Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19. METHODS: A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684. RESULTS: Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: -2.31%; 95% CI: -3.19, -1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: -1.73%; 95% CI: -3.04, -0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: -2.20%; 95% CI: -3.35, -1.05; p < 0.0001) and long-term follow-up (MD: -2.53%; 95% CI: -4.19, -0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: -2.09; p = 0.037). CONCLUSIONS: Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.Key messagesThe mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated.Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist.Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.

Role of frailty on cardiac rehabilitation in hospitalized older patients.

BACKGROUND: Cardiovascular diseases are the leading cause of mortality, morbidity, and disability in the world, especially in the older adults. A relevant proportion of patients admitted to Cardiac Rehabilitation (CR) may suffer from frailty, a complex geriatric syndrome with multifactorial aetiology. AIMS: The hypothesis underlying the study is that frailty complicates the management of older patients undergoing CR. The main objective is, therefore, to determine the relationship between frailty and CR outcomes in hospitalized older adults. METHODS: The participants have been recruited among patients aged ≥ 65 years admitted at the hospital for CR. A Comprehensive Geriatric Assessment (CGA)-based Frailty Index (FI) was created following a standard procedure. The outcome was measured as the ratio between 6-min walk test (6MWT) distance at the end of CR and normal predicted values for a healthy adult of same age and gender, according to reference equations. RESULTS: The study population consisted of 559 elderly patients, 387 males (69.2%), with age of 72 (69-76) years. The most frequent diagnosis at admission was ischaemic heart disease (231, 41.5%) and overall 6MWT ratio was 0.62 ± 0.21. At the multivariable regression analysis, gender, diagnosis and FI were significantly and independently associated with 6MWT ratio (p ≤ 0.0001, p ≤ 0.001 and p ≤ 0.0001, respectively), while no significant association emerged for age. CONCLUSION: FI resulted independently correlated to 6MWT ratio in a population of older patients undergoing in-hospital CR programs. Frailty is a multifactorial geriatric syndrome whose assessment is essential for prognostic evaluation of older patients, also in CR clinical setting.

Mechanisms and Clinical Implications of Endothelial Dysfunction in Arterial Hypertension.

The endothelium is composed of a monolayer of endothelial cells, lining the interior surface of blood and lymphatic vessels. Endothelial cells display important homeostatic functions, since they are able to respond to humoral and hemodynamic stimuli. Thus, endothelial dysfunction has been proposed as a key and early pathogenic mechanism in many clinical conditions. Given the relevant repercussions on cardiovascular risk, the complex interplay between endothelial dysfunction and systemic arterial hypertension has been a matter of study in recent years. Numerous articles have been published on this issue, all of which contribute to providing an interesting insight into the molecular mechanisms of endothelial dysfunction in arterial hypertension and its role as a biomarker of inflammation, oxidative stress, and vascular disease. The prognostic and therapeutic implications of endothelial dysfunction have also been analyzed in this clinical setting, with interesting new findings and potential applications in clinical practice and future research. The aim of this review is to summarize the pathophysiology of the relationship between endothelial dysfunction and systemic arterial hypertension, with a focus on the personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction while treating hypertension and cardiovascular comorbidities.

Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting.

Cardiopulmonary Exercise Performance and Endothelial Function in Convalescent COVID-19 Patients.

