary artery disease who receive optimal pharmacological therapy.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) and has been regarded as a parameter associated with a poor outcome. AIM: We investigated whether indices of cardiovascular autonomic function have prognostic value in the current era of pharmacological therapy recommended for DM patients with coexisting coronary artery disease (CAD), which consists of drugs that affect autonomic balance, i.e. angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers, and statins. METHODS: We studied 127 consecutive patients with type 2 DM and angiographically documented stable CAD (age: 64 years, women: 28%, treatment: ACEI/ARBs: 100%, statins: 98%, beta-blockers: 88%, insulin therapy: 46%). The assessment of autonomic balance within the cardiovascular system included heart rate variability (HRV) (time and spectral-domain analyses) and non-invasive evaluation of baroreflex sensitivity (sequence and controlled breathing methods). Primary end-points were cardiovascular mortality and urgent hospital admissions due to cardiovascular symptoms. RESULTS: During the mean follow-up of 502 +/- 161 days, 28 patients (22%) experienced a cardiovascular event: 7 died and 21 were admitted to hospital. We found the following predictors of an increased risk of the combined end point (cardiovascular death and hospitalisation): elevated level of N-terminal BNP (for log NT-proBNP - HR = 2.6, p = 0.004), severe CAD (3-vessel disease - HR = 2.4, p = 0.02), renal insufficiency (eGFR < 60 ml/min/1.73 m2 - HR = 2.7, p = 0.008), and female gender (HR = 3.2, p = 0.002). None of the indices of autonomic balance had prognostic value (p > 0.2 for all). CONCLUSION: In the population of diabetic patients with stable CAD who receive optimal pharmacological therapy, indices of impaired autonomic function are no longer predictors of poor outcome.

Synthesis and Investigation of 2,3,5,6-Tetra-(1H-tetrazol-5-yl)pyrazine Based Energetic Materials.

The structures and properties of several energetic compounds based on a high-nitrogen-content anion, namely 2,3,5,6-tetra(1H-tetrazol-5-yl)pyrazine (H4 TTP) are reported here for the first time. These energetic salts were synthesized by reacting H4 TTP with various alkali metal hydroxides (sodium, potassium, rubidium, caesium) and N-based (ammonia, hydrazine, hydroxylamine, guanidine carbonate, aminoguanidine bicarbonate). The resulting materials were comprehensively characterized by multinuclear (1 H, 13 C) NMR spectroscopy, infrared spectroscopy, elemental analysis, DSC, as well as low-temperature single-crystal X-ray diffraction. Heats of formation for the metal-free species as well as detonation parameters were calculated. The presented energetic materials (EMs) show high thermal stability (207 °C≤Tdec ≤300 °C), while the metal-free ionic derivatives exhibit desirable properties such as detonation velocity (6873 m s-1 ≤VC-J ≤8364 m s-1 ), detonation pressure (14.3 GPa≤pC-J ≤24.9 GPa), and specific impulse (141.4≤Isp ≤192.5 s).

A nitrogen-rich ligand as a scaffold for slow magnetic relaxation in dysprosium-based 0D and 1D architectures.

A recently designed nitrogen-rich ligand is successfully applied as a scaffold for lanthanide ions to show that the intricate chemistry of energetic materials can be combined with other fields of research, including that of molecular magnetism. Herein, we report the synthesis of two different types of molecular architectures using a single ligand template, in which the discrete monomer exhibits single-molecule magnet-like behaviour along with two well-isolated modes of magnetic relaxation.

Excessive ventilation during early phase of exercise: a new predictor of poor long-term outcome in patients with chronic heart failure.

