Giuseppe Furgi

Left ventricular diastolic filling in diabetes mellitus with and without hypertension

Left ventricular diastolic filling by Doppler echocardiography was investigated in 84 diabetic patients without evidence of heart disease and in 84 normotensive nondiabetic age- and sex-matched control subjects. Diabetic patients were subdivided into two groups on the basis of the presence of arterial hypertension. Group 1 comprised 41 normotensive diabetic patients (19 men, 22 women, mean age 63.7 +/- 9.1 years); Group 2 comprised 43 hypertensive diabetics (15 men, 28 women, mean age 65.6 +/- 9.6 years). Doppler measures of diastolic filling were significantly altered in the two groups as compared with control subjects. Peak atrial flow velocity, velocity integral for the atrial filling period, and atrial filling fraction were increased, whereas the ratio of peak early to peak atrial flow velocity and the ratio of flow velocity integrals were decreased, especially in Group 2 patients. Thirteen patients in Group 1 (32%) and 17 in Group 2 (40%) had evidence of diastolic dysfunction, as assessed by the presence of at least two independent abnormal indices (outside age-corrected 95% confidence interval). In each group, patients with altered diastolic filling differed slightly from diabetic patients with normal Doppler indices, tending to increased wall thickness and left ventricular mass. In conclusion, diastolic filling of the left ventricle is frequently altered in diabetic patients and is adversely affected by arterial hypertension whose coexistence further impairs left ventricular relaxation.

β-adrenergic receptor responsiveness in aging heart and clinical implications.

Elderly healthy individuals have a reduced exercise tolerance and a decreased left ventricle inotropic reserve related to increased vascular afterload, arterial-ventricular load mismatching, physical deconditioning and impaired autonomic regulation (the so called “β-adrenergic desensitization”). Adrenergic responsiveness is altered with aging and the age-related changes are limited to the β-adrenergic receptor density reduction and to the β-adrenoceptor-G-protein(s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. Epidemiological studies have shown an high incidence and prevalence of heart failure in the elderly and a great body of evidence correlate the changes of β-adrenergic system with heart failure pathogenesis. In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β1-adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. In this review we focus on the cardiovascular β-adrenergic changes involvement in the aging process and on similarities and differences between aging heart and heart failure.

Adrenergic signaling and oxidative stress: a role for sirtuins?

The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. β-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of β2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic β2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of β2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1), an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-β. βAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the β-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such as heart failure.

Effect of beta-adrenoceptor blockade on dipyridamole-induced myocardial asynergies in coronary artery disease.

Twenty-one patients with angiographic evidence of significant coronary artery disease, and positive dipyridamole echocardiographic test results at basal condition and after 7 days of placebo treatment were prospectively studied to see whether beta blockade modifies the effects of dipyridamole echocardiographic testing on regional myocardial contractility. Patients were randomized to propranolol (120 mg/day) or placebo treatment in 3 divided doses for 7 days, after which each patient crossed over to the alternate regimen. Dipyridamole-echocardiographic testing was repeated at the end of each treatment. Propranolol abolished new mechanical signs of transient dipyridamole-induced ischemia (new wall motion abnormalities or an increase in degree of basal asynergies, or both) in 13 of 21 patients. The remaining 8 patients had positive results on dipyridamole echocardiographic testing after the propranolol treatment period. At basal conditions both heart rate and rate-pressure product were significantly reduced with propranolol; there was also a significant decrease in these parameters at peak dipyridamole infusion. At peak dipyridamole infusion heart rate and rate-pressure product were significantly lower in patients with negative than in those with positive echocardiographic test results after propranolol. Our data show that administration of beta blockade significantly reduces the development of transient dipyridamole-induced myocardial asynergies, the earliest markers of acute myocardial ischemia, detected with 2-dimensional echocardiography.

