Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.

Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by "Federico II" University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.

Efficacy and safety of glucagon-like peptide-1 agonists on macrovascular and microvascular events in type 2 diabetes mellitus: A meta-analysis.

AIMS: Glucagon-like peptide-1 (GLP-1) agonists improve glycaemic control in type 2 diabetes mellitus (DM). Outcome trials investigating macro and microvascular effects of GLP-1 agonists reported conflicting results. The aim of this study was to assess, in a meta-analysis, the effects of GLP-1 agonists on mortality, major nonfatal cardiovascular (CV) events, renal and retinal events. DATA SYNTHESIS: MEDLINE, Cochrane, ISI Web of Science, SCOPUS and ClinicalTrial.gov databases were searched for articles published until June 2017. Randomized trials enrolling more than 200 patients, comparing GLP-1 versus placebo or active treatments in patients with DM, and assessing outcomes among all-cause death, CV death, MI, stroke, HF, diabetic retinopathy and nephropathy were included. 77 randomized trials enrolling 60,434 patients were included. Compared to control, treatment with GLP-1 significantly reduced the risk of all-cause death (RR: 0.888; CI: 0.804-0.979; p = 0.018) and the risk of CV death (RR: 0.858; CI: 0.757-0.973; p = 0.017). GLP-1 agonists did not affect the risk of MI (RR: 0.917; CI: 0.830-1.014; p = 0.092) as well as the risk of stroke (RR: 0.882; CI: 0.759-1.023; p = 0.097), HF (RR: 0.967; CI: 0.803-1.165; p = 0.725), retinopathy (RR: 1.000; CI: 0.807-1.238; p = 0.997) and nephropathy (RR: 0.866; CI: 0.625-1.199; p = 0.385). CONCLUSIONS: Treatment with GLP-1 agonists in DM patients is associated with a significant reduction of all cause and CV mortality.

Vitamin D deficiency and clinical outcome in patients with chronic heart failure: A review.

AIM: The aim of this review was to summarize evidence on the role of Vitamin D deficiency in heart failure (HF), from pathophysiological mechanisms to clinical effects of Vitamin D supplementation. DATA SYNTHESIS: Chronic HF secondary to left ventricular (LV) systolic dysfunction is a growing health problem, still associated with poor clinical outcome. In recent years, experimental and epidemiological evidence focused on the role of Vitamin D in HF. Cross sectional studies demonstrated that prevalence of HF is increased in patients with Vitamin D deficiency or parathyroid hormone (PTH) plasma level increase, whereas longitudinal studies showed enhanced risk of developing new HF in patients with Vitamin D deficiency. In addition, in patients with established HF, low plasma levels of Vitamin D are associated with worsening clinical outcome. Yet, clinical studies did not definitively demonstrate a benefit of Vitamin D supplementation for preventing HF or ameliorating clinical outcome in patients with established HF. CONCLUSIONS: Despite convincing experimental and epidemiological data, treatment with Vitamin D supplementation did not show clear evidence of benefit for preventing HF or influencing its clinical course. Ongoing clinical studies will hopefully shed lights on the effects of Vitamin D supplementation on clinical endpoints along the spectrum of HF.

Insulin resistance is associated with impaired cardiac sympathetic innervation in patients with heart failure.

AIMS: Insulin resistance (IR) represents, at the same time, cause and consequence of heart failure (HF) and affects prognosis in HF patients, but pathophysiological mechanisms remain unclear. Hyperinsulinemia, which characterizes IR, enhances sympathetic drive, and it can be hypothesized that IR is associated with impaired cardiac sympathetic innervation in HF. Yet, this hypothesis has never been investigated. Aim of the present observational study was to assess the relationship between IR and cardiac sympathetic innervation in non-diabetic HF patients. METHODS AND RESULTS: One hundred and fifteen patients (87% males; 65 ± 11.3 years) with severe-to-moderate HF (ejection fraction 32.5 ± 9.1%) underwent iodine-123 meta-iodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy to assess sympathetic innervation and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) evaluation to determine the presence of IR. From (123)I-MIBG imaging, early and late heart to mediastinum (H/M) ratios and washout rate were calculated. Seventy-two (63%) patients showed IR and 43 (37%) were non-IR. Early [1.68 (IQR 1.53-1.85) vs. 1.79 (IQR 1.66-1.95); P = 0.05] and late H/M ratio [1.50 (IQR 1.35-1.69) vs. 1.65 (IQR 1.40-1.85); P = 0.020] were significantly reduced in IR compared with non-IR patients. Early and late H/M ratio showed significant inverse correlation with fasting insulinemia and HOMA-IR. CONCLUSION: Cardiac sympathetic innervation is more impaired in patients with IR and HF compared with matched non-IR patients. These findings shed light on the relationship among IR, HF, and cardiac sympathetic nervous system. Additional studies are needed to clarify the pathogenetic relationship between IR and HF.

