Geometry Does Impact on the Plane Strain Directions of the Human Left Ventricle, Irrespective of Disease.

The directions of primary strain lines of local deformation in Epicardial and Endocardial layers have been the subject of debate in recent years. Different methods led to different conclusions and a complete assessment of strain direction patterns in large and variable (in terms of pathology) cohorts of healthy and diseased patients is still lacking. Here, we use local deformation tensors in order to evaluate the angle of strain lines with respect to the horizontal circumferential direction in both Epi- and Endo-layers. We evaluated this on a large group of 193 subjects including 82 healthy control and 111 patients belonging to a great variety of pathological conditions. We found that Epicardial strain lines obliquely directed while those of Endocardium are almost circumferential. This result occurs irrespective of pathological condition. We propose that the geometric vinculum characterizing Endocardium and Epicardium in terms of different lever arm length and orientation of muscular fibers during contraction inescapably requires Endocardial strain lines to be circumferentially oriented and this is corroborated by experimental results. Further investigations on transmural structure of myocytes could couple results presented here in order to furnish additional experimental explanations.

Toll-like receptor 4 activation in platelets from myocardial infarction patients.

INTRODUCTION: Platelet toll-like receptor 4 (TLR4) is overexpressed in patients with myocardial infarction (MI) but it remains to elucidate if it is activated and the potential trigger. METHODS: Serum levels of lipopolysaccharides (LPS) and platelet aggregation (PA) by collagen alone or in combination with a TLR4 inhibitor (TLR4i) were studied ex vivo in platelets from 40 MI patients and 40 controls matched for age, sex and atherosclerotic risk factors; platelet TIR domain-containing adaptor protein (TIRAP) and TIRAP-MyD88 interaction were also investigated by western blot and co-immunoprecipitation, respectively. In vitro experiments were conducted to see if LPS triggers platelet TIRAP phosphorylation. RESULTS: Serum LPS was significantly higher in patients compared to controls (29.5±7.1 vs 16.2±3.8 pg/mL; p<0.001). Collagen-stimulated platelets from MI pre-treated with TLR4i showed a significant decrease of PA compared to platelets stimulated with collagen. Ex vivo study showed that TIRAP phosphorylation as well as TIRAP-MyD88 co-immunoprecipitation were higher in patients compared to controls. In vitro study showed that LPS, at concentrations like those found in MI, dose-dependently activated TIRAP and amplified the platelet response to the agonist, an effect blunted by TLR4i. CONCLUSION: The study provides evidence that in MI patients platelet TLR4 is activated and suggests circulating LPS as potential trigger.

Glutathione Infusion Before and 3 Days After Primary Angioplasty Blunts Ongoing NOX2-Mediated Inflammatory Response.

Background Glutathione is a water-soluble tripeptide with a potent oxidant scavenging activity. We hypothesized that glutathione administration immediately before and after primary angioplasty (primary percutaneous coronary intervention) could be effective in modulating immune cell activation, thereby preventing infarct expansion. Methods and Results One hundred consecutive patients with ST-segment-elevation myocardial infarction, scheduled to undergo primary percutaneous coronary intervention were randomly assigned before the intervention to receive an infusion of glutathione (2500 mg/25 mL over 10 minutes), followed by drug administration at the same doses at 24, 48, and 72 hours elapsing time or placebo. Total leukocytes, NOX2 (nicotinamide adenine dinucleotide phosphate oxidase 2) activation, NO bioavailability, cTpT (serum cardiac troponin T), hsCRP (high-sensitivity C-reactive protein), and TNF-α (tumor necrosis factor α) levels were measured. Left ventricular size and function were assessed within 120 minutes, 5 days, and 6 months from percutaneous coronary intervention. Following reperfusion, a significant reduction of neutrophil to lymphocyte ratio (P<0.0001), hsCRP generation (P<0.0001), NOX2 activation (P<0.0001), TNF-α levels (P<0.001), and cTpT release (P<0.0001) were found in the glutathione group compared with placebo. In treated patients, blunted inflammatory response was linked to better left ventricular size and function at follow-up (r=0.78, P<0.005). Conclusions Early and prolonged glutathione infusion seems able to protect vital myocardial components and endothelial cell function against harmful pro-oxidant and inflammatory environments, thus preventing maladaptive cardiac repair and left ventricular adverse remodeling. Registration URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2014-004486-25.

