Davide Lazzeroni

From Left Ventricular Hypertrophy to Dysfunction and Failure

Left ventricular hypertrophy (LVH) is growth in left ventricular mass caused by increased cardiomyocyte size. LVH can be a physiological adaptation to strenuous physical exercise, as in athletes, or it can be a pathological condition, which is either genetic or secondary to LV overload. Physiological LVH is usually benign and regresses upon reduction/cessation of physical activity. Pathological LVH is a compensatory phenomenon, which eventually may become maladaptive and evolve towards progressive LV dysfunction and heart failure (HF). Both interstitial and replacement fibrosis play a major role in the progressive decompensation of the hypertrophied LV. Coronary microvascular dysfunction (CMD) and myocardial ischemia, which have been demonstrated in most forms of pathological LVH, have an important pathogenetic role in the formation of replacement fibrosis and both contribute to the evolution towards LV dysfunction and HF. Noninvasive imaging allows detection of myocardial fibrosis and CMD, thus providing unique information for the stratification of patients with LVH. (Circ J 2016; 80: 555-564).

Prognostic role of stress echocardiography in hypertrophic cardiomyopathy: The International Stress Echo Registry.

BACKGROUND Stress echo (SE) may have a role in the outcome in patients with hypertrophic cardiomyopathy (HCM). OBJECTIVES The aim was to assess the prognostic value of SE in a retrospective multicenter study in HCM. METHODS We enrolled 706 HCM patients. The employed stress was exercise (n=608) and/or vasodilator (n=146, dipyridamole in 98 and adenosine in 48). We defined SE positivity according to clinical/hemodynamic criteria including: symptoms (all stress modalities), exercise-induced hypotension (failure to increase or fall >20mmHg, exercise) and exercise-induced left ventricular outflow tract obstruction (left ventricular outflow tract obstruction >50mmHg); and ischemic criteria, such as new wall motion abnormalities (new wall motion abnormality) and/or reduction of coronary flow reserve velocity (CFVR≤2.0) on left anterior descending coronary artery with vasodilator stress assessed in 116 patients. All patients completed the clinical follow-up. RESULTS Positive SE showed more frequently CFVR reduction, exercise-induced hypotension, left ventricular outflow tract obstruction, and symptoms (38, 23, 20 and 15% respectively), but new wall motion abnormality only in 6%. During a median follow-up of 49months 180 events were observed, including 40 deaths. Clinical/hemodynamic criteria did not predict outcome (X2 0.599, p=0.598), whereas ischemia-related SE criteria (X2: 111.120, p<0.0001) was significantly related to outcome. Similarly, mortality was predicted with SE ischemic-criteria (X2 16.645, p<0.0001). CONCLUSIONS SE has an important prognostic significance in HCM patients, with ischemia-related end-points showing greater predictive accuracy than hemodynamic endpoints. New wall motion abnormalities and impairment of CFVR should be specifically included in SE protocols for HCM.

Hemodynamic and Autonomic Response to Different Salt Intakes in Normotensive Individuals

Background Even if sodium sensitivity represents a risk factor at any blood pressure (BP) level, limited evidence is available that it may influence cardiovascular control in normotensives, particularly in white individuals. Therefore, the aim of the study was to investigate whether sodium sensitivity alters hemodynamic or autonomic responses to salt in normotensives. Methods and Results We evaluated the Sodium‐Sensitivity Index (SS‐Index) in 71 white normotensives after 5 days of high‐ and low‐sodium diets. We measured BP continuously at the end of each period, estimating hemodynamic indices from BP waveform analysis, and autonomic indices from heart rate (HR) and BP variability. According to the SS‐Index distribution, we defined 1 sodium‐sensitive group (SS, with SS‐Index >15 mm Hg/[mmol·day]), 1 sodium‐resistant group, (unresponsive to sodium load with −15≤ SS‐Index ≤+15), and 1 inverse sodium‐sensitive group, responsive to sodium by decreasing BP, with SS‐Index <−15). We compared the effects of the diets among groups, and correlated autonomic/hemodynamic indices with the SS‐Index. After sodium loading, a significant decrease in systemic peripheral resistances, HR, spectral indices of BP modulation, and a significant increase of indices of HR vagal modulation were found in the inverse sodium‐sensitive group but not in SS normotensives. Moreover, the highest SS‐Indices were associated with the lesser vagal HR decelerations. Conclusions Our data suggest that salt sensitivity in white normotensive individuals is associated with impaired vasodilation and altered autonomic response to dietary salt. Such dysfunction may critically contribute to induce a BP response to dietary salt.

Improvement in aerobic capacity during cardiac rehabilitation in coronary artery disease patients: Is there a role for autonomic adaptations?