The lipid theory in the pathogenesis of calcific aortic stenosis.

AIMS: Biologically active phenomena, triggered by atherogenesis and inflammation, lead to aortic valve (AV) calcification. Lipids play an important role in activating the cell signaling leading to AV bone deposition. This review, based on evidence from animal and human studies, mainly focused on the involvement of lipids and atherogenic phenomena in the pathogenesis of calcific aortic stenosis (AS). DATA SYNTHESIS: The role of elevated low density lipoproteins for the risk of both vascular atherosclerosis and AS has been elucidated. Lipid disorders act synergistically with other risk factors to increase prevalence of calcific AS. Atherosclerosis is also involved in the pathogenesis of bone demineralization, a typical hallmark of aging, which is associated with ectopic calcification at vascular and valvular levels. Animal studies have recently contributed to demonstrate that lipids play an important role in AS pathogenesis through the activation of molecular cell signalings, such as Wnt/Lrp5 and RANK/RANKL/Osteprotegerin, which induce the transition of valvular myofibroblasts toward an osteogenic phenotype with consequent valvular bone deposition. Although all these evidence strongly support the lipid theory in AS pathogenesis, lipids lowering therapies failed to demonstrate in controlled trials a significant efficacy to slow AS progression. Encouraging results from animal studies indicate that physical activity may counteract the biological processes inducing AV degeneration. CONCLUSIONS: This review indicates a robust interplay between lipids, inflammation, and calcific AS. This new pathophysiological scenario of such an emerging valvular disease paves the way to the next challenge of cardiovascular research: "prevent and care aortic valve stenosis".

Changes in serum uric acid levels and cardiovascular events: a meta-analysis.

BACKGROUND AND AIMS: The association between serum uric acid (SUA) levels and cardiovascular (CV) risk or all-cause death has been repeatedly reported. However, it has not been assessed whether reduction of SUA levels is associated with reduced CV risk. The aim of the current study was to evaluate the relationship between changes of SUA levels and CV events as well as all-cause death. METHODS AND RESULTS: Randomised trials reporting SUA at baseline and at the end of follow-up and clinical end-points (all-cause death, myocardial infarction (MI), stroke, heart failure (HF) and CV death) were included in the study. Meta-regression analysis was performed to test the relationship between SUA changes and clinical end-points. Eleven trials enrolling 21,373 participants followed up for 2.02 ± 1.76 years and reporting 4533 events were included. In meta-regression analysis, no relationship between SUA changes from baseline to end of follow-up and the composite outcome including CV death, stroke, MI and HF was found (change in Tau(2) (t) = -0.64; p Tau (p) = 0.541). Similarly, no relationship was found between SUA changes and single components of the composite outcome (MI: t = -0.83; p = 0.493; stroke: t = 0.46; p = 0.667; HF: t = 2.44; p = 0.162; CV death: t = -0.54; p = 0.614) and all-cause death (t = -0.72; p = 0.496). Results were confirmed by sensitivity analysis. No heterogeneity among studies or publication bias was detected. CONCLUSIONS: Changes in SUA levels observed during pharmacologic treatments do not predict the risk of all-cause death or CV events. As SUA levels are associated with increased CV risk, additional studies with direct xanthine-oxidase inhibitors are requested.

Ultrasound and radiology surrogate endpoints in pharmacological studies.

Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials.

Blockade of ß-adrenoceptors restores the GRK2-mediated adrenal α(2) -adrenoceptor-catecholamine production axis in heart failure.