Acute atrial ischemia associates with early but not late new-onset atrial fibrillation in STEMI patients treated with primary PCI: relationship with in-hospital outcomes.

BACKGROUND: New-onset atrial fibrillation (NOAF), both early (EAF) or late (LAF), may complicate ST-segment elevation myocardial infarction (STEMI). The mechanisms underlying EAF or LAF are poorly described. We investigated atrial branch occlusion and EAF or LAF onset in STEMI patients undergoing primary percutaneous coronary intervention. METHODS: This was a retrospective cohort study including 155 STEMI patients. Patients were divided into 3 groups: sinus rhythm (SR), EAF, or LAF. Clinical characteristics, angiographic features including occlusion of atrial branches, namely ramus ostia cavae superioris (ROCS), atrio-ventricular node artery (AVNA), right intermediate atrial artery (RIAA), and left intermediate atrial artery, were assessed. We also investigated in-hospital adverse events (AEs) and death. RESULTS: Mean age was 63.8±11.9 years; 78.7% were men. NOAF was detected in 22 (14.2%) patients: 10 (6.4%) EAF and 12 LAF (7.7%). Compared to EAF, LAF patients were older (p=0.013), with higher GRACE risk score (p=0.014) and Killip class (p=0.015), depressed ejection fraction (p=0.007), elevated filling pressures (p=0.029), higher C-reactive protein (p=0.014) and more with thrombolysis in myocardial infarction flow <3 (p=0.015). Compared to SR, EAF was associated with higher prevalence of occluded ROCS (p=0.010), AVNA (p=0.005), and RIAA (p<0.001). Moreover, EAF patients had more frequently ≥2 diseased atrial branches than SR (19.5%, p<0.001) and LAF (25%, p<0.030) patients. LAF patients had a higher in-hospital AEs (p=0.019 vs SR; p=0.029 vs EAF) and death (p=0.004 vs SR). CONCLUSIONS: The occlusion of atrial branches is associated with EAF but not LAF following STEMI. LAF patients had worse in-hospital AEs and mortality.

Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report.

BACKGROUND: Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: < 1/1000000) which clinically manifests in early infancy. CASE PRESENTATION: We describe the case of a 31 years old woman who at the age of 30 days presented with the classical clinical and laboratory signs of an inborn error of vitamin B12 metabolism. Family history revealed a sister who died at the age of 3 months with a similar clinical syndrome and with pancytopenia. She was started on empirical intramuscular (IM) cobalamin supplements (injections of hydroxocobalamin 1 mg/day for 1 week and then 1 mg twice a week) and several transfusions of washed and concentrated red blood cells. With these treatments a clear improvement in symptoms was observed, with the disappearance of vomiting, diarrhea and normalization of the full blood count. At 8 years of age injections were stopped for about two and a half months causing the appearance of pancytopenia. IM hydroxocobalamin was then restarted sine die. The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed the homozygous c.1115_1116delCA mutation of TCN2 gene (p.Q373GfsX38). Currently she is healthy and she is taking 1 mg of IM hydroxocobalamin once a week. CONCLUSIONS: Our case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.

Myocardial Metastasis of Tongue Cancer: A Rare Localization.

BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.

Local and global energies for shape analysis in medical imaging.

In a previous contribution, a new Riemannian shape space, named TPS space, was introduced to perform statistics on shape data. This space was endowed with a Riemannian metric and a flat connection, with torsion, compatible with the given metric. This connection allows the definition of a Parallel Transport of the deformation compatible with the three-fold decomposition in spherical, deviatoric, and non-affine components. Such a parallel transport also conserves the Γ-energy, strictly related to the total elastic strain energy stored by the body in the original deformation. A new approach is here presented in order to calculate the bending energy on the body alone (body bending energy) and to restrict it exclusively within physical boundaries of objects involved in the deformation analysis. The novelty of this new procedure resides in the fact that we propose a new metric to be preserved during the TPS direct transport. This allows transporting the shape change more coherently with the mechanical meaning of the deformation. The geometry of the TPS space is then further discussed in order to better represent the relationship between the Γ-energy, the strain energy, and the so-called bending energy densities.

