Paolo Coruzzi’s research while affiliated with Fondazione Don Carlo Gnocchi and other places

Background Heart failure with preserved ejection fraction (HFpEF) diagnosis remains challenging, since several mechanisms (diastolic and systolic reserve abnormalities, chronotropic incompetence, ventricular or vascular stiffening, atrial dysfunction, pulmonary hypertension, impaired vasodilation, endothelial dysfunction, energetic abnormalities and autonomic dysfunction) play different roles in HFpEF development. European Society of Cardiology HF guidelines recently suggested a stepwise non-invasive diagnostic approach consisting of three steps: the first is clinical, the second includes echocardiographic and laboratory data (natriuretic peptides), named HFA-PEEF score, and finally, in case of inconclusive findings, diastolic stress echocardiography is recommended. On the other hand, in United States, another multiparametric score, named H2FPEF, has been proposed for HFpEF diagnosis, and including, in addition to echocardiographic parameters, also clinical data; thereby more applicable in the outpatient clinical arena. Purpose Whether there is a clinical overlap between the two scores (HFA-PEEF and H2FPEF) as well as whether the addition of clinical data to the HFA-PEEF could improve its ability to identify different HFpEF phenotypes is still an open issue and these were the aims of our study. Methods HFA-PEEF and H2FPEF scores were systematically applied on 1,156 consecutive subjects with preserved ejection fraction who undergone cardiovascular evaluation at the Cardiovascular Prevention Center of Fondazione Don Gnocchi & University of Parma. All subjects underwent cardiovascular risk assessment followed by echocardiography and cardiopulmonary exercise testing; due to the outpatient (non-acute) setting of the evaluation, natriuretic peptides assay was not performed. Clinical data and cardiovascular risk factors data were compared between different groups of HFpEF risk. Results According to H2FPEF score, low risk (<40%) of HFpEF was found in 659 (57%), moderate in 300 (26%) and high (>75%) in 197 (17%); according to HFA-PEEF score, 675 (58%) had 0 or 1 point, 253 (22%) had 2 points and 230 (20%) had 3 or 4 points (moderate-to-high risk). Patients with higher HFA-PEEF score were older (p<0.001), had higher prevalence of HTN (p<0.001), diabetes (p<0.001), obesity (p<0.001), sedentary lifestyle (p<0.001), AF (p<0.001) and CCS (p<0.001) (figure 1). More specifically, AF was associated to a 6.3-fold higher risk (p<0.001) of high (3–4) HFA-PEEF Score, age >75 years to a 4.6-fold higher risk, HTN to a 3.6-fold higher risk (p<0.001), CCS to a 3.3-fold higher risk (p<0.001), obesity to a 2.2-fold higher risk (p<0.001), diabetes to a 1.9-fold higher risk (p<0.001) and sedentary to a 1.7-fold higher risk (p=0.001). Conclusions Although HFA-PEEF score does not include clinical data, patients with older age, atrial fibrillation, hypertension, hypertensive heart, diabetes, sedentary lifestyle and chronic coronary syndrome show a higher ESC risk of HFpEF. Funding Acknowledgement Type of funding sources: None.