BACKGROUND AND PURPOSE: Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of ß-adrenoceptor antagonist (ß-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. ß-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-α(2) adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing α(2) -adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if ß-blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels. EXPERIMENTAL APPROACH: Four weeks after myocardial infarction-induced HF, adult rats were randomized to 10-week treatment with vehicle (HF/C) or bisoprolol (HF/B). Cardiac function and dimensions were measured. In heart and adrenal gland, GRK2 levels were assessed by RT-PCR and Western blotting and adrenoceptors studied with radioligand binding. Catecholamines and α(2) adrenoceptors in adrenal medulla chromaffin cell cultures were also measured. KEY RESULTS: Bisoprolol treatment ameliorated HF-related adverse cardiac remodelling and reduced plasma catecholamine levels, compared with HF/C rats. Bisoprolol also attenuated adrenal GRK2 overexpression as observed in HF/C rats and increased α(2) adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related α(2) adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression. CONCLUSION AND IMPLICATIONS: Blockade of ß-adrenoceptors normalized the adrenal α(2) adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by ß-blockers.

Myocardial ß(2) -adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure.

BACKGROUND AND PURPOSE: We investigated whether ß(2) -adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. EXPERIMENTAL APPROACH: We explored the angiogenic effects of ß(2) -adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated ß(2) -adrenoceptor overexpression was obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to ß(2) -adrenoceptor -/- mice undergoing MI. KEY RESULTS: Transgenes were robustly expressed in the LV at 2 weeks post-gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac ß(2) -adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-ß(2) -adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, ß(2) -adrenoceptor overexpression was associated with a markedly increased capillary and arteriolar length density and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac ß(2) -adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In ß(2) -adrenoceptor-/- mice, we found a ~25% reduction in cardiac capillary density compared with ß(2) -adrenoceptor+/+ mice. The lack of ß(2) -adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls. CONCLUSIONS AND IMPLICATION: ß(2) -Adrenoceptors play an important role in the regulation of the angiogenic response in HF. The activation of VEGF/PKB/eNOS pathway seems to be strongly involved in this mechanism.

Implementation of cardiovascular secondary prevention guidelines in clinical practice: a nationwide survey in Italy.

AIMS: To report the implementation of cardiovascular secondary prevention guidelines following a cardiovascular event in Italy. METHODS AND RESULTS: Data were collected from 878 consecutive patients, who had suffered a cardiovascular event requiring hospitalisation in the preceding 12-24 months and who presented at 49 outpatient clinics across Italy. Cardiovascular risk markers were assessed through clinical examination, interview and reviewing of patients' charts; in addition, we collected information on changes in prevalence of selected risk factors that occurred since the time of index event. At the time of evaluation, increased body mass index (BMI) was observed in 35% of patients, with 20% being obese; 26% had diabetes and 21% uncontrolled hypertension. Although 91% of patients were on statins, no measurement of low-density lipoprotein (LDL)-cholesterol was available in the previous 6 months in 27% of patients and 16% had no knowledge of any lipid parameter in the same period. In the remaining patients, LDL was <100 mg dl(-1) in 57% and <70 mg dl(-1) in 20% of them. From the time of index event to interview, prevalence of uncontrolled hypertension remained stable, from 24% to 21% of patients; according to the patients' self-reporting, smoking had declined from 32% to 13% of patients and physical inactivity from 43% to 33% of patients. CONCLUSIONS: This survey shows, in a large national cohort, a suboptimal implementation of lifestyle changes and inadequate lipid control in patients at high cardiovascular risk after a cardiovascular event. Reinforcement of patients and physicians, implementation and adherence to guidelines is needed to reduce the burden of cardiovascular disease.

Use of carotid intima-media thickness regression to guide therapy and management of cardiac risks.

OPINION STATEMENT: Although carotid intima-media thickness (IMT) has been broadly used as a tool to evaluate cardiovascular risk, its role as a surrogate endpoint is still debated. The main issue is the fact that no study has ever been powered to show a relationship between changes in carotid IMT during follow-up and cardiovascular events. A meta-analysis of existing clinical studies was performed to investigate this relationship but it failed to demonstrate a predictive role of regression in carotid IMT for cardiovascular events. The reasons for the lack of a clear evidence for a predictive role of IMT progression are unknown but are likely multifactorial. Firstly, it may depend on the fact that this index is not a pure atherosclerosis index. Second, carotid atherosclerosis does not always reflect coronary atherosclerosis. Furthermore, methodologic problems related to intra- and interobserver variability make this index not adequately reproducible when tracking the progression of carotid atherosclerosis. A further meta-analysis based on individual patient data, instead of published data, has been planned to better address the predictive role of IMT. Lastly, in the future, the variability of ultrasound measurements of carotid IMT are likely to be reduced by further development of automatic calculation of this index by magnetic resonance imaging.