BACKGROUND: Studies demonstrating prognostic value of excessive exercise ventilation in chronic heart failure (CHF) have focused on data derived from the whole cardiopulmonary exercise test (CPET). Whether ventilatory response to early phase of exercise is useful for risk stratification in CHF is unknown. METHODS AND RESULTS: We evaluated 216 patients with systolic CHF who underwent CPET (age: 60+/-11 years, NYHA class [I/II/III/IV]: 18/104/77/17). Ventilatory response to exercise (slope of regression line relating ventilation to carbon dioxide production) was calculated from the whole exercise test (VE-VCO(2)-all) and from the first 3 min of exercise (early phase - VE-VCO(2)-3 min). During follow-up (mean: 40+/-20 months, >3 years in survivors), 89 (41%) CHF patients died. High VE-VCO(2)-all and VE-VCO(2)-3 min predicted poor outcome in single predictor analyses, and in multivariable models when adjusted for prognosticators (age, NYHA class, ejection fraction, peak VO(2)) (P<0.0001). In receiver operating characteristic curve analysis, areas under curve for 3-year follow-up were similar for VE-VCO(2)-all and VE-VCO(2)-3 min. VE-VCO(2)-3 min maintained its prognostic value in patients taking beta-blockers (P<0.0001) and those unable to perform maximal CPET (P=0.0009). CONCLUSIONS: In CHF patients, excessive ventilation assessed over the first 3 min predicts poor outcome. Assessment of ventilatory response to exercise for prognostic stratification may be extended to patients unable to perform maximal CPET.

5,5'-Bis(2,4,6-trinitrophenyl)-2,2'-bi(1,3,4-oxadiazole) (TKX-55): Thermally Stable Explosive with Outstanding Properties.

The novel, thermally stable explosive 5,5'-bis(2,4,6-trinitro-phenyl)-2,2'-bi(1,3,4-oxadiazole) (TKX-55) is reported. This compound can be prepared by means of a facile synthetic procedure and shows outstanding properties (detonation velocity, detonation pressure, sensitivity toward mechanical stimuli, and temperature of decomposition). TKX-55 was isolated and characterized by means of mass spectrometry, multinuclear (1 H, 13 C) NMR spectroscopy, and vibrational spectroscopy (IR and Raman). The structure in the crystalline state was determined by low-temperature single-crystal X-ray diffraction. From the calculated standard molar enthalpy of formation (CBS-4M) and the densities, the Chapman-Jouguet detonation properties were predicted by using the EXPLO5 V6.01 thermochemical computer code. The sensitivity of TKX-55 towards impact, friction, and electrostatic discharge was determined. The shock reactivity (explosiveness) of TKX-55 was measured by applying the small-scale shock reactivity test.

Detection of subtle left ventricular systolic dysfunction in patients with significant aortic regurgitation and preserved left ventricular ejection fraction: speckle tracking echocardiographic analysis.

AIMS: The aim of this study was to characterize left ventricular (LV) mechanics in symptomatic and asymptomatic patients with moderate-to-severe or severe aortic regurgitation (AR) and preserved ejection fraction (left ventricular ejection fraction) using two-dimensional speckle tracking echocardiography (2D-STE). The association between baseline LV strain and development of indications for surgery in asymptomatic patients was also evaluated. METHODS AND RESULTS: A total of 129 patients with moderate-to-severe or severe AR and LVEF >50% (age 55 ± 17 years, 64% male, 53% asymptomatic at baseline) were included. Standard echocardiography and 2D-STE were performed at baseline. Compared with asymptomatic patients, symptomatic patients had significantly impaired LV longitudinal (-14.9 ± 3.0 vs. -16.8 ± 2.5%, P < 0.001), circumferential (-17.5 ± 2.9 vs. -19.3 ± 2.8%, P = 0.001), and radial (35.7 ± 12.2 vs. 43.1 ± 14.7%, P = 0.004) strains. Among 49 asymptomatic patients who were followed up, 26 developed indications for surgery (symptoms onset or LVEF ≤50%). These patients had comparable LV volumes, LVEF, and colour Doppler assessments of AR jet at baseline, but more impaired LV longitudinal (P = 0.009) and circumferential (P = 0.017) strains compared with patients who remained asymptomatic. Impaired baseline LV longitudinal (per 1% decrease, HR = 1.21, P = 0.04) or circumferential (per 1% decrease, HR = 1.22, P = 0.04) strain was independently associated with the need for surgery. CONCLUSION: Multidirectional LV strain was more impaired in symptomatic than in asymptomatic patients with moderate-to-severe or severe AR, despite preserved LVEF. In asymptomatic AR patients, longitudinal and circumferential strains identified patients who would require surgery during follow-up.

