Rafal Dworakowski

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

BACKGROUND The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

Involvement of NADPH oxidase in age-associated cardiac remodeling

Increased activation of the renin–angiotensin–aldosterone system (RAAS) and an increase in oxidative stress are both implicated in age-related cardiac remodeling but their precise interrelationship and linkage to underlying molecular and cellular abnormalities remain to be defined. Recent studies indicate that NADPH oxidases are major sources of oxidative stress and are activated by the RAAS. This study investigated the relationship between the NADPH oxidase system, age-related cardiac remodeling and its underlying mechanisms. We studied male Fisher 344 cross Brown Norway rats aged 2 months (young rats), 8 months (young adult rats) or 30 months (old rats). Aging-dependent increases in blood pressure, cardiomyocyte area, coronary artery remodeling and cardiac fibrosis were associated with increased myocardial NADPH oxidase activity attributable to the Nox2 isoform. These changes were accompanied by evidence of local RAAS activation, increased expression of connective tissue growth factor (CTGF) and TGF-β1, and a significant activation of MMP-2 and MT1-MMP. The changes in old rats were replicated in 8 month old rats that were chronically treated with angiotensin II for 28 days. Increased RAAS activation may drive age-related cardiac remodeling through the activation of Nox2 NADPH oxidase and subsequent increases in MMP activation, fibrosis and cardiomyocyte hypertrophy.

Effects of Neuronal Nitric Oxide Synthase on Human Coronary Artery Diameter and Blood Flow In Vivo

Background— Nitric oxide (NO)-mediated local regulation of vascular tone is considered to involve endothelial NO synthase (eNOS). However, we recently reported that human forearm basal microvascular tone in vivo is tonically regulated by neuronal NO synthase (nNOS), in contrast to an acetylcholine-stimulated reduction in tone, which is eNOS dependent. Here, we investigated the in vivo effects of an nNOS-selective inhibitor, S-methyl-l-thiocitrulline (SMTC), on the human coronary circulation and on flow-mediated dilatation in the forearm. Methods and Results— In patients with angiographically normal coronary arteries, intracoronary infusion of SMTC (0.625 &mgr;mol/min) reduced basal coronary blood flow by 34.1±5.2% (n=10; P<0.01) and epicardial coronary diameter by 3.6±1.2% (P=0.02) but had no effect on increases in flow evoked by intracoronary substance P (20 pmol/min). The nonselective NOS inhibitor NG-monomethyl-l-arginine (25 &mgr;mol/min) also reduced basal coronary flow (by 22.3±5.3%; n=8; P<0.01) but, in contrast to SMTC, inhibited substance P-induced increases in flow (P<0.01). In healthy volunteers, local infusion of SMTC (0.2 &mgr;mol/min) reduced radial artery blood flow by 36.0±6.4% (n=10; P=0.03) but did not affect flow-mediated dilatation (P=0.55). In contrast, NG-monomethyl-l-arginine (2 &mgr;mol/min) infusion reduced radial blood flow to a similar degree (by 39.7±11.8%; P=0.02) but also inhibited flow-mediated dilatation by ≈80% (P<0.01). Conclusions— These data indicate that local nNOS-derived NO regulates basal blood flow in the human coronary vascular bed, whereas substance P-stimulated vasodilatation is eNOS mediated. Thus, nNOS and eNOS have distinct local roles in the physiological regulation of human coronary vascular tone in vivo.

Real-Time Three-Dimensional Transesophageal Echocardiography Adds Value to Transcatheter Aortic Valve Implantation