BACKGROUND: Endothelial dysfunction has been proposed as the common pathogenic background of most manifestations of coronavirus disease 2019 (COVID-19). Among these, some authors also reported an impaired exercise response during cardiopulmonary exercise testing (CPET). We aimed to explore the potential association between endothelial dysfunction and the reduced CPET performance in COVID-19 survivors. METHODS: 36 consecutive COVID-19 survivors underwent symptom-limited incremental CPET and assessment of endothelium-dependent flow-mediate dilation (FMD) according to standardized protocols. RESULTS: A significantly higher FMD was documented in patients with a preserved, as compared to those with a reduced, exercise capacity (4.11% ± 2.08 vs. 2.54% ± 1.85, p = 0.048), confirmed in a multivariate analysis (ß = 0.899, p = 0.038). In the overall study population, FMD values showed a significant Pearson's correlation with two primary CPET parameters, namely ventilation/carbon dioxide production (VE/VCO2) slope (r = -0.371, p = 0.026) and end-tidal carbon dioxide tension (PETCO2) at peak (r = 0.439, p = 0.007). In multiple linear regressions, FMD was the only independent predictor of VE/VCO2 slope (ß = -1.308, p = 0.029) and peak PETCO2 values (ß = 0.779, p = 0.021). Accordingly, when stratifying our study population based on their ventilatory efficiency, patients with a ventilatory class III-IV (VE/VCO2 slope ≥ 36) exhibited significantly lower FMD values as compared to those with a ventilatory class I-II. CONCLUSIONS: The alteration of endothelial barrier properties in systemic and pulmonary circulation may represent a key pathogenic mechanism of the reduced CPET performance in COVID-19 survivors. Personalized pharmacological and rehabilitation strategies targeting endothelial function may represent an attractive therapeutic option.

Cognitive Impairment in Convalescent COVID-19 Patients Undergoing Multidisciplinary Rehabilitation: The Association with the Clinical and Functional Status.

BACKGROUND: Cognitive impairment has been reported in the aftermath of severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) infection. We investigated the possible association between cognitive impairment and the main clinical and functional status variables in a cohort of convalescent COVID-19 patients without premorbid diseases potentially affecting cognition. METHODS: We consecutively screened for inclusion of convalescent COVID-19 patients referring to a post-acute care facility for pulmonary rehabilitation. All the enrolled patients were assessed for cognitive functions. We also investigated features of psychological distress (anxiety, depression, symptoms of posttraumatic stress disorder and quality of life) and cardiac and pulmonary functional status. RESULTS: The 63 enrolled patients (mean age 59.82 ± 10.78, male gender = 47) showed a high frequency of depressive symptoms (76.2%) and anxiety (55.5%), and a high prevalence of symptoms of posttraumatic stress disorder (PTSD, 44.4%). About half of the total sample showed reduced cognitive efficiency (RCE, 44.4%) in the domains of spatial and verbal long-term memory and executive functions. Patients with RCE more frequently showed alteration of blood pressure (BP) circadian rhythm (p = 0.01), higher levels of D-Dimer (p = 0.03), had experienced a severe illness (p = 0.02), had longer disease duration (p = 0.04), more clinically relevant symptoms of PTSD (p = 0.02), more frequent cognitive complaints (p = 0.002), higher anxiety scores (p = 0.01) and lower quality of life (p = 0.02) than patients with normal cognitive efficiency. CONCLUSIONS: Our findings indicated a possible association between the RCE after COVID-19 and some cardiological variables, including some indirect measures of a residual autonomic disorder, such as the presence of an altered BP circadian rhythm. Future research studies with large samples are needed to provide valid conclusions.

Performance of fractional exhaled nitric oxide in predicting response to inhaled corticosteroids in chronic cough: a meta-analysis.

Background. Chronic cough is a disabling condition with a high proportion of diagnostic and therapeutic failures. Fractional exhaled nitric oxide (FeNO) has been considered a useful biomarker for predicting inhaled corticosteroids (ICS) response. We evaluated the relationship between FeNO and ICS response in chronic cough by performing a systematic review with meta-analysis.Methods. PubMed, Web of Science, Scopus and EMBASE databases were systematically searched. Differences were expressed as Odds Ratio (OR) with 95% confidence intervals (95%CI). Pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and area under the hierarchical summary receiver operating characteristic curve (HSROCAUC) were estimated.Results. Nine articles on 740 chronic-cough patients showed that the response rate to ICS was 87.4% (95%CI: 83.8-91.0) in 317 patients with a high FeNO and 46.3% (95%CI: 41.6-51.0) in 423 controls, with an attributable proportion of 47.0% and a diagnostic OR of 9.1 (95%CI: 3.7-22.4, p < .001). The pooled estimate of diagnostic indexes resulted in a sensitivity of 68.5% (95%CI: 46.7-84.4) and specificity of 81.9% (95%CI: 63.0-92.3), with a HSROCAUC of 0.82 (95%CI: 0.64-0.90). In a realistic scenario with a pre-test probability set at 30%, based on a pooled PLR of 3.79 (95%CI: 1.24-7.47) and NLR of 0.38 (95%CI: 0.22-0.66), the post-test probability was 62% with a high FeNO and 14% if the test was negative. Subgroup analyses confirmed a better performance for the recommended FeNO cut-off greater than 25 ppb. Meta-regression and sensitivity analyses showed no impact of major demographic and clinic variables on results.Conclusions. A high FeNO before starting ICS therapy may help identify chronic-cough patients responding to treatment, with a better performance ofhigher cut-off values. Further studies are needed to evaluate the real usefulness of this biomarker to guide cough therapy and optimise strategies in different healthcare settings (community, hospital, rehabilitation).Key messagesChronic cough is a disabling condition with a high proportion of diagnostic and therapeutic failures.Fractional exhaled nitric oxide (FeNO) may be a useful biomarker for identifying chronic cough patients who respond to steroid treatment.A FeNO cut-off lower than 25 ppb should be considered irrelevant for this clinical application.