Background Exercise intolerance evaluation in Heart failure with preserved ejection fraction (HFpEF) remains challenging, since several mechanisms (diastolic and systolic reserve abnormalities, low chronotropic reserve (CR), ventricular or vascular stiffening, atrial dysfunction, pulmonary hypertension, endothelial dysfunction, energetic abnormalities and autonomic dysfunction) play different roles. European Society of Cardiology HF guidelines recently suggested a stepwise non-invasive HFpEF diagnostic approach consisting of three steps: clinical, echocardiographic and laboratory data (natriuretic peptides), named HFA-PEEF Score, and finally, in case of inconclusive findings, diastolic stress echocardiography data. Cardiopulmonary exercise testing (CPET) may represent a promising further non-invasive diagnostic tool in HFpEF evaluation since allow to assess the presence of reduced functional capacity as well as to differentiate between cardiovascular, ventilatory or peripheral causes. Purpose Whether increased risk of HFpEF is associated with different and specific cardiopulmonary responses to exercise is still an open issue and this was the aim of our study. Methods 1.156 consecutive subjects with preserved ejection fraction undergoing cardiovascular evaluation at the Cardiovascular Prevention Center of Fondazione Don Gnocchi & University of Parma were enrolled. All subjects underwent cardiovascular evaluation and echocardiography, HFA-PEEF and H2FPEF Score assessment and cardiopulmonary exercise testing. Different cardiopulmonary response to exercise were compared between different groups of HFpEF risk. Results According to HFA-PEEF Score, 675 (58%) had 0 or 1 point, 253 (22%) had 2 points and 230 (20%) had 3 or 4 points (moderate-to-high risk). Patients with both higher HFA-PEEF and H2FPEF Score showed lower functional capacity, expressed as low peak V02 (p<0.001) associated with lower oxygen pulse (V02/HR) (p<0.001), cardiac output (CO) at peak (p<0.001), CR (p<0.001), ventilatory efficiency (expressed as VE/VC02 slope) (p<0.001) and oxygen uptake extraction (OUES) (p<0.001). Moreover, higher H2FPEF Score patients showed lower stroke volume (SV) at peak (p<0.001), while high HFA-PEEF score was not associated to SV at peak (Table 1 and Figure 1). More specifically, the presence of reduced cardiovascular efficiency (V02/Watt Slope <7) was associated to a 2.2-fold higher risk of HFpEF (p=0.003), impaired ventilator efficiency (VE/VCO2 Slope >35) to a 2.4-fold higher risk (p<0.001), reduced CR (<70%) 4.3-fold higher risk (p<0.001). Conclusions Different degrees HFpEF risk, estimated using both HFA-PEEF and H2FPEF score, are associated with different cardiopulmonary responses to exercise. High HFpEF risk patients show low functional capacity, cardiovascular and ventilator efficiency due to lower cardiac output at peak, despite preserved ejection fraction, associated to lower chronotropic response to exercise. Funding Acknowledgement Type of funding sources: None.

Background: Anxiety and depressive disorders represent predisposing factors for the autonomic dysfunctions that characterize the acute phase of Takotsubo syndrome (TS). However, there is insufficient data on this relationship after the acute event. The present study aimed at evaluating the psychological and autonomic status of patients with a history of TS. Methods: Ten TS patients whose acute event occurred at least 1 year prior to the evaluation and nine healthy age- and sex-matched subjects were evaluated. The cardiovascular assessment included a clinical examination, beat-to-beat heart rate monitoring to assess heart rate variability, and a psychological examination using the 16 Personality Factors-C Form (16PF), the Acceptance and Action Questionnaire-II, the Coping Orientations to Problems Experienced (COPE), the Beck Depression Inventory-II, and the State-Trait Anxiety Inventory (STAI). Results: TS patients scored significantly higher on the STAI (i.e., Anxiety Trait), 16PF (i.e., Tension), and COPE (i.e., Transcendental Orientation). TS patients also showed lower heart rate variability. Moreover, a significant inverse correlation was found between sympathetic tone (LF/HF ratio) and coping orientation. Conclusions: Long after the acute event, TS patients are characterized by elevated anxiety, high tension, and a specific religious coping strategy.

Aims The key role of systemic vascular resistance (SVR) in cardiovascular performance during exercise has been invasively demonstrated, however no data have been non-invasively obtained by analysing SVR response using cardiopulmonary exercise testing (CPET). To investigate the relationship between SVR at peak, maximum oxygen uptake (VO2 peak), and its determinants using CPET. Methods and results 1130 consecutive subjects were enrolled; according to physiology, SVR was determined as the ratio between mean arterial pressure (MAP) and cardiac output (CO). A novel parameter, named oxygen pressure (MAP peak/VO2 peak) was also created. Mean age was 61 ± 12 years and male gender was prevalent (61%); 66% of patients had arterial hypertension, 74% dyslipidaemia, 19% diabetes, 20% had smoking habit, and 26% previous history of cardiovascular (CV) disease. Significant inverse correlations between SVR peak and VO2/kg peak (P < 0.001), oxygen pulse (P < 0.001), CV efficiency (P < 0.001), chronotropic response (P < 0.001), and oxygen uptake exaction slope (P < 0.001) were found. Moreover, positive correlation between SVR peak and VE/VCO2 slope (P < 0.001) was observed. After multivariate analysis, the inverse correlation between peak SVR and peak VO2 remained significant (P < 0.001). Similar results were found considering oxygen pressure. Conclusions Low values of SVR at peak exercise, non-invasively evaluated with CPET, are associated with high levels of cardiorespiratory fitness. Oxygen pressure may represent a novel and simple CPET marker of peripheral vascular response to exercise, thereby representing a promising field of research in exercise medicine.