BACKGROUND Successful transcatheter aortic valve implantation (TAVI) mandates comprehensive, accurate multimodality imaging. Echocardiography is involved at all key stages and, with the advent of real-time three-dimensional (3D) transesophageal echocardiography, is uniquely placed to enable periprocedural monitoring. The investigators describe a comprehensive two-dimensional (2D) and 3D echocardiographic protocol, and the additional benefits of 3D TEE, within a high-volume TAVI program. METHODS TAVI was performed with 2D and 3D transesophageal echocardiographic and fluoroscopic guidance in consecutive high-risk patients with symptomatic severe aortic stenosis. The role of TEE, including the additive value of 3D TEE, was examined, and procedural and echocardiographic outcomes were evaluated. A 3D sizing transcatheter heart valve (THV) strategy was used, except as mandated by study protocol. RESULTS Procedural success was achieved in 99% of 256 patients (mean age, 82.9 ± 7.1 years, mean logistic European System for Cardiac Operative Risk Evaluation score, 21.6 ± 11.2%; mean aortic valve area, 0.63 ± 0.19 cm(2)), with no procedural deaths. Acceptable 2D and 3D transesophageal echocardiographic images were achieved in all patients. Aortic valve annular dimensions by 2D transthoracic echocardiography, 2D TEE, and 3D TEE were 21.6 ± 1.9 mm, 22.5 ± 2.2 mm (P < .001), and 23.0 ± 2.0 mm (P = .004 vs 2D TEE), respectively. The 2D THV sizing strategy would have changed THV selection in 23% of patients, downsizing in most. Three-dimensional TEE provided superior spatial visualization and anatomic orientation and optimized procedural performance. Postprocedural mild, moderate, and severe paravalvular aortic regurgitation was observed in 24%, 3%, and 0% of patients, respectively, with no or trace transvalvular aortic regurgitation in 95%. A second valve was successfully deployed in five patients, and TEE detected five other periprocedural complications. CONCLUSIONS A systematic, comprehensive echocardiographic protocol, incorporating the additional benefits of 3D TEE, has a vital role within a TAVI program and, combined with a 3D THV sizing strategy, contributes to excellent outcomes.

Transcatheter aortic valve implantation for severe aortic stenosis—a new paradigm for multidisciplinary intervention: A prospective cohort study

BACKGROUND Transcatheter aortic valve implantation (TAVI) is an alternative treatment option for patients with aortic stenosis deemed high risk or unsuitable for aortic valve replacement. The aim of this study was to assess the feasibility of TAVI in elderly patients, the delivery of this technology with a multidisciplinary approach, and the use of traditional surgical scoring systems. METHODS One hundred fifty-one consecutive patients (mean age 82.6 +/- 7.3 years) with severe aortic stenosis underwent TAVI with the Edwards Lifesciences (Irvine, CA) Sapien bioprosthesis using the transapical (n = 84; 56%) or transfemoral (n = 67; 44%) approach from August 2007 to September 2009 at Kings Health Partners, London, United Kingdom. We analyzed procedural outcome, complications, functional status, and midterm outcome of patients. RESULTS The multidisciplinary team comprised interventional cardiologists, cardiothoracic surgeons, imaging specialists, cardiac anesthetists, and specialist nurses. Seventy percent of patients were in New York Heart Association class III/IV, and logistic EuroSCORE was 21.6 +/- 11.9. Procedural success was achieved in 98%. Postoperative complications included stroke (6%), complete atrioventricular block (5.3%), renal failure requiring hemofiltration (9.3%), and vascular injury (8.6%). Overall 30-day mortality was 9.9% (n = 15). The logistic EuroSCORE was a predictor of short-term mortality (logistic regression model, P < .05). Thirty-day mortality post-TAVI for patients with logistic EuroSCORE <20, 20 to 40, and >40 was 5.4%, 13.2%, and 22.2%, respectively. CONCLUSIONS Transcatheter aortic valve implantation is a feasible treatment option in this patient group with promising short/medium-term results. Renal failure is the commonest short-term complication, and the incidence of vascular complications remains high. Risk prediction/case selection remains challenging, and a multidisciplinary team approach appears to be helpful in appropriate patient selection.

Standalone balloon aortic valvuloplasty: Indications and outcomes from the UK in the transcatheter valve era

We sought to characterize UK‐wide balloon aortic valvuloplasty (BAV) experience in the TAVI era.

Usefulness of periprocedural bleeding to predict outcome after transcatheter aortic valve implantation.