Clinical frailty and triggers in Takotsubo syndrome: the notable role of a new classification.

AIMS: Takotsubo syndrome (TTS) is a mainly transient and acute heart failure mimicking an acute coronary syndrome. Originally described in postmenopausal women, over time TTS has been associated with an increasingly advanced age. Emotional and physical triggers precipitating TTS have been correlated in most cases. The aim of our work was to detect differences between patients with or without recognizable triggers preceding the onset of symptoms. METHODS: We enrolled 22 consecutive patients. They were all women with an average age of 71 ±â€Š12 (range 40-90) years. Twelve patients correlated the onset of TTS symptoms with a trigger (group 1) and 10 patients (group 2) denied any correlation with stressful events. RESULTS: Patients in group 1 showed a higher average age than group 2 (76 ±â€Š10 vs. 64 ±â€Š12 years; P = 0.023), a longer hospitalization period (22 ±â€Š12 vs. 11 ±â€Š10 days; P = 0.01) and greater value of frailty score (P = 0.004). Despite a decrease and subsequent recovery of systolic function, there was no significant difference between groups. Group 1 showed a longer corrected QT (QTc) (505 ±â€Š53 vs. 453 ±â€Š42 ms, P = 0.03), a greater decrease in QTc at discharge (-57 ±â€Š44 vs. 0.3 ±â€Š39 ms; P = 0.004), with the result that at discharge both groups showed a comparable QTc. CONCLUSION: Our results emphasized that typical TTS female patients with precipitating triggers have advanced age, clinical frailty and QTc abnormalities.

Non-invasive prediction of genotype positive-phenotype negative in hypertrophic cardiomyopathy by 3D modern shape analysis.

NEW FINDINGS: What is the central question of this study? Can impaired deformational indicators for genotype positive for hypertrophic cardiomyopathy in subjects that do not exhibit a left-ventricular wall hypertrophy condition (G+LVH-) be determined using non-invasive 3D echocardiography? What is the main finding and its importance? Using 3D-STE and modern shape analysis, peculiar deformational impairments can be detected in G+LVH- subjects that can be classified with good accuracy. Moreover, the patterns of impairment are located mainly on the apical region in agreement with other evidence coming from previous biomechanical investigations. ABSTRACT: We propose a non-invasive procedure for predicting genotype positive for hypertrophic cardiomyopathy (HCM) in subjects that do not exhibit a left-ventricular wall hypertrophy condition (G+LVH-); the procedure is based on the enhanced analysis of medical imaging from 3D speckle tracking echocardiography (3D-STE). 3D-STE, due to its low quality images, has not been used so far to detect effectively the G+LVH- condition. Here, we post-processed echocardiographic images exploiting the tools of modern shape analysis, and we studied the motion of the left ventricle (LV) during an entire cycle. We enrolled 82 controls, 21 HCM patients and 11 G+LVH- subjects. We followed two steps: (i) we selected the most impaired regions of the LV by analysing its strains; and (ii) we used shape analysis on these regions to classify the subjects. The G+LVH- subjects showed different trajectories and deformational attributes. We found high classification performance in terms of area under the receiver operating characteristic curve (∼90), sensitivity (∼78) and specificity (∼79). Our results showed that (i) G+LVH- subjects present important deformational impairments relative to healthy controls and (ii) modern shape analysis can efficiently predict genotype by means of a non-invasive and inexpensive technique such as 3D-STE.

Clinical and prognostic association of total atrial conduction time in patients with heart failure: a report from Studies Investigating Co-morbidities Aggravating Heart Failure.