Background It has been previously shown in patients with heart failure that exercise-based rehabilitation programmes may improve functional capacity and autonomic response. The aim of this study was to investigate this issue further by evaluating whether an association exists between autonomic adaptations and improvements of aerobic capacity in a general population of coronary artery disease patients undergoing cardiac rehabilitation. Methods Ninety consecutive patients (age 60 ± 11 years) attended a rehabilitation programme of moderate continuous training (25 ± 8 sessions, 2–3 sessions/week). Functional capacity expressed as oxygen uptake (peak VO2) and autonomic function expressed as chronotropic response and heart rate recovery were evaluated by cardiopulmonary exercise tests before and after the rehabilitation programme. According to the expected mean increase in functional capacity, coronary artery disease patients were divided into two groups: those who improved peak VO2 by more than 2.6 ml/kg/min (R group) and those who did not (NR group). Effects of the rehabilitation programme were compared in R and NR groups. Results The number and intensity of exercise sessions did not differ between R (N = 39) and NR (N = 51) groups. However, only R patients improved chronotropic response (R: from 45.1 ± 16.9% to 72.7 ± 34.1%, P < 0.01; NR: from 49.3 ± 18.6% to 48.2 ± 36.5%, P = NS) and heart rate recovery (R: from 16.9 ± 7.0 bpm to 21.0 ± 8.7 bpm, P < 0.01; NR: from 15.2 ± 9.9 bpm to 15.8 ± 8.5 bpm, P = NS). After training both chronotropic response and heart rate recovery were significantly higher in R than NR patients. Conclusions The improvement in aerobic capacity of coronary artery disease patients following exercise-based cardiac rehabilitation programmes is associated with positive adaptations of autonomic function.

Autonomic function in Takotsubo syndrome long after the acute phase

OBJECTIVES Although it is well documented that an exaggerated sympathetic stimulation plays a role in the development of Takotsubo Syndrome (TS) during the acute phase, only few studies have focused on autonomic adaptations in stress-induced cardiomyopathy long after the acute phase. Aim of the study was to investigate whether an impairment of the autonomic function is still present long after a TS event. This was done by comparing the response to a maximal exercise test in TS patients after apparent recovery (>1-year after the acute event) with that obtained in healthy subjects and in post-myocardial infarction (post-MI) patients. METHODS To assess heart rate recovery (HRR) and chronotropic response (CR), 24 TS patients, 25 healthy subjects and 22 post-MI patients underwent maximal exercise test, after at least 3 days of β-blockers wash-out. RESULTS HRR in TS patients (19.2±9.7bpm) was lower than in healthy subjects (27.7±8.3, p=0.003), and similar to post-MI patients (19.3±8.4; p=0.99). A decreasing CR trend (p=0.06), higher in healthy subjects (72±13%) than in TS (65±22%) and post-MI (57±21%) patients, was also found. CONCLUSION Compared to healthy subjects, TS patients showed a blunted parasympathetic reactivation after exercise, similar to that observed in post-MI patients, thereby suggesting that vagal control of heart rate after exercise is abnormal long after the acute presentation of TS.

Predictive role of P-wave axis abnormalities in secondary cardiovascular prevention

Background Abnormal P-wave axis has been correlated with an increased risk of all-cause and cardiovascular mortality in a general population. We aimed to evaluate the prognostic role of abnormal P-wave axis in patients undergoing myocardial revascularisation or cardiac valve surgery. Methods We considered data of 810 patients with available P-wave axis measure from a prospective monocentric registry of patients undergoing cardiovascular rehabilitation. A total of 436 patients (54%) underwent myocardial revascularisation, 253 (31%) valve surgery, 71 (9%) combined valve and coronary artery bypass graft surgery and 50 (6%) cardiac surgery for other cardiovascular disease. Mean follow-up was 47 ± 27 months. Results Over the whole group, P-wave axis was 43.8° ± 27.5° and an abnormal P-wave axis was found in 94 patients (12%). The risk of overall (hazard ratio (HR) 2.5, 95% confidence interval (CI) 1.6–4.0, P < 0.001) and cardiovascular mortality (HR 2.9, 95% CI 1.5–5.8, P = 0.002) was significantly higher in patients with abnormal P-wave axis even after adjustment for age, other electrocardiographic variables (PR, QRS, QTc intervals), left ventricular ejection fraction and left atrial volume index. After dividing the population according to the type of disease, patients with abnormal P-wave axis and ischaemic heart disease had 3.9-fold higher risk of cardiovascular mortality (HR 3.9, 95% CI 1.3–12.1, P = 0.017), while a 2.2-fold higher risk of cardiovascular mortality (HR 3.6, 95% CI 1.3–10.1, P = 0.015) was found in those with cardiac valve disease. Conclusion An abnormal P-wave axis represents an independent predictor of both overall and cardiovascular mortality in patients undergoing myocardial revascularisation or cardiac valve surgery.