The role of exercise ventilation in clinical evaluation and risk stratification in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) are characterised by an increased ventilatory response to exercise. The role of exercise ventilation in the risk stratification and evaluation of patients with CHF has not yet been established. AIM: To examine the relationship between exercise ventilation indices and clinical parameters of CHF and to assess the prognostic value of the ventilatory response to exercise. METHODS: The study group consisted of 87 patients with CHF (72 males, mean age 58 years) with a mean left ventricular ejection fraction of 32%. Ten patients were in NYHA class I, 38 - in NYHA class II, 34 - in NYHA class III, and 5 - in NYHA class IV. The control group consisted of 20 patients without CHF (13 males, mean age 58 years, mean LVEF - 61%). All studied subjects underwent maximal exercise test with gas-exchange measurement. The following parameters were analysed: peak exercise oxygen consumption [peak VO(2) (ml/kg/min)], VE-VCO(2) index [a coefficient of linear regression analysis depicting an association between ventilation (VE) and carbon dioxide production (VCO(2)) during exercise] and VE/VCO(2) ratio at peak exercise to VE/VCO(2) ratio while at rest (VE/VCO(2 peak/rest)). RESULTS: Ventilatory response indices were significantly higher in patients with CHF compared with controls: VE-VCO(2) - 37.9+/-11.1 vs 27.1+/-4.1; VE-VCO(2 peak/rest) - 0.89+/-0.14 vs 0.75+/-0.10 (p<0.001). In CHF patients a significant positive correlation between ventilatory response parameters and NYHA class (VE-VCO(2) - r=0.52; VE/VCO(2 peak/rest) - r=0.47) and a negative correlation with peak VO(2) (VE-VCO(2) - r=-0.52; VE/VCO(2 peak/rest) - r=-0.49) were noted (p<0.0001 for all correlations). No correlation was found between ventilatory parameters and echocardiographic variables or CHF aetiology. During the follow-up period lasting at least 12 months, 17 (22%) patients died. In the univariate Cox model, NYHA class III-IV, decreased peak VO(2) and increased VE-VCO(2) and VE/VCO(2 peak/rest) values were significantly associated with the risk of death. The multivariate analysis revealed that VE/VCO(2 peak/rest) > or =1.0 was the adverse prognostic factor, independent of peak VO(2) (p=0.02) and NYHA class (p=0.01). The Kaplan-Meier analysis showed that prognosis during the 18-month follow-up period in patients with enhanced exercise ventilation was worse than in the remaining patients (59% survival in patients with VE/VCO(2 peak/rest) > or =1.0 59% vs 91% survival in patients with VE/VCO(2 peak/rest) <1.0, p=0.001). CONCLUSIONS: In patients with stable CHF simple exercise ventilation parameters may provide important clinical and prognostic information.

Chronic heart failure. The relationship between increased activity of skeletal muscle ergoreceptors and reduced exercise tolerance.

BACKGROUND: In chronic heart failure (CHF), skeletal muscle abnormalities may lead to the overactivation of ergoreceptors which in turn may cause sympathetic overactivation and increased ventilatory response to exercise. AIM: To assess ergoreceptor reflex response to exercise and to evaluate whether ergoreceptor overactivity is related to the progression of CHF. METHODS: In 69 patients with CHF (66 males, mean age 62.7+/-11.6 years, NYHA class I/II/III/IV - 11/32/24/2 patients, respectively) and 24 controls without CHF (22 males, mean age 59+/-4.6 years) the ergoreflex contribution to the ventilatory and haemodynamic responses to exercise was evaluated. Moreover, in 13 patients with CHF, reproducibility of the measurements was assessed by repeating the test 1 to 7 days later. RESULTS: Enhanced ergoreflex effects on ventilation (1.9+/-1.6 vs 0.14+/-0.7 l/min, p<0.05) and systolic blood pressure (19.2+/-14.9 vs 6.1+/-5.9 mmHg, p<0.05) were found in patients with CHF compared with control subjects. Ergoreceptor overactivity was associated with a worse symptomatic state (NYHA class I vs II vs III, IV: 0.9 vs 1.5 vs 2.9 l/min, p<0.05) and lower exercise tolerance (peak V0(2): r=-0.51, p<0.0001; VE/VC0(2): r=0.50, p<0.0001). The mean values of the ergoreceptor reflex did not differ significantly between the two tests (t=1.5, p=0.14; variability coefficient = 21.5%). CONCLUSIONS: In CHF, overactivation of the ergoreflex is associated with the progression of the syndrome and may be responsible for reduced exercise tolerance. Reproducibility of ergoreflex measurements is satisfactory.