Reproducibility of short- and long-term Poincare plot parameters compared with frequency-domain HRV indexes in congestive heart failure

Poincare plot analysis allows a beat-to-beat approach of HRV detecting pattern resulting from non-linear processes not observable by other methods in a time- or frequency-domain analysis. With a view to its clinical application, the authors evaluated the short- and long-term reproducibility and reliability of the analysis. The main 2D and 3D parameters were automatically measured with a dedicated software developed by the authors. Three 24 hours ECG Holter recordings for each of 22 CHF clinically stable patients were analyzed, performing a frequency-domain and a Poincare plot analysis. Results showed a high short- and long-term reliability, a higher short-term reproducibility versus frequency domain parameters, and a comparable long-term reproducibility, suggesting that some parameters might be very useful in clinical setting.

Six-minute walking test but not ejection fraction predicts mortality in elderly patients undergoing cardiac rehabilitation following coronary artery bypass grafting

Background: Age-related effects on the ability of 6-min walking test (6MWT) and ejection fraction (EF) to predict mortality in coronary artery bypass grafting (CABG) patients undergoing cardiac rehabilitation (CR) is still debated. Design and methods: In order to verify the role of 6MWT and EF on all-cause mortality in patients undergoing CR following CABG, 882 CABG patients undergoing CR stratified in adults (<65 years) and elderly (≥65 years) were studied. Results: At the admission, EF was 52.6 ± 9.1% in adults and 51.3 ± 8.9% in elderly (p = 0.234, NS) while 6MWT was 343.8 ± 93.5 m in adults and 258.9 ± 95.7 m in elderly (p < 0.001). After 42.9 ± 14.1 months follow up, mortality was 8.2% in adults and 10.9% in elderly (p = 0.176, NS). Cox regression analysis shows that EF ≥ 50% and 6MWT ≥300 m are protective on mortality in all CABG patients before CR. However, EF ≥50% in adults (HR 0.18, 95% CI 0.06–0.49, p < 0.005) but not in elderly (HR 1.16, 95% CI 0.45–3.42, p = 0.354, NS) and 6MWT ≥300 m in elderly (HR 0.34, 95% CI 0.10–0.79, p = 0.033) but not in adults (HR 0.76, 95% CI 0.31–2.12, p = 0.654, NS) exert a protective role on mortality. Conclusions: Our results indicate that both EF ≥ 50% and 6MWT ≥ 300 m independently protect against mortality in CABG patients before CR. However, their protective role is age dependent. In fact, EF ≥ 50% is protective in adults but not in elderly while 6MWT ≥ 300 m is protective in elderly but not in adult patients.

Hypermagnesemia predicts mortality in elderly with congestive heart disease: relationship with laxative and antacid use.

The aim of this study was to evaluate the role of magnesium levels on 3-year survival in the elderly with congestive heart failure (CHF) admitted to the Rehabilitative Cardiology Unit of S. Maugeri Foundation Scientific Institute of Telese/Campoli. All elderly patients > or = 65 years old with a diagnosis of CHF underwent clinical and instrumental examination, and their demographics, co-morbidity, and in-hospital and 3-year mortality rates were recorded. Hypomagnesemia was found in 4.8%, normomagnesemia in 67.5%, and hypermagnesemia in 27.8% of subjects. The hypomagnesemic group was excluded for numerical exiguity; the analysis was performed on a total of 199 elderly patients. Hypermagnesemia was found in 29.1% and normomagnesemia in 70.9%. At the univariate analysis no differences were found in hypermagnesemia in respect to normomagnesemia group, except for slightly higher levels of creatininemia (1.35 +/- 0.61 vs. 1.13 +/- 0.55 mg/dL, respectively; p < 0.02), greater disability (lost ADL, 2.69 +/- 1.57 vs. 2.15 +/- 1.56, respectively; p < 0.05), more mortality for CHF (32.6 vs. 48.3%; p < 0.05), and higher antacid and laxative use (82.7 vs. 24.8%, respectively; p < 0.0001). Patients with higher magnesium showed less probability to survive at a 3-year follow-up than did patients with lower levels (17.32 +/- 15.93 vs. 22.46 +/- 16.16 months; p < 0.05), and this finding remained significant in the multivariate analysis after adjusting for some confounders. Finally hypermagnesemia should also be considered in the absence of pre-existing renal failure clinical evidence because of its negative prognostic value, especially in elderly patients with CHF. The shown relationship between hypermagnesemia and laxative/antacid use should induce physicians to pay more attention to abuse of these drugs.