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study.

BACKGROUND: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. METHODS: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. RESULTS: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (ß = -0.427, p < 0.001). CONCLUSIONS: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients Undergoing Multidisciplinary Pulmonary Rehabilitation.

BACKGROUND: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). METHODS: After swab test negativization, convalescent COVID-19 patients referring to a post-acute care facility for PR were consecutively screened for inclusion. Study procedures were performed at the time of hospitalization and discharge. RESULTS: We enrolled 82 convalescent COVID-19 patients (85.4% males, mean age 60.4 years). After PR, a significant improvement in most pulmonary function tests and exercise capacity was documented. FMD changed from 2.48% ± 2.01 to 4.24% ± 2.81 (p < 0.001), corresponding to a 70.9% increase. Significantly higher changes in FMD were found in patients without a history of vascular events as compared to those with (+2.04% ± 2.30 vs. +0.61% ± 1.83, p = 0.013). Values of forced expiratory volume in 1 s (FEV1%), forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%) significantly and directly correlated with FMD both at baseline and after PR. Patients with normal FEV1% (≥80% predicted) during the overall study period or those normalizing FEV1% after PR showed a more significant FMD change as compared to patients with persistently impaired FEV1% (<80% predicted) (p for trend = 0.029). This finding was confirmed in a multivariate analysis. CONCLUSIONS: Clinically evaluated endothelial function improves after PR in convalescent COVID-19 patients. A direct and persistent association between the severity of pulmonary and vascular disease can be hypothesized. Endothelial function testing may be useful in the follow-up of convalescent COVID-19 patients.

Preexisting cardiorespiratory comorbidity does not preclude the success of multidisciplinary rehabilitation in post-COVID-19 patients.

Patients recovering from coronavirus disease 2019 (COVID-19) may not return to a pre-COVID functional status and baseline levels of healthcare needs after discharge from acute care hospitals. Since the long-term outcomes of COVID-19 can be more severe in patients with underlying cardiorespiratory diseases, we aimed at verifying the impact of a preexisting cardiorespiratory comorbidity on multidisciplinary rehabilitation in post-COVID-19 patients. We enrolled 95 consecutive patients referring to the Pulmonary Rehabilitation Unit of Istituti Clinici Scientifici Maugeri Spa SB, IRCCS of Telese Terme, Benevento, Italy after being discharged from the COVID-19 acute care ward and after recovering from acute COVID-19 pneumonia. Forty-nine of them were not suffering from underlying comorbidities, while 46 had a preexisting cardiorespiratory disease. Rehabilitation induced statistically significant improvements in respiratory function, blood gases and the ability to exercise both in patients without any preexisting comorbidities and in those with an underlying cardiorespiratory disease. Response to the rehabilitation cycle tended to be greater in those without preexisting comorbidities, but DLco%-predicted was the only parameter that showed a significant greater improvement when compared to the response in the group of patients with underlying cardiorespiratory comorbidity. This study suggests that multidisciplinary rehabilitation may be useful in post-COVID-19 patients regardless of the presence of preexisting cardiorespiratory comorbidities.