Low dose dobutamine echocardiography for predicting functional recovery after coronary revascularisation.

OBJECTIVE: To evaluate the effects of chronic coronary occlusion on the accuracy of low dose dobutamine echocardiography in predicting recovery of dysfunctional myocardium after revascularisation. DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: 53 consecutive patients with >/= 70% stenosis of the left anterior descending coronary artery (LAD) and regional ventricular dysfunction (group 1, non-occluded LAD; group 2, occluded LAD) who underwent dobutamine echocardiography. INTERVENTIONS: 26 patients underwent coronary artery bypass grafting and 27 had percutaneous transluminal coronary angioplasty. MAIN OUTCOME MEASURES: Baseline studies before revascularisation included cross sectional echocardiography at rest and during dobutamine infusion (5-10 microgram), and coronary angiography. The dobutamine study was performed mean (SD) 35 (28) days before revascularisation. Echocardiography at rest was repeated 90 (48) days after revascularisation. RESULTS: Of 296 dysfunctional segments, 63 in group 1 (43%; 63/146) and 69 in group 2 (46%; 69/150) (NS) improved at follow up. Mean (SD) regional wall motion score index decreased from 1.97 (0.48) (95% confidence interval (CI) 1.01 to 2.93) before revascularisation to 1.74 (0.52) (95% CI 0.70 to 2.78) at follow up in group 1 (p = 0.001), and from 2.12 (0.41) (95% CI 1.30 to 2.98) to 1.88 (0.36) (95% CI 1.16 to 2.60) in group 2 (p = 0.0006). In group 1, sensitivity (87% v 52%; p < 0.0001), negative predictive value (88% v 65%; p = 0.001), and accuracy (77% v 64%; p = 0.01) were all significantly higher than in group 2, despite the angiographic evidence of collaterals in patients with occluded vessels. CONCLUSIONS: Dobutamine echocardiography shows reduced sensitivity in predicting recovery of dysfunctional myocardium supplied by totally occluded vessels. Thus caution should be used in selecting such patients for revascularisation on the basis of a viability assessment made in this way.

What is the relevance of the HOPE study in general practice?

The unique findings from the HOPE (Heart Outcomes Prevention Evaluation) study strongly support extending the use of the angiotensin-converting enzyme (ACE) inhibitor ramipril as a preventive agent for patients at high risk of cardiovascular events with normal left ventricular function. In addition, ramipril provides significant benefit in diabetic patients. These findings will impact on how ramipril is used in primary care, where ACE inhibitors are currently underprescribed. Patients reflecting the inclusion criteria of the HOPE study should be considered as suitable candidates for long-term ramipril therapy as an addition to their existing drug regimen. Screening should include control of kidney function (by serum creatinine), particularly within the first two weeks of treatment, in addition to regular monitoring of serum potassium. However, the HOPE study shows that ramipril is well tolerated at high doses and over a long treatment period. The effectiveness of therapy should also be regularly reviewed and dose adjustments made where necessary. If concern remains, referral to a specialist--a cardiologist or a diabetologist--may ultimately be necessary.

The identification of myocardial hibernation in patients with ischemic heart failure by echocardiography and radionuclide studies.

Dobutamine echocardiography and myocardial radionuclide tomography are widely used to assess viability in patients with ischemic cardiomyopathy and left ventricular dysfunction. The main goal of viability evaluation has been the identification of reversible regional dysfunction in the attempt to identify patients in whom revascularization may determine an improvement of global left ventricular ejection fraction. In this application, echocardiographic and radionuclide techniques are used to characterize different pathophysiologic aspects of viable myocardium, ie, integrity of cell membrane and contractile reserve. This explains why the information of the 2 techniques are often divergent and why radionuclide techniques have the highest sensitivity but reduced specificity compared with echocardiography for predicting recovery of regional dysfunction. The identification of residual viable myocardium by either technique is strongly associated with adverse prognosis if the patients are not revascularized, and this substantially contributes to the decision-making process in individual patients. Although it has been assumed that prognostic advantages of revascularization are linked to an increase of ejection fraction, pathophysiologic and clinical observations challenge us with the possibility that benefits of revascularization may also ensue independently on the recovery of ejection fraction through alternative pathophysiologic mechanisms. Therefore, clinical application of viability tests should be evaluated against relevant endpoints, mainly represented by prolongation of life and improvement of life quality, and not by surrogate endpoints as represented by recovery of global ejection fraction. Future studies are needed to assess whether a more clinically oriented approach will provide a better selection of patient candidates for revascularization.

