Patrick Mathieu

Calcific Aortic Valve Disease: Not Simply a Degenerative Process A Review and Agenda for Research From the National Heart and Lung and Blood Institute Aortic Stenosis Working Group Executive Summary: Calcific Aortic Valve Disease - 2011 Update

Calcific aortic valve disease (CAVD) encompasses the range of disease from initial alterations in the cell biology of the leaflets to end-stage calcification resulting in left ventricular outflow obstruction. The first detectable macroscopic changes in the leaflets, seen as calcification, or focal leaflet thickening with normal valve function, is termed aortic valve sclerosis, but it is likely that the initiating events in the disease process occur much earlier. Disease progression is characterized by a process of thickening of the valve leaflets and the formation of calcium nodules – often including the formation of actual bone – and new blood vessels, which are concentrated near the aortic surface. End stage disease, e.g. calcific aortic stenosis, is characterized pathologically by large nodular calcific masses within the aortic cusps that protrude through the outflow surfaces into the sinuses of Valsalva, interfering with opening of the cusps. For decades, this disease was thought to be a passive process in which the valve degenerates with age in association with calcium accumulation. Moreover, although calcific aortic valve disease is more common with age, it is not an inevitable consequence of aging. Instead, CAVD appears to be an actively regulated disease process that cannot be characterized exclusively as “senile” or “degenerative.” The NHLBI convened a group of scientists from different fields of study, including cardiac imaging, molecular biology, cardiovascular pathology, epidemiology, cell biology, endocrinology, bioengineering, and clinical outcomes, to review the scientific studies from the past decade in the field of CAVD. The purpose was to develop a consensus statement on the current state of translational research related to CAVD. Herein, we summarize recent scientific studies and define future directions for research to diagnose, treat and potentially prevent this complex disease process.

Visceral Obesity: The Link Among Inflammation, Hypertension, and Cardiovascular Disease

The worldwide epidemic of obesity, fostered by the modern lifestyle characterized by the lack of physical activity and an energy-dense diet, has contributed to create an unprecedented condition in human history where a majority of overfed individuals will soon surpass the number of malnourished.1 Obesity-associated disorders, such as diabetes mellitus, an atherogenic dyslipidemia, and hypertension, have undoubtedly contributed to create an atherosclerosis-prone environment and thereby the development of cardiovascular disease (CVD), a leading cause of mortality in Westernized societies. A growing body of evidence indicates that obesity is a heterogeneous condition in which body fat distribution is closely associated with metabolic perturbations and, thus, with CVD risk.2 In this regard, accumulation of visceral (intra-abdominal) fat is strongly associated with insulin resistance and with a typical atherogenic dyslipidemic state.3 The adipose tissue, once considered a simple energy warehouse, is now regarded as a complex organ not only contributing to the management of energy flux within the body but also interacting with the inflammatory system and the vascular wall. Furthermore, recent studies have underlined that there are intricate interplays among adipocytes, the sympathetic nervous system (SNS), and the renin-angiotensin system (RAS), which participate in the obesity-associated dysmetabolic state. Thus, the adipose tissue is believed to play an important role in the development of both hypertension and other complications related to insulin resistance. However, it should be pointed out that different fat depots have distinct metabolic characteristics, leading to individual differences in the impact of obesity on cardiometabolic risk. Herein, we reviewed the complex links among visceral adiposity, inflammation, and hypertension, along with an attempt to address the clinical implications of these interactions. ### Small, Dense Low-Density Lipoprotein By its peculiar location, the expanded visceral fat depot has easy access to the liver via the portal circulation, where it could influence metabolism and promote insulin …

Mechanisms, prevention, and treatment of atrial fibrillation after cardiac surgery.