Aims Autonomic dysfunction is a prevalent and independent risk factor for adverse cardiovascular events and mortality in chronic coronary syndrome (CCS). Beta-blockers (BB), directly inhibiting adrenergic receptors, have been associated with a significant reduction in mortality and/or cardiovascular events in patients with recent acute coronary syndrome (ACS) or in those with heart failure (HF) with reduced left ventricular ejection fraction (LV-EF); on the other hand, the protective benefit in CCS patients without prior ACS or HF is less well established and lacks placebo-controlled trials. The aim of the study was to investigate the prevalence of hyper-adrenergic tone in CCS with preserved LV-EF in patients with or without BB as well as to assess related factors of hyper-adrenergic tone despite BB. Methods A total of 165 consecutive CCS patients have been enrolled. Inclusion criteria were documented coronary artery disease and preserved left-ventricular ejection fraction (>50%). Exclusion criteria were: recent ACS (<6 months), HF symptoms (NYHA >1) and atrial fibrillation. According to Heart rate variability (HRV) guidelines, 5 min beat-to-beat analysis was performed in order to assess sympatho-vagal balance (without BB wash-out). Patients were then divided into in two groups: hyper adrenergic tone (LF/HF > 2.01) and normal adrenergic tone (LF/HF < 2.01). Moreover, patients with hyper-adrenergic tone despite BB were classified as ‘BB non-responders’ while patients with normal adrenergic tone as ‘BB responders’. Results Mean age was 64 ± 12 years and male gender was prevalent (75%). Patients treated with BB were 56% and the majority (96%) were treated with high selective. Overall hyper adrenergic tone (isolated or associated with blunted vagal tone) was found in 47% of CCS patients and no difference was found in the percentage of hyper-adrenergic tone between patients with or without beta-blockers (45% vs. 55% P = 0.716). Within the BB groups, 89% had heart rate at target (<70 b.p.m.), while only 11% showed heart rate not at target (>70 b.p.m.). Among the heart rate not at target 80% had hyper-adrenergic tone despite beta-blockers (non-responders); on the other hand, among the heart rate not at target hyper-adrenergic tone despite beta-blockers was found in 43%. No differences in types of BB (metoprolol vs. bisoprolol) between BB responders and non-responders was found (P = 0.714). Higher left atrial volume index (36 ± 8 vs. 42 ± 14; P = 0.029) and E/e’ ratio (an echocardiographic marker of high left ventricular filling pressure) (9.4 ± 2.1 vs. 7.4 ± 2.1; P = 0.038) were found in patients with hyper-adrenergic tone despite beta-blockers (non-responder). Moreover, a trend toward significance of higher Lown’s arrhythmic risk was found in non-responders (19% vs. 8%; P = 0.066) (Figure). Finally, Beta-blockers patients with bradycardia and hyper-adrenergic tone (non-responders) had higher prevalence of carotid artery disease (64% vs. 44%; P = 0.047), where baroreceptors are located. Conclusion The prevalence of hyper-adrenergic tone is high in CCS patients with preserved ejection fraction; about half of patients treated with beta-blockers had residual hyper-adrenergic tone (non-responders). Hyper-adrenergic tone in BB patients is higher in those with 24-h heart rate not at target (>70 b.p.m.), thereby suitable of BB titration, as well as in those with diastolic dysfunction or with carotid artery disease, where baroceptors are located.