The assessment of myocardial viability and hibernation using resting thallium imaging.

Rest-redistribution thallium-201 imaging is widely used to assess recovery of regional systolic dysfunction in patients with chronic coronary artery disease. In several studies, this technique has demonstrated very high sensitivity but reduced specificity, as reported in general for radionuclide imaging. In clinical terms, this implicates that many dysfunctional territories will not recover after revascularization despite a substantial amount of tracer uptake. Yet, the amount of tracer uptake in a given myocardial segment, although not perfect, remains the best indicator for predicting reversible dysfunction. In fact, the occurrence of redistribution after rest injection is not very common and it does not substantially contribute to the accuracy of the test. However, it is still undetermined whether the presence of redistribution is relevant for prognostic implications.

Prediction of improvement in global left ventricular function in patients with chronic coronary artery disease and impaired left ventricular function: rest thallium-201 SPET versus low-dose dobutamine echocardiography.

Accurate assessment of myocardial viability permits selection of patients who would benefit from myocardial revascularization. Currently, rest-redistribution thallium-201 scintigraphy and low-dose dobutamine echocardiography are among the most used techniques for the identification of viable myocardium. Thirty-one consecutive patients (all men, mean age 60 +/- 8 years) with chronic coronary artery disease and reduced left ventricular ejection fraction (31% +/- 7%) were studied. Rest 201Tl single-photon emission tomography (SPET), low-dose dobutamine echocardiography and radionuclide angiography were performed before revascularization. Radionuclide angiography and echocardiography were repeated after revascularization. An a/dyskinetic segment was considered viable on 201Tl SPET when tracer uptake was >65%, while improvement on low-dose dobutamine echocardiography was considered a marker of viability. Increase in global ejection fraction was considered significant at > or = 5%. In identifying viable segments, rest 201Tl SPET showed higher sensitivity than low-dose dobutamine echocardiography (72% vs 53%, P<0.05), while specificity was not significantly different (86% vs 88%). In 17 patients, global ejection fraction increased > or = 5% (group 1) while in 14 it did not (group 2). A higher number of a/dyskinetic segments were viable on 201Tl SPET in group 1 than in group 2 (2.6 +/- 1.9 vs 0.6 +/- 1.2, P < 0.005), while no significant differences were observed on low-dose dobutamine echocardiography (1.7 +/- 1.6 vs 1.1 +/- 1.6). A significant correlation was found between the number of a/dyskinetic segments viable on 201Tl SPET and post-revascularization changes in ejection fraction (r = 0.52, P < 0.05), but such a correlation was not observed for low-dose dobutamine echocardiography. Using as the cut-off the presence of at least one viable a/dyskinetic segment, rest 201Tl SPET had a higher sensitivity (82% vs 53%, P = 0.07) and showed a trend towards higher accuracy and specificity (77% vs 58%, and 71% vs 64%, respectively) as compared with low-dose dobutamine echocardiography. In conclusion, these findings suggest that when severely reduced global function is present, rest 201Tl SPET evaluation of viability is more accurate than low-dose dobutamine echocardiography for the identification of patients who will benefit most from revascularization.

Rest-injected 201thallium in the evaluation of myocardial viability.

In recent years 201thallium scintigraphy at rest has been used for evaluating myocardial viability in patients with chronic ischemic coronary artery disease and left ventricular dysfunction. Based on the assumption that reversible myocardial dysfunction arises from chronic hypoperfusion (hibernation), resting 201thallium scintigraphy is performed by acquiring two sets of images, one early after tracer injection and a second following 3 to 4 hours to allow for the redistribution process to take place. However, redistribution of 201thallium following injection at rest rarely occurs, and in many studies it does not significantly contribute to the identification of reversibly dysfunctional myocardium. In fact, current interpretation of resting 201thallium scintigraphy is based on the measurement of regional tracer uptake on the redistribution images, using a fixed threshold value (most commonly from 50 to 65% of maximal uptake) that arbitrarily identify viable (presumably reversible) and nonviable (presumably irreversible) dysfunctional myocardium. The practical implication of this approach is relevant as it implies that analysis of a single set of images is adequate for viability information. As with other nuclear techniques, sensitivity of 201thallium scintigraphy for predicting functional recovery following revascularization is very high, but specificity is suboptimal, reflecting the identification of substantial residual tracer uptake in territories that will remain dysfunctional at rest following successful revascularization. Inadequate timing of follow-up functional evaluation, ongoing degeneration of hibernating myocytes, admixture of necrotic and normal myocardium in dysfunctional areas are among factors that likely explain this discrepancy. It remains to be evaluated in future studies whether revascularization of these areas that contain viable myocardium but where resting function does not change, may also contribute to the beneficial effects of revascularization in patients with left ventricular dysfunction.