Diffuse Idiopathic Skeletal Hyperostosis Prevalence in Subjects With Severe Atherosclerotic Cardiovascular Diseases

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of different entheseal sites. Several metabolic factors have been suggested to be involved in DISH development. We assessed the prevalence of DISH and its relationship to traditional vascular risk factors in a cohort of patients diagnosed with cardiovascular diseases.

Angiotensin II-receptor antagonist losartan does not prevent nitroglycerin tolerance in patients with coronary artery disease.

The study evaluated the effect of Losartan in preventing nitrate tolerance during continuous transdermal nitroglycerin (TD-GTN) therapy in patients with coronary disease.Fifteen subjects with chronic stable ischemia evaluated by exercise test, were randomized to 28 days of TD-GTN 20 mg once a day without free interval plus Losartan 100 mg or Losartan-placebo with a double blind crossover design. Myocardial ischemic parameters during stress test were evaluated after each test period and results of Losartan therapy were compared to those with placebo.Time to onset 1 mm ST-depression was significantly higher after acute TD-GTN 20 mg with respect to placebo run-in, sustained TD-GTN 20 mg plus Losartan 100 mg or Losartan-placebo (p < 0.001). ST-depression at peak exercise and time to recovery of ST segment were markedly lower after acute TD-GTN 20 mg compared to placebo run-in (p < 0.05), sustained TD-GTN 20 mg plus Losartan 100 mg (p < 0.001) or Losartan-placebo (p < 0.05).At 1 mm-ST depression and at peak exercise, systolic blood pressure and rate-pressure product significantly decreased after sustained TD-GTN 20 mg plus Losartan 100 mg (p < 0.001, p < 0.05 respectively) with respect to placebo run-in, acute and sustained TD-GTN 20 mg plus Losartan-placebo. Moreover at peak exercise, these data were also observed after acute TD-GTN 20 mg compared to placebo run-in and sustained TD-GTN 20 mg plus Losartan-placebo (p < 0.001).The AT1 antagonist Losartan administration does not prevent the development of nitrate tolerance during continuous TD-GTN therapy.

Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure

Background Increased cardiac G protein-coupled receptor kinase-2 (GRK2) expression has a pivotal role at inducing heart failure (HF)-related β-adrenergic receptor (βAR) dysfunction. Importantly, abnormalities of βAR signalling in the failing heart, including GRK2 overexpression, are mirrored in circulating lymphocytes and correlate with HF severity. Exercise training has been shown to exert several beneficial effects on the failing heart, including normalization of cardiac βAR function and GRK2 protein levels. In the present study, we evaluated whether lymphocyte GRK2 levels and short-term changes of this kinase after an exercise training programme can predict long-term survival in HF patients. Methods For this purpose, we prospectively studied 193 HF patients who underwent a 3-month exercise training programme. Lymphocyte GRK2 protein levels, plasma N-terminal pro-brain natriuretic peptide, and norepinephrine were measured at baseline and after training along with clinical and functional parameters (left ventricular ejection fraction, NYHA class, and peak-VO2). Cardiac-related mortality was evaluated during a mean follow-up period of 37 ± 20 months. Results Exercise was associated with a significant reduction of lymphocyte GRK2 protein levels (from 1.29 ± 0.52 to 1.16 ± 0.65 densitometric units, p < 0.0001). Importantly, exercise related changes of GRK2 (delta values) robustly predicted survival in our study population. Interestingly, HF patients who did not show reduced lymphocyte GRK2 protein levels after training presented the poorest outcome. Conclusions Our data offer the first demonstration that changes of lymphocyte GRK2 after exercise training can strongly predict outcome in advanced HF.