Aims Arterial hypertension (AHT) represents the leading cause of cardiovascular disease (CVD) and premature death worldwide. Essential AHT accounts for 95% of all cases of hypertension; although the aetiology of essential AHT is still largely unknown, a pivotal role of autonomic nervous system has been proposed and demonstrated. Both excessive sympathetic tone and vagal withdrawal, that define autonomic dysfunction, has been associated with essential AHT. The aim of our study was to investigate the relationship between blood pressure and autonomic function in essential hypertension; this was done comparing 24 h heart rate variability and 24 h blood pressure data, simultaneously collected, in a population of essential AHT subjects. Methods A prospective registry of 179 consecutive not selected essential AHT patients were considered in the present study. All patients underwent cardiac evaluation at the Primary and Secondary Cardiovascular Prevention Unit of the Don Gnocchi Foundation of Parma. All subjects underwent 24 h ECG monitoring, and 24 h Ambulatory Blood Pressure Monitoring, during the same day. Twenty-four hours Heart Rate variability analysis included: Time-domain, frequency-domain and non-linear domain. Results Mean age was 60 0a11.7 years, male gender was prevalent (68.4%). Among the population 26 (14.7%) subjects had diabetes; the prevalence of family history of CVD was 61.7% and 66.5% had dyslipidaemia; body mass index mean values were 27.6 7.4.3. In the whole population, the prevalence of uncontrolled AHT was 80.5%, divided into: 53.1% systo-diastolic, 17.9% isolated systolic, and 9.5% isolated diastolic. The prevalence of untreated AHT (recent diagnosis) was 40.2%, while treated AHT was 59.8% and only 19.6% had controlled blood pressure values (AHT at target). 12.3% of patients were treated with Beta Blockers. A significant correlations between diastolic blood pressure (DBP) values (24 h and day-time), LF/HF ratio (24 h) (r = 0.200; P = 007) and DFA alfa1 (24 h) (r = 0.325; P = 0.000), two know markers of sympathetic tone, were found. A higher sympathetic tone, expressed as high LF/HF, was found in isolated diastolic AHT compared to other types of AHT and the lowest sympathetic tone was found in isolated systolic AHT. Considering non-linear (complexity) analysis, DFA alfa1 (24 h) showed a significant correlation with DBP values that remained independent even after multiple adjustment for BMI, age, gender and Beta Blockers (β = 0.218; P = 0.011). Moreover, the lack of DBP control was associated with high sympathetic tone (LF/HF 3.8 112.3 vs 5.5 .33.3; P < 0.0001). On the other hand, no significant correlations between all DBP data and vagal markers, such as SDNN index, RMSSD and HF, were found. Again, no significant correlations between 24 h, daytime, night-time SBP and time or frequency HRV data as well as with non-linear (complexity) analysis were found. Finally, considering ‘autonomic dipping’, expressed as changes in HRV data between day and night, a strong inverse correlation between vagal markers and Heart Rate Dipping (r = −0.297; P < 0.0001) was found; correlation that remain independent even adjusted for age, gender, BMI, and BB. On the other hand, no association between blood pressure dipping and autonomic dipping was found. Conclusion Diastolic blood pressure and uncontrolled diastolic AHT, rather than systolic AHT, are associated with a hyper-sympathetic tone rather than with blunted vagal tone. The lack of heart rate dipping during night-time in AHT is associated with blunted vagal activation rather than a persistent night-time hyper-adrenergic tone.

Aims Arterial hypertension (AHT) represents the leading cause of heart failure (HF). A complex cardiovascular (CV) continuum of events leads to the progression from AHT to left ventricular hypertrophy (LVH), the hallmark of hypertensive heart (HH), towards heart failure with preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF). Cardiopulmonary exercise testing (CPET) represents an important tool to evaluate HF patients (both with HFpEF and HFrEF) allowing quantification of functional capacity and mechanisms of dyspnoea as well as providing prognostic markers. To investigate CPET responses in AHT patients at various stages of disease progression from AHT to LVH and HF with preserved and reduced ejection fraction. Methods and results From a CPET registry of 1.397 consecutive subjects, 92 patients were selected (matched according to age, gender, BMI, CV risk factors, beta-blockers) and divided into four groups: 23 AHT patients without LVH, 23 HH patients, 23 HFpEF patients and 23 HFrEF. HFrEF were defined according to LV-EF values while HFpEF were defined according to the presence of NYHA Class ≥2 and HFA-PEFF Score. Mean age was 65 ± 10 years, mean BMI was 28.5 ± 5, male gender was prevalent 83% and 33% had diabetes. Both HFpEF and HFrEF showed lower cardiorespiratory fitness (peak VO2; P < 0.001), cardiovascular efficiency (VO2/Watt slope: P < 0.001), oxygen pulse (VO2/HR: P < 0.001), cardiac output (P < 0.001) and stroke volume (P < 0.001) at peak as well as lower chronotropic response (P < 0.001), ventilatory efficiency (VE/VCO2 slope: P < 0.001), and heart rate recovery (HRR: P = 0.004) compared with both AHT and HH groups. Interestingly, no differences between HFpEF and HFrEF have been found in all CPET data except for chronotropic response (using Tanaka equation), lower in HFpEF (37.5 ± 16.5 vs. 53.5 ± 20.5; P < 0.001) and ventilatory efficiency, lower in HFrEF (VE/VCO2 slope: 32 ± 5 vs. 37 ± 10; P < 0.001). Finally, adding functional capacity (peak VO2) data to ESC Criteria an improvement in HFpEF diagnosis accuracy was found, with 82% sensitivity and 90% specificity (AUC: 859—95% CI: 754–963; P < 0.0001). Conclusions Despite the intrinsic differences in ejection fraction, both HFpEF and HFrEF shares similar cardiopulmonary mechanisms and cardiovascular responses to exercise. CPET may represent a useful tool in order to identify and stratify hypertensive heart patients with HFpEF with high diagnostic accuracy.