BACKGROUND: The total atrial conduction time can be measured as the time from the onset of the P wave on the ECG to the peak of the A wave recorded at the mitral annulus using tissue Doppler imaging (A'; P-A'TDI); when prolonged, it might predict incident atrial fibrillation. METHODS: We measured P-A'TDI in outpatients with heart failure and sinus rhythm enrolled in the SICA-HF programme. RESULTS: P-A'TDI measured at the lateral mitral annulus was longer in patients with HF with reduced [LVEF<50%, N = 141; 126 (112-146) ms; P = 0.005] or preserved left ventricular ejection fraction [LVEF>50% and NT-proBNP > 125 ng/l, N = 71; 128 (108-145) ms; P = 0.026] compared to controls [N = 117; 120 (106-135) ms]. Increasing age, left atrial volume and PR interval were independently associated with prolonged P-A'TDI. During a median follow-up of 1251 (956-1602) days, 73 patients with heart failure died (N = 42) or developed atrial fibrillation (N = 31). In univariable analysis, P-A'TDI was associated with an increased risk of the composite outcome of death or atrial fibrillation, but only increasing log [NT-proBNP], age and more severe symptoms (NYHA III vs. I/II) were independently related to this outcome. Patients in whom both P-A'TDI and left atrial volume were above the median (127 ms and 64 ml, respectively) had the highest incidence of atrial fibrillation (hazard ratio 6.61, 95% CI 2.27-19.31; P < 0.001 compared with those with both P-A'TDI and LA volume below the median). CONCLUSION: Measuring P-A'TDI interval identifies patients with chronic heart failure at higher risk of dying or developing atrial fibrillation during follow-up.

Antiplatelet therapy in elderly patients with acute coronary syndrome: Between scientific evidence and future perspectives.

Dual antiplatelet therapy (DAPT) is an important strategy for reducing cardiovascular events (CV) after an acute coronary syndrome (ACS). Elderly patients undergoing DAPT have a higher risk of bleeding than younger patients for a variety of reasons. Stratification of thrombotic/hemorrhagic risk is mandatory in order to decide on the type and duration of DAPT. The percentage of patients ≥ 75 years represented in clinical trials is not large, so very often elderly people are prescribed treatment protocols only experimented on younger patients with a lower hemorrhagic risk. However, even in patients aged ≥ 75 treated with invasive or conservative therapy, after an ACS, a DAPT with aspirin 80-100 mg/day plus a P2Y12 receptor inhibitor for 12 months is recommended. In elderly patients, DAPT should be considered a dynamic process that can be modified over time based on the patient's clinical conditions, or any other necessities (non-procrastinating surgical interventions, comorbid-like effects that can increase hemorrhagic risk). In patients with moderate-high or very high hemorrhagic risk, DAPT treatment should last less than 12 months. A prolongation of DAPT beyond 12 months in this setting is limited to a very low percentage of patients, after careful assessment of ischemic/hemorrhagic profile.

The decomposition of deformation: New metrics to enhance shape analysis in medical imaging.

In landmarks-based Shape Analysis size is measured, in most cases, with Centroid Size. Changes in shape are decomposed in affine and non affine components. Furthermore the non affine component can be in turn decomposed in a series of local deformations (partial warps). If the extent of deformation between two shapes is small, the difference between Centroid Size and m-Volume increment is barely appreciable. In medical imaging applied to soft tissues bodies can undergo very large deformations, involving large changes in size. The cardiac example, analyzed in the present paper, shows changes in m-Volume that can reach the 60%. We show here that standard Geometric Morphometrics tools (landmarks, Thin Plate Spline, and related decomposition of the deformation) can be generalized to better describe the very large deformations of biological tissues, without losing a synthetic description. In particular, the classical decomposition of the space tangent to the shape space in affine and non affine components is enriched to include also the change in size, in order to give a complete description of the tangent space to the size-and-shape space. The proposed generalization is formulated by means of a new Riemannian metric describing the change in size as change in m-Volume rather than change in Centroid Size. This leads to a redefinition of some aspects of the Kendall's size-and-shape space without losing Kendall's original formulation. This new formulation is discussed by means of simulated examples using 2D and 3D platonic shapes as well as a real example from clinical 3D echocardiographic data. We demonstrate that our decomposition based approaches discriminate very effectively healthy subjects from patients affected by Hypertrophic Cardiomyopathy.

Morphologically normalized left ventricular motion indicators from MRI feature tracking characterize myocardial infarction.