Pathophysiology of heart failure.

Heart failure is a leading cause of mortality and morbidity in Western countries. Common etiology is mostly represented by ischemic and hypertensive heart disease. Clinically, heart failure can be defined as an impaired cardiac performance, unable to meet the energy requirements of the periphery. Pathophysiologically, the clinical onset of heart failure symptoms already represents an advanced stage of disease when compensatory mechanisms triggered by the underlying decrease in contractility are no longer capable of maintaining adequate cardiac performance during exercise and, subsequently, under resting conditions. Independent of its underlying etiology, cardiac failure is always characterized by an impairment in the intrinsic contractility of myocytes. As a consequence of reduced contractility, a number of central and peripheral compensatory mechanisms take place that are capable of effectively counteracting reduced intravascular intrinsic performance for a long period of time. Among them, recruitment of preload reserve, enhanced neurohormonal stimulation and cardiac hypertrophy are the most important. All of them, however, also carry unfavorable effects that contribute to further deterioration of cardiac function. In fact, increased end-diastolic volume determines increased wall stress that further reduces systolic performance; sympathetic and angiotensin stimulation increases peripheral resistance and contributes to increase volume expansion; hypertrophic myocytes demonstrate impaired intrinsic contractility and relaxation, and hypertrophy causes a clinically relevant deterioration of ventricular relaxation and compliance that substantially participates in increased end-diastolic pressure, and, therefore, to limited exercise performance. Diastolic dysfunction usually accompanies systolic dysfunction, although in some cases it may represent the prevalent mechanism of congestive heart failure in patients in whom systolic performance is preserved. Biological causes of reduced contractility in heart failure are not completely elucidated. Changes in myosin composition and in sarcoplasmic ATPase activity, causing reduced Ca2+ availability during contraction, have been reported, although their exact contribution is not clear. Recently, impaired endothelial function has also been described in heart failure, and new appealing hypotheses have been made regarding the causative role of circulating cytokines like tumor necrosis factor in the pathogenesis of heart failure.

Influence of left ventricular cavity size on clinical presentation in hypertrophic cardiomyopathy.

The aim of this study was to assess whether left ventricular (LV) cavity size relates to functional impairment and syncope in patients with hypertrophic cardiomyopathy (HC). LV diastolic dysfunction influences functional limitation in HC. A reduced LV end-diastolic dimension may underlie impaired diastolic properties and be implicated in hemodynamic syncope. Eighty-two consecutive patients with HC (off drugs, in sinus rhythm) underwent echocardiography to measure LV end-diastolic dimension in the short-axis view (indexed to the body surface area) and radionuclide angiography (n = 50) to calculate peak filling rate (normalized to stroke counts/s). Patients in New York Heart Association functional classes II to IV had smaller LV end-diastolic dimension (23.2 +/- 2.6 vs 25.5 +/- 2.5 mm/M2, p = 0.0001) and lower peak filling rate (4.3 +/- 1.4 vs 5.1 +/- 1.3 stroke counts/s, p = 0.036) than those in New York Heart Association class I. LV end-diastolic diameter was correlated to peak filling rate (r = 0.37; p = 0.008). The most potent predictors of functional limitation were LV end-diastolic dimension (relative risk [RR] 0.63, confidence interval [CI] 0.45 to 0.88; p = 0.008), age (RR 1.09, CI 1.03 to 1.17; p = 0.003), and LV thickness score (RR 1.08, CI 1.02 to 1.13; p = 0.003). LV cavity size was smaller in patients with functional limitation irrespective of obstruction and hypertrophy. Patients with differed from those without a history of syncope for a smaller LV end-diastolic dimension (23.2 +/- 2.5 vs 25.0 +/- 2.7 mm/M2, p = 0.008), which was the only independent predictor of syncope (RR 0.77, CI 0.63 to 0.95; p = 0.013). Thus, a small LV cavity size is associated with functional limitation and history of syncope in HC.