Aims Takotsubo Syndrome (TS) occurs as an acute coronary syndrome (ACS) characterized by severe left ventricular (LV) dysfunction that typically recovers spontaneously within days or weeks and in the absence of obstructive coronary artery disease. Although during the acute phase it is well documented that an exaggerated sympathetic tone plays a central role in the development of TS, whether an impaired sympatho-vagal balance may persist long after the acute phase, despite the recovery of left ventricular function, is still an open issue. Interestingly, recent evidences suggest that an impairment in central autonomic network not only persist long after the acute event but also may be pre-existent before the acute onset of TS. The Aim of the study was to investigate whether an impairment of the autonomic function is still present long after a TS event. Methods and results We evaluated 67 patients (91% female, mean age 66 ± 8 years) divided into three groups: 24 with a history of TS (1 year after acute event), 21 subjects with a previous history of acute coronary syndrome (ACS) and complete LV ejection fraction recovery (1 year after acute event) and 22 age- and gender-matched healthy subjects. All patients underwent a non-invasive beat-to-beat arterial blood pressure and heart rate recording (short term: 5 min), after at least 3 days of β-blockers wash-out, to obtain heart rate variability (HRV) and spontaneous baroreflex sensitivity (sBRS) data. An overall autonomic dysfunction was found in both TS and ACS groups compared to controls. In particular, a lower heart rate variability, expressed as lower SDNN, has been found in TS and ACS groups compared to controls (31 ± 12 vs. 25 ± 11 vs. 41 ± 22; P = 0.006—Figure A) as a consequence of blunted vagal tone, expressed as lower RMSSD (20 ± 12 vs. 19 ± 11 vs. 40 ± 37; P = 0.007—Figure B) and higher sympathetic tone, expressed as higher LF/HF ratio (P = 0.007 Figure C) which was found to be higher in TS even when compared to ACS (TS: 3.5 ± 2.5 vs. ACS: 2.1 ± 1.7; P = 0.011). Moreover, fractal analysis of HRV showed higher complexity of heart rate regulation, expressed as higher fractal dimension (DFA 1.48 ± 0.06 vs. 1.53 ± 0.05 vs. 1.40 ± 0.10; P < 0.0001—Figure D), in both TS and ACS compared to controls. Interestingly, spontaneous BRS showed the lowest values in the TS group (sSBP: 5.6 ± 2.6 vs. 7.5 ± 3.0 vs. 12.1 ± 11.9; P = 0.027—Figure E), associated with highest levels of sympathetic peripheral control of systolic blood pressure (SBP), expressed as LF-BRS (13.7 ± 9.6 vs. 8.3 ± 5.2 ± 6.8 ± 5.8; P = 0.008—Figure F). Conclusions An autonomic dysfunction, characterized by a hyper-sympathetic tone, reduced baroreflex sensitivity and increased peripheral adrenergic control of blood pressure, persists in TS patients long after the acute phase.