We characterized motion attributes arising from LV spatio-temporal analysis of motion distributions in myocardial infarction. Time-varying 3D finite element shape models were obtained in 300 Controls and 300 patients with myocardial infarction. Inter-individual left ventricular shape differences were eliminated using parallel transport to the grand mean of all cases. The first three principal component (PC) scores were used to characterize trajectory attributes. Scores were tested with ANOVA/MANOVA using patient disease status (Infarcts vs. Controls) as a factor. Infarcted patients had significantly different magnitude, orientation and shape of left ventricular trajectories in comparison to Controls. Significant differences were found for the angle between PC scores 1 and 2 in the endocardium, and PC scores 1 and 3 in the epicardium. The largest differences were found in the magnitude of endocardial motion. Endocardial PC scores in shape space showed the highest classification power using support vector machine, with higher total accuracy in comparison to previous methods. Shape space performed better than size-and-shape space for both epicardial and endocardial features. In conclusion, LV spatio-temporal motion attributes accurately characterize the presence of infarction. This approach is easily generalizable to different pathologies, enabling more precise study of the pathophysiological consequences of a wide spectrum of cardiac diseases.

Homeostatic Left Heart integration and disintegration links atrio-ventricular covariation's dyshomeostasis in Hypertrophic Cardiomyopathy.

Left ventricle and left atrium are and have been practically always analyzed separately in common clinically and non-clinically oriented cardiovascular investigations. Both classic and speckle tracking echocardiographic data contributed to the knowledge about deformational impairments occurring in systo-diastolic differences. Recently new trajectory based approaches allowed a greater awareness about the entire left ventricle or left atrium revolution and on their deficiencies that take place in presence of hypertrophic cardiomyopathy. However, surprisingly, the concomitant function of the two left heart chambers has not been analyzed for their geometrical/mechanical relationship. For the first time we study here, by acquiring left ventricle and left atrial geometries on the same heartbeat, the trajectory attributes of the entire left heart treated as a whole shape and the shape covariation of its two subunits. We contrasted healthy subjects with patients affected by hypertrophic cardiomyopathy. We found impaired left heart trajectory mainly in terms of orientation and size. More importantly, we found profound differences in the direction of morphological covariation of left ventricle and left atrium. These findings open to new perspectives in pathophysiological evaluation of different diseases by allowing the appreciation of concomitant functioning of both left heart whole geometry and of its two chambers.

Two cases of acute chest discomfort and the Central Italy earthquake.

We present the cases of two postmenopausal women presenting to our emergency department with acute chest discomfort soon after the Central Italy earthquake. Different diagnoses were made in the two patients. The role of the earthquake as a stressful event triggering diverse chest pain syndromes is discussed.

Survival at 2 years among liver cirrhotic patients is influenced by left atrial volume and left ventricular mass.

BACKGROUND & AIMS: Cirrhotic cardiomyopathy (CC) may interact with the clinical course of cirrhosis and can be implicated in the development of several complications in advanced liver disease. The best and easiest parameters which should define a condition of reduced cardiac reserve in cirrhosis are still controversial. This study was aimed at selecting the cardiac parameters, derived by Doppler echocardiography, predictive of survival during follow-up. METHODS: This study included cirrhotic patients without cardiovascular or pulmonary diseases. Patients were studied in stable conditions. Doppler echocardiography was used to select parameters associated with survival. Among the others, left atrial volume (LAVi) and left ventricular mass indexed to body surface area (LVMi) were evaluated. A comparison was performed with the parameters presently applied for the definition of CC according to the Montreal criteria. RESULTS: Ninety cirrhotic patients have been included (males 66%, alcohol origin 31%, post-viral 54%, Child-Pugh A 53%, B 29% and C 18%). Patients were followed up for at least 24 months. Twenty-six patients had a diagnosis of CC according to the Montreal criteria. During follow-up, 24 patients died. Overall mortality was 26.7%. Patients presenting higher LAVi and lower LVMi were those at higher risk to die (P=.04 and P=.007 respectively). No difference in survival was seen in patients with a diagnosis of CC. CONCLUSIONS: An increased LAVi and a decreased LVMi were able to differentiate among patients with a lower survival at 2 years. These parameters need to be considered for prognostic evaluation in cirrhotics.

Left Atrial trajectory impairment in Hypertrophic Cardiomyopathy disclosed by Geometric Morphometrics and Parallel Transport.

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction.

Ivabradine in Patients with ST-Elevation Myocardial Infarction Complicated by Cardiogenic Shock: A Preliminary Randomized Prospective Study.