Blood pressure changes after high- and low-salt diets: are intermittent arm measures and beat-by-beat finger measures equivalent?

The assessment of sodium sensitivity requires to measure the difference in mean arterial pressure (MAP) at the end of sodium-loading (SLoad) and sodium-depletion (SDepl) maneuvers with an arm-cuff manometer. Aim of this study is to evaluate whether MAP measuring devices based on the volume-clamp method at the finger can also be used for assessing sodium sensitivity. Sixty-eight normotensive volunteers underwent SLoad and SDepl diets in random order. MAP was simultaneously measured at the end of each diet with arm (Spacelabs 90207) and finger (Portapres model-2) cuff devices. The sodium sensitivity was assessed as the difference in MAP at the end of SLoad and SDepl diets (ΔMAP), and as salt-sensitivity index (SSI; SSI=ΔMAP divided by the difference in urinary-sodium-excretion rate at the end of the diets). Discrepancies between finger and arm-cuff devices in ΔMAP or SSI were evaluated by Bland and Altman analysis. Even if discrepancies between devices had null-fixed bias, results showed a significant proportional bias and large limits of agreement (between −25 and 25 mm Hg for ΔMAP, between −196 and 180 mm Hg mol−1 per day for SSI). The SSI distribution over the group was larger, flatter and less symmetric if derived from finger-cuff rather than arm-cuff devices, and this influenced substantially the identification of salt-sensitive individuals. Therefore, the response of MAP to SLoad/SDepl diets and consequently the assessment of the salt-sensitivity condition depends importantly on the measurement site, and brachial measures should be preferred for consistency with literature and normative data.

Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans

Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 μg·kg-1·min-1 NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP (P < 0.005 vs. baseline), -10% GFR, -20% RBF, -49% UNaV (P < 0.001), and +120% U8-iso-PGF2αV (P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME (P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (-6%), RBF (-12%), and UNaV (-34%) were blunted vs. PL + l-NAME and LOS + l-NAME (P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.

The fractal structure of cardiovascular beat-to-beat series described over a broad range of scales: Differences between blood pressure and heart rate, and the effect of gender.

The fractal characteristics of heart rate variability are usually assessed by estimating short- and long-term scale coefficients, α<;sub>1<;/sub>and α<;sub>2<;/sub>, by detrended fluctuation analysis. Recently we extended this approach introducing a temporal spectrum of scale coefficients, α(τ), that describes the deviations of self-similarity from the bi-fractal model at each scale τ. Until now relatively short recordings were considered and α(τ) was characterized only for scales τ<;100 s. Aim of this work is to describe α(τ) of cardiovascular signals extending the range τ by an order of magnitude with respect to previous studies. We considered 2-hour recordings of systolic and diastolic blood pressure (SBP and DBP) and of pulse interval (PI) in 68 volunteers (26 males, 42 females) sitting at rest. The α(τ) spectra were estimated for 5s ≤τ ≤1000s and compared. We found important differences between α(τ) of SBP, DBP and PI. In particular, α(τ) of PI was lower than α(τ) of SBP at all the scales τ, with a relative maximum at τ =26 s and a minimum at τ =300 s that were completely missing in α(τ) of DBP. Significant differences were also found between α(τ) of males and females, probably linked to gender differences in the cardiovascular autonomic tone.

Anxiety disorders and stressful events in Takotsubo syndrome

BACKGROUND Anxiety disorders are more common in Takotsubo syndrome (TS) than in acute coronary syndrome patients. The aim of this study was to investigate whether pre-existing anxiety disorders predispose to TS triggered by exclusively emotional stressful events. METHODS Triggering events were compared in 58 TS patients with and without pre-existing anxiety disorders; clinical, electrocardiographic and echocardiographic data were also collected. RESULTS Thirty-one (53%) patients had a previous history of anxiety disorders. The exclusively emotional stressful event-rate was higher in TS patients with pre-existing anxiety disorder (74% vs. 30%, p = 0.001), while TS caused by an undetermined trigger were significantly higher in patients without anxiety disorders (33% vs. 10%, p = 0.027). Moreover, in TS patients without a previous history of anxiety disorders, a trend of higher prevalence of physical events was found (16% vs. 37%, p = 0.07). CONCLUSIONS In patients with pre-existing anxiety disorders, TS was predominantly triggered by exclusively emotional stressful events, thereby suggesting a possible relationship between anxiety and emotional cardiac frailty in TS patients.