The red blood cell distribution width (RDW) measures the variability in the size of circulating erythrocytes. Previous studies suggested a powerful correlation between RDW obtained from a standard complete blood count and cardiovascular diseases in both primary and secondary cardiovascular prevention. The current study aimed to evaluate the prognostic role of RDW in patients undergoing cardiac rehabilitation after myocardial revascularization and/or cardiac valve surgery. The study included 1.031 patients with available RDW levels, prospectively followed for a mean of 4.5 ± 3.5 years. The mean age was 68 ± 12 years, the mean RDW was 14.7 ± 1.8%; 492 patients (48%) underwent cardiac rehabilitation after myocardial revascularization, 371 (36%) after cardiac valve surgery, 102 (10%) after valve-plus-coronary artery by-pass graft surgery, 66 (6%) for other indications. Kaplan–Meier analysis and Cox hazard analysis were used to associate RDW with mortality. Kaplan–Meier analysis demonstrated worse survival curves free from overall (log-rank p < 0.0001) and cardiovascular (log-rank p < 0.0001) mortality in the highest RDW tertile. Cox analysis showed RDW levels correlated significantly with the probability of overall (HR 1.26; 95% CI 1.19–1.32; p < 0.001) and cardiovascular (HR 1.31; 95% CI 1.23–1.40; p < 0.001) mortality. After multiple adjustments for cardiovascular risk factors, hemoglobin, hematocrit, C-reactive protein, microalbuminuria, atrial fibrillation, glomerular filtration rate,left ventricular ejection fraction and number of exercise training sessions attended, the increased risk of overall (HR 1.10; 95% CI 1.01–1.27; p = 0.039) and cardiovascular (HR 1.13; 95% CI 1.01–1.34; p = 0.036)mortality with increasing RDW values remained significant. The RDW represents an independent predictor of overall and cardiovascular mortality in secondary cardiovascular prevention patients undergoing cardiac rehabilitation.

Aortic stiffness (AS), defined as the elastic resistance to deformation resulting from complex interactions between vascular smooth muscle cells and the extracellular matrix is a marker of increased cardiovascular (CV) risk and mortality. Age, hypertension, diabetes, atherosclerosis, and chronic kidney disease may represent the most important contributors to its increase.¹ A low cardiorespiratory fitness, estimated through peak V02 value obtained during a cardiopulmonary exercise test (CPET), has been also shown to represent an independent marker of adverse CV outcome.² Nowadays, only few studies explored the correlation between arterial stiffness and cardiorespiratory fitness in patients undergoing cardiopulmonary exercise testing.3–6 The aim of the present study was to evaluate the association between two markers of AS, pulse wave velocity (PWV) and augmentation index (AI), on different CPET-derived data, such as ventilatory efficiency (VE/VCO2 slope), CV efficiency (VO2/WR slope), and oxygen uptake extraction slope (OUES). This prospective cross-sectional study included individuals who underwent CV evaluation at ‘CV Prevention Unit of Fondazione Don Gnocchi, Parma’ from 2017 to 2018. Our ethics committee on human research approved the collection of data in accordance with the Declaration of Helsinki after having obtained written informed consent from all the subjects. Incremental and maximal cardiopulmonary tests were performed with the Cosmed Quark C-PET system (COSMED, Rome, Italy) until maximal perceived exertion; cardiorespiratory fitness was evaluated as peak VO2 (mL/kg/min) (mean oxygen uptake over the last 30 s of exercise). Before CPET examination, pulse wave analysis was performed using the Vicorder (Skidmore Medical, Bristol, UK) with oscillometric technique to detect the pulse waveform between the two recording sites.⁶,⁷ Measurements were obtained by using a 10-cm-wide cuff around the right upper thigh to detect the femoral pulse and a 10-cm-wide cuff around the arm to detect the right brachial pulse. The cuffs were automatically inflated simultaneously and pulse waveform was recorded for 3–5 s, while the patient was in supine position, before freezing the display screen and obtaining the pulse wave analysis. Carotid-femoral PWV was calculated by the formula: PWV (m/s) = distance between measurement locations (m)/transit time. Augmentation index was calculated by the formula: AI (%): (Augmentation pressure/Pulse pressure) × 100.⁸,⁹ Differences among groups were tested by ANOVA, with Least-Significant Difference post-hoc analysis. The Shapiro–Wilk test was used to check the normality distribution of continuous variable. Linear regression analysis was performed and the relationship between potential predictors and main outcome measures was analysed using stepwise logistic regression models including different covariates. Statistical significance was set at P < 0.05.