Post-operative atrial fibrillation (POAF) is a frequent complication occurring in 30% to 50% of patients after cardiac surgery. It is associated with an increased risk of mortality and morbidity, predisposes patients to a higher risk of stroke, requires additional treatment, and increases the costs of the post-operative care. The aim of this review is to present the current state of knowledge about the risk factors, mechanisms, prevention, and treatment of this complication. In addition to the well known risk factors for the development of POAF such as age, left atrial enlargement, and valvular surgery, new metabolic risk factors related to visceral obesity have been identified. With regard to the prevention of POAF, beta-blocker drugs are effective and safe and can be used in most patients, whereas amiodarone can be added in high-risk patients. Biatrial pacing was shown to be effective; however, its complexity might limit its application. Although there are only few data regarding the usefulness of magnesium, statins, N-3 polyunsaturated fatty acids, and corticosteroids, their addition to beta-blocker drugs might be of benefit for further reducing POAF. Treatment includes the use of an AV nodal blocking agent to achieve the rate control. If AF does not spontaneously convert to sinus rhythm within 24 h, anticoagulation should be initiated and a rhythm control strategy should be attempted. More investigations are warranted to explore mechanisms by which POAF occurs. This new knowledge would undoubtedly translate into a more efficient prevention and treatment of this common post-operative complication that is associated with a major health and economic burden.

Obesity, Inflammation, and Cardiovascular Risk

Obesity, a highly prevalent condition, is heterogeneous with regard to its impact on cardiovascular disease (CVD) risk. Epidemiological observations and metabolic investigations have consistently demonstrated that the accumulation of excess visceral fat is related to an increased risk of CVD as well as several metabolic and inflammatory perturbations. In the past decade, data from several studies have served to emphasize that atherosclerosis has an inflammatory component that may contribute to several key pathophysiological processes. Study data have also highlighted the finding that the expanded visceral fat is infiltrated by macrophages that conduct “cross‐talk” with adipose tissue through several significant mechanisms. In this review, we provide, in the context of CVD risk, an up‐to‐date account of the complex interactions that occur between a dysfunctional adipose tissue phenotype and inflammation.

Comparison Between Transcatheter and Surgical Prosthetic Valve Implantation in Patients With Severe Aortic Stenosis and Reduced Left Ventricular Ejection Fraction

Background— Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. Methods and Results— Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm2) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (&Dgr;LVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. Conclusion— In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

Outcome of Patients With Aortic Stenosis, Small Valve Area, and Low-Flow, Low-Gradient Despite Preserved Left Ventricular Ejection Fraction

OBJECTIVES The aim of this case match study was to compare the outcome of patients with paradoxical low-flow (left ventricular ejection fraction [LVEF] ≥50% but stroke volume index <35 ml/m(2)), low-gradient (mean gradient [MG] <40 mm Hg), a priori severe (aortic valve area [AVA] ≤1.0 cm(2)) aortic stenosis (AS) (PLG-SAS group) with that of patients with a severe AS (AVA ≤1.0 cm(2)) and consistent high-gradient (MG ≥40 mm Hg) (HG-SAS group) and with that of patients with a moderate AS (AVA >1.0 cm(2) and MG <40 mm Hg) (MAS group). BACKGROUND In patients with preserved LVEF, a discordance between the AVA (in the severe range) and the gradient (in the moderate range) raises uncertainty with regard to the actual severity of the stenosis and thus the therapeutic management of the patient. METHODS In a prospective cohort of AS patients with LVEF ≥50%, we identified 187 patients in the PLG-SAS group. These patients were retrospectively matched: 1) according to the gradient, with 187 patients with MAS; and 2) according to the AVA, with 187 patients with HG-SAS. RESULTS Patients with PLG-SAS had reduced overall survival (1-year: 89 ± 2%; 5-year: 64 ± 4%) compared with patients with HG-SAS (1-year: 96 ± 1%; 5-year: 82 ± 3%) or MAS (1-year: 96 ± 1%; 5-year: 81 ± 3%). After adjustment for other risk factors, patients with PLG-SAS had a 1.71-fold increase in overall mortality and a 2.09-fold increase in cardiovascular mortality compared with the 2 other groups. Aortic valve replacement was significantly associated with improved survival in the HG-SAS group (hazard ratio: 0.18; p = 0.001) and in the PLG-SAS group (hazard ratio: 0.50; p = 0.04) but not in the MAS group. CONCLUSIONS Prognosis of patients with paradoxical low-flow, low-gradient severe AS was definitely worse than those with high-gradient severe AS or those with moderate AS. The finding of a low gradient cannot exclude the presence of a severe stenosis in a patient with a small AVA and preserved LVEF and should mandatorily prompt further investigation.