Diagnostic accuracy of D-Dimer testing for recurrent venous thromboembolism: A systematic review with meta-analysis.: VTE recurrence and D-dimer.

OBJECTIVE: Venous thromboembolism (VTE) recurrence is a major concern after a first symptomatic episode, potentially impacting survival and healthcare needs in community, hospital and rehabilitation settings. We evaluated the association of D-Dimer positivity after oral anticoagulant therapy (OAT) discontinuation with VTE recurrence. METHODS: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched. Differences were expressed as Odds Ratio (OR) with 95% confidence intervals (95%CI). Pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and summary ROC (sROC) curve were calculated. RESULTS: Twenty-six articles on 10,725 VTE patients showed that the absolute risk of recurrence was 16.1% (95%CI: 13.2%-19.5%) among 4,049 patients with a positive D-Dimer and 7.4% (95%CI: 6.0%-9.0%) in 6,676 controls (OR: 2.1, 95%CI: 1.7-2.8, P<0.001), with an attributable risk of 54.0%. sROC curve of the association between positive D-Dimer and recurrence showed a diagnostic AUC of 63.8 (95%CI: 60.3-67.4), with a pooled sensitivity of 54.3% (95%CI: 51.3%-57.3%), specificity of 64.2% (95%CI: 63.2-65.1), PLR of 1.53 (95%CI: 1.37-1.72), and NLR of 0.71 (95%CI: 0.60-0.84). Subgroup and meta-regression analyses suggested that a positive D-Dimer may have a higher discriminatory ability for patients with provoked events, confirmed by better pooled diagnostic indexes for recurrence and a diagnostic AUC of 70.6 (95%CI: 63.8-77.4). Regression models showed that the rate of OAT resumption after the evidence of D-Dimer positivity was inversely associated with VTE recurrence (Z-score: -3.91, P<0.001). CONCLUSIONS: D-Dimer positivity after OAT may identify VTE patients at higher risk of recurrence, with a better diagnostic accuracy for provoked events.

Clinical assessment of endothelial function in heart failure with preserved ejection fraction: A meta-analysis with meta-regressions.

BACKGROUND: Endothelial dysfunction is a key mechanism in the development of cardiac remodelling and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Flow-mediated (FMD) and nitrate-mediated dilation (NMD) are noninvasive methods to assess endothelial function. We performed a meta-analysis evaluating the impact of HFpEF on FMD and NMD. METHODS: PubMed, Web of Science, Scopus and EMBASE databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences were expressed as mean difference (MD) with 95% confidence intervals (95%CI). The random effects method was used. RESULTS: A total of seven studies were included in the final analysis, 7 with data on FMD (326 HFpEF patients and 417 controls) and 3 on NMD (185 HFpEF patients and 271 controls). Compared to controls, HFpEF patients showed significantly lower FMD (MD: -1.929; 95%CI: -2.770, -1.088; P < .0001) and NMD values (MD: -2.795; 95%CI: -3.876, -1.715; P < .0001). Sensitivity analyses substantially confirmed results. Meta-regression models showed that increasing differences in E/A ratio (Z-score: -2.002; P = .045), E/E' ratio (Z-score: -2.181; P = .029) and left atrial diameter (Z-score: -1.951; P = .050) were linked to higher differences in FMD values between cases and controls. CONCLUSIONS: Impaired endothelial function can be documented in HFpEF, with the possibility of a direct association between the severity of diastolic and endothelial dysfunction. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.

Clinical application of nasal nitric oxide measurement in allergic rhinitis: A systematic review and meta-analysis.