BACKGROUND AND OBJECTIVE: An elevated heart rate (HR) is an independent risk factor for mortality and morbidity in patients with acute heart failure (HF). The purpose of this study was to evaluate the impact of ivabradine, a selective HR-lowering agent, in patients with cardiogenic shock (CS) complicating ST-elevation acute myocardial infarction (AMI). METHODS: Patients with post-AMI CS were randomized to standard treatment (SDT, 28 patients) or to standard treatment plus ivabradine (I + SDT, 30 patients). In the presence of orotracheal intubation (OTI), ivabradine was administered by nasogastric intubation. HR, BP, New York Heart Association (NYHA) class, NT-proBNP, left ventricular ejection fraction (LVEF) and diastolic function (LVDF) were monitored at specific times after the onset of AMI. The primary (surrogate) end-point was the in-hospital halving of plasma NT-proBNP levels. The secondary end-points were cardiovascular death, hospital re-admission for worsening HF, and clinical and haemodynamic improvement. RESULTS: Treatment groups were statistically similar with regard to age, gender distribution, cardiovascular risk factors, number of diseased vessels and overall treated lesions, AMI site and occurrence of OTI. In-hospital mortality was double in the SDT group in comparison with the I + SDT group (14.3 vs. 6.7 %), but the difference was not statistically significant. HR, BP, NT-proBNP and LVEF favorably changed in both groups, but the change was more relevant in the I + SDT group. LVDF significantly changed only in the I + SDT group (p < 0.01). Patients in the I + SDT group did not experience adverse effects. CONCLUSION: Ivabradine in CS complicating AMI is safe, is associated with a short-term favourable outcome and can be effectively administered by nasogastric intubation.

Gender and Cardiovascular Mortality in Northern and Southern European Populations.

BACKGROUND: There are no ready explanations for differences in ischemic heart disease incidence between women and men under an epidemiological perspective. However, when myocardial infarction occurs, there are more likely individuals who happen to die. METHODS: This review from a more recent literature was performed for a two-fold purpose, to describe gender wise: a) the role of classical and novel factors defined to evaluate coronary artery disease (CAD) risk and mortality, aimed at assessing applicability and relevance for primary and secondary prevention; b) the differences in northern versus southern European Countries in risk factors and CAD mortality. RESULTS: Age-related risk patterns differ in men and women. It is uncertain whether standard factors may index CAD risk, including mortality, in different ways and/or whether specific factors might be targeted gender-wise. A list might be compiled: HDL-cholesterol levels, higher in pre-menopausal women than in men, are more strictly related to CAD; high triglycerides and Lp(a) have a similar relationship; HDL-cholesterol levels have an inverse relation with CAD incidence and mortality. The role of statins is not completely defined in primary prevention for women. However, in secondary prevention statins are equally effective in both genders. Weight and glycemic control are effective to reduce cardiovascular disease (CVD) mortality in women from middle to older age. Similarly, CVD mortality in women, from middle to older age, might be reduced by controlling blood pressure, particularly among diabetic or over weighted women. Renal dysfunction, either defined by UAE or eGFR or both may usefully predict primary CVD incidence and risk in both genders. In secondary prediction, kidney dysfunction predicts sudden death in women when left ventricular ejection fraction is also evaluated. Serum uric acid that normally increases with age, differentiates gender-related CVD incidences with a peculiar importance in women as compared to men. There has been much interest to investigate loss of ovarian function in explaining age-related differences between genders. More recently, some emphasis has been laid on the loss of ovarian function-related iron stores. There are subgroups of women as those with mitral valve prolapse and increased circulating levels of catecholamines in whom QT interval, physiologically longer in women than men, may be an arrhythmogenic risk index. However, no large population-based studies were ever conducted to assess this. Therefore, in the future, it will be important to implement risk score instruments (charts and softwares) in women using novel parameters, and among these inflammatory markers and reproductive hormones and serum uric acid. The important results of the WHO MONICA Project confirmed the northern versus southern European gradient in both men and women, for death rates and the proportion of all deaths from cardiovascular causes (including CAD, stroke and other CVD causes). The coronary event rate was initially as high as 1, 000 per 100, 000 inhabitants in Finland and less than 1 fifth of that in Spain with the corresponding figures in women of 200 and 30, respectively. CONCLUSION: No doubt might still exist that all efforts need be undertaken for both men and women, for health and prolongation of life to effectively treat common risk factors such as cigarette consumption, high blood pressure, cholesterol levels and physical inactivity by also paying attention to optimal diet.