Nonrandomized Comparison of Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention for the Treatment of Unprotected Left Main Coronary Artery Disease in Octogenarians

Background— The objective of the present study was to compare the midterm follow-up results of percutaneous coronary intervention (PCI) and coronary bypass graft surgery (CABG) for the treatment of unprotected left main coronary artery disease in octogenarians. Methods and Results— A total of 249 consecutive patients ≥80 years of age diagnosed with left main coronary artery disease underwent coronary revascularization in our center between January 2002 and January 2008; 145 patients underwent CABG, and 104 patients had PCI. Major adverse cardiac and cerebrovascular events (MACCE [cardiac death, myocardial infarction, cerebrovascular event, revascularization]) were evaluated at a mean follow-up of 23±16 months. Patients who underwent PCI were older; had higher creatinine levels, lower ejection fraction, and higher EuroSCORE; and presented more frequently with an acute coronary syndrome. Drug-eluting stents were used in 48% of PCI patients. A propensity score analysis was performed to adjust for baseline differences between the 2 groups. Survival free of cardiac death or myocardial infarction (PCI, 65.4%; CABG, 69.7%) and MACCE-free survival (PCI, 56.7%; CABG, 64.8%) at follow-up were similar between the groups (adjusted hazard ratio for survival free of cardiac death or myocardial infarction, 1.28; 95% CI, 0.64 to 2.56; P=0.47; adjusted hazard ratio for MACCE-free survival, 1.11; 95% CI, 0.59 to 2.0; P=0.73). The EuroSCORE value was an independent predictor of MACCE regardless of the type of revascularization (hazard ratio, 1.17 for each EuroSCORE increase of 1 point; 95% CI, 1.09 to 1.25; P<0.0001). Conclusions— In this single-center, nonrandomized study, there were no significant differences in cardiac death or myocardial infarction and MACCE between CABG and PCI for the treatment of left main coronary artery disease in octogenarians after a mean follow-up of 2 years. Baseline EuroSCORE was the most important predictor of MACCE regardless of the type of revascularization. Randomized studies comparing both revascularization strategies in this high-risk coronary population are warranted.

Impact of Prosthesis-Patient Mismatch on Long-Term Survival After Aortic Valve Replacement Influence of Age, Obesity, and Left Ventricular Dysfunction

OBJECTIVES This study was designed to evaluate the effect of valve prosthesis-patient mismatch (PPM) on late survival after aortic valve replacement (AVR) and to determine if this effect is modulated by patient age, body mass index (BMI), and pre-operative left ventricular (LV) function. BACKGROUND We recently reported that PPM is an independent predictor of operative mortality after AVR, particularly when associated with LV dysfunction. METHODS The indexed valve effective orifice area (EOA) was estimated in 2,576 patients having survived AVR and was used to define PPM as not clinically significant if it was >0.85 cm(2)/m(2), as moderate if >0.65 and < or =0.85 cm(2)/m(2), and severe if < or =0.65 cm(2)/m(2). RESULTS After adjustment for other risk factors, severe PPM was associated with increased late overall mortality (hazard ratio [HR]: 1.38; p = 0.03) and cardiovascular mortality (HR: 1.63; p = 0.0006) in the whole cohort. Severe PPM was also associated with increased overall mortality in patients <70 years old (HR: 1.77; p = 0.002) and in patients with a BMI <30 kg/m(2) (HR: 2.1; p = 0.006), but had no impact in older patients or in obese patients. Moderate PPM was a predictor of mortality in patients with LV ejection fraction <50% (HR: 1.21; p = 0.01), but not in patients with preserved LV function. CONCLUSIONS Moderate PPM is associated with increased late mortality in patients with LV dysfunction, but with normal prognosis in those with preserved LV function. Notwithstanding the previously demonstrated deleterious effect of severe PPM on early mortality, this factor appears to increase late mortality only in patients <70 years old and/or with a BMI <30 kg/m(2) or an LV ejection fraction <50%.