BACKGROUND: Nasal nitric oxide (nNO) is considered a biomarker of nasal inflammation. OBJECTIVE: To perform a systematic review with meta-analysis and meta-regressions on the association between nNO levels and allergic rhinitis (AR). METHODS: PubMed, Web of Science, Scopus, and EMBASE databases were systematically searched. Differences between cases and controls were expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). RESULTS: Overall, 39 articles were included: 30 containing data on nNO measured by nasal aspiration (1881 patients with AR and 1337 controls) and 12 assessing nNO by nasal exhalation (525 patients with AR and 350 controls). Compared with controls, AR presented significantly higher nNO values both during nasal aspiration (SMD, 1.309; 95% CI, 0.841-1.777; P < .001) and nasal exhalation (SMD, 0.708; 95% CI, 0.303-1.114; P = .001). Sensitivity and subgroup analyses confirmed that the results for the evaluated outcomes were not affected by the presence of clinical confounding factors (asthma, nasal polyps, inhaled corticosteroids, smoking history), this being valid for both perennial and seasonal diseases during exposure to allergens. For the aspiration method, meta-regressions indicated that older age and a better pulmonary function were associated with a lower difference in nNO levels between patients with AR and controls, whereas an increasing aspiration flow was associated with a high effect size. CONCLUSION: nNO levels are higher in AR, particularly when using high aspiration flows and in younger patients, who often perceive this condition as a source of disability. Further studies are needed to evaluate the usefulness of this biomarker for monitoring airway disorders and optimizing strategies in different settings (community, hospital, rehabilitation).

A randomized, double-blind comparison of lercanidipine 10 and 20 mg in patients with stable effort angina: clinical evaluation of cardiac function by ambulatory ventricular scintigraphic monitoring.

We evaluated the antiischemic action and the effects on left ventricular response to exercise of lercanidipine, a long-acting dihydropyridine calcium antagonist, in 23 patients with stable effort angina in a randomized, double-blind, parallel trial. Left ventricular function was assessed during upright bicycle exercise using an ambulatory radionuclide detector for continuous noninvasive monitoring of cardiac function. Exercise was performed under control conditions before (run-in placebo period) and after 2-week treatment with lercanidipine 10 or 20 mg once daily. During the placebo run-in period and at the study end, patients underwent clinical examination, ECG, exercise tests, ambulatory ventricular scintigraphic monitoring (VEST). Results showed that both drug doses increased time to onset of ST segment depression >/=1 mm and peak ST segment depression, with improvement of total exercise duration. Heart rate, blood pressure, and the rate-pressure product did not significantly change with respect to pretreatment value. The left ventricular ejection fraction, indicating contractility state of myocardium, was unchanged at rest and during exercise after both lercanidipine doses. In conclusion, lercanidipine is safe and effective in reducing ischemia in patients with stable effort angina without any deterioration of cardiac function.

A randomized, double-blind comparison of 10 and 20 mg lercanidipine in patients with stable effort angina: effects on myocardial ischemia and heart rate variability.

We evaluated the anti-ischemic action and the effects on autonomic function of lercanidipine, a long-acting dihydropyridine calcium antagonist, in 25 patients with stable effort angina in a randomized, double-blind, parallel trial. After a 2-week placebo run-in period, patients entered a 2-week treatment period with 10 or 20 mg of lercanidipine once daily. During the placebo run-in period and at the study end, the patients underwent clinical examination, electrocardiography, exercise tests, 24-hour Holter electrocardiography for long-term heart rate variability evaluation, and short-term spectral analysis of heart rate and systolic blood pressure variability and plasma epinephrine and norepinephrine levels at rest and during tilting. Results showed that time to onset of ST segment depression > or =1 mm was significantly increased by both drug doses. No significant change was recorded in the average hourly heart rate after treatment with both 10 and 20 mg of lercanidipine. During the 24-hour recordings, no significant change was observed in low-frequency power, high-frequency power, or low frequency/high frequency. In the standing position, there was a significant increase in plasma norepinephrine and epinephrine concentration in both groups, and no change in the supine position after 10 and 20 mg of lercanidipine. When considering short-term heart rate variability, no significant difference was observed in either treatment group in low frequency, high frequency, or their ratio on electrocardiographic R-R spectra. The blood pressure spectral component was also unchanged. In conclusion, lercanidipine is effective in reducing ischemia in patients with stable effort angina. Moreover, lercanidipine does not cause adrenergic activation, which is the main mechanism hypothesized to explain the negative effect on cardiovascular mortality assigned to short-acting dihydropyridine calcium antagonists.