Restrictive annuloplasty for ischemic mitral regurgitation may induce functional mitral stenosis.

OBJECTIVES The purpose of this study was to evaluate mitral valve hemodynamic performance and functional capacity in patients with ischemic mitral regurgitation (MR) who underwent restrictive mitral valve annuloplasty (MVA). BACKGROUND Restrictive MVA combined with coronary artery bypass graft is the conventional approach for the surgical management of patients with ischemic MR. We hypothesized that the restriction of the mitral annulus could cause an obstruction to antegrade mitral flow that may affect the patients functional capacity. METHODS A dobutamine stress echocardiography (DSE) and a 6-min walk test (6MWT) were performed in 24 patients with ischemic MR 13 +/- 3 months after restrictive MVA and coronary artery bypass graft and in 20 control patients with coronary artery disease matched for age, gender, and left ventricular ejection fraction. RESULTS None of the 24 MVA patients had significant MR after operation. Compared with control patients, MVA patients had significantly (p < 0.001) higher resting and stress peak gradients (rest: 13 +/- 4 mm Hg vs. 4 +/- 1 mm Hg; DSE: 19 +/- 6 mm Hg vs. 6 +/- 3 mm Hg) and systolic pulmonary arterial pressures (PAP) (rest: 42 +/- 13 mm Hg vs. 27 +/- 8 mm Hg; DSE: 58 +/- 12 mm Hg vs. 38 +/- 11 mm Hg) and lower (p = 0.01) 6MWT distance (358 +/- 95 m vs. 433 +/- 61 m). The resting peak mitral gradient correlated with systolic PAP (r = -0.67; p = 0.001) and 6MWT distance (r = -0.78; p < 0.0001) in the MVA group. CONCLUSIONS The results suggest that performing a restrictive MVA in patients with ischemic MR may create a functional mitral stenosis. This hemodynamic sequel is associated with higher PAP and a worse functional capacity.

Calcific Aortic Valve Disease: Not Simply a Degenerative Process A Review and Agenda for Research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group

Calcific aortic valve disease (CAVD) encompasses the range of disease from initial alterations in the cell biology of the leaflets to end-stage calcification resulting in left ventricular outflow obstruction. The first detectable macroscopic changes in the leaflets, seen as calcification, or focal leaflet thickening with normal valve function, is termed aortic valve sclerosis, but it is likely that the initiating events in the disease process occur much earlier. Disease progression is characterized by a process of thickening of the valve leaflets and the formation of calcium nodules – often including the formation of actual bone – and new blood vessels, which are concentrated near the aortic surface. End stage disease, e.g. calcific aortic stenosis, is characterized pathologically by large nodular calcific masses within the aortic cusps that protrude through the outflow surfaces into the sinuses of Valsalva, interfering with opening of the cusps. For decades, this disease was thought to be a passive process in which the valve degenerates with age in association with calcium accumulation. Moreover, although calcific aortic valve disease is more common with age, it is not an inevitable consequence of aging. Instead, CAVD appears to be an actively regulated disease process that cannot be characterized exclusively as “senile” or “degenerative.” The NHLBI convened a group of scientists from different fields of study, including cardiac imaging, molecular biology, cardiovascular pathology, epidemiology, cell biology, endocrinology, bioengineering, and clinical outcomes, to review the scientific studies from the past decade in the field of CAVD. The purpose was to develop a consensus statement on the current state of translational research related to CAVD. Herein, we summarize recent scientific studies and define future directions for research to diagnose, treat and potentially prevent this complex disease process.