Bleeding is a known predictor of poor outcome after a number of cardiac interventions. We investigated whether using the new bleeding definition of the Valve Academic Research Consortium predicts a poor outcome after transcatheter aortic valve implantation. In addition, we sought to identify those patient characteristics that predict periprocedural bleeding and investigated the effect of blood transfusion. This was a retrospective study of 101 patients undergoing transapical or transfemoral transcatheter aortic valve implantation at Kings College Hospital from August 2007 to November 2010. The association among bleeding, blood transfusion, and in-hospital and 6-month mortality was examined. Of the 101 patients, 5 (4.9%) had life-threatening periprocedural bleeding related to vascular or apical complications, 17 (17%) had major bleeding, and 79 (78%) had minor or no bleeding. The in-hospital mortality rate for the cohort was 9.9% (n = 10) and the 6-month mortality rate was 18.8% (n = 19). Those patients with life-threatening bleeding and those who were transfused had significantly greater in-hospital mortality rates than the patients without life-threatening bleeding or transfusion (60.0% vs 7.3%, p <0.05; and 14.8% vs 4.3%, p <0.05, respectively). Life-threatening bleeding, a decrease in hemoglobin >5 g/dl, and a blood transfusion of >2 U were associated with increased mortality at 6 months. In a logistic regression model, coexisting vascular disease, diabetes, and preprocedural anemia significantly affected the incidence of life-threatening or major bleeding. In conclusion, consistent with many other cardiac interventions, life-threatening periprocedural bleeding after transcatheter aortic valve implantation is associated with poorer outcomes.

Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Derived Superoxide and Vascular Endothelial Dysfunction in Human Heart Failure

OBJECTIVES We investigated the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in endothelial dysfunction in human heart failure. BACKGROUND Vascular endothelial dysfunction in human heart failure contributes to increased tone, exercise limitation, and dysregulation of venous capacitance and vascular volume. The NADPH oxidases (Nox) are an important source of oxidative stress, but their role in the endothelial dysfunction of human heart failure remains unknown. METHODS Endothelium-dependent and -independent vasorelaxation were assessed in saphenous vein segments obtained from consecutive patients with heart failure (n = 19) or normal left ventricular function (control; n = 35) undergoing coronary artery bypass graft. Saphenous vein superoxide production was measured by lucigenin-enhanced chemiluminescence and messenger ribonucleic acid expression of relevant transcripts quantified by real-time polymerase chain reaction. RESULTS Heart failure patients had significantly worse endothelial function than control subjects (15.2 +/- 3% vs. 40.5 +/- 8.4% relative relaxation; p < 0.05), elevated C-reactive protein (CRP) levels (8.6 +/- 2.7 mg/l vs. 2.6 +/- 0.4 mg/l; p < 0.05), over 2-fold higher NADPH-dependent superoxide generation (p < 0.05), and significantly higher expression of the Nox4 isoform and regulatory subunit p67phox. Superoxide levels were positively correlated with New York Heart Association functional class (r = 0.684; p < 0.05) and CRP (r = 0.501; p < 0.005; n = 32). CONCLUSIONS Venous endothelial dysfunction in human heart failure is associated with increased Nox-derived superoxide generation. Inflammatory mechanisms may be involved in the increased reactive oxygen species generation.

Progressive rise in red cell distribution width is associated with poor outcome after transcatheter aortic valve implantation

Objective To investigate the prognostic value of baseline and temporal changes in red cell distribution width (RDW) in patients undergoing transcatheter aortic valve implantation (TAVI). Design Single-centre retrospective observational study. Setting Tertiary cardiac centre. Patients 175 patients undergoing TAVI were included in this study. Main outcome measure Survival. Results We analysed data from 175 TAVI patients (mean (±SD) age 83±7 years, 49% men, mean Logistic EuroSCORE 23±1, 66% preserved left ventricular ejection fraction (LVEF)). Immediately pre-TAVI, mean RDW was 14.6±1.6% with an RDW>15% in 29% of patients. Over median follow-up of 12 months, the median rate of change in RDW was 0.2% per month, and 51 (29%) patients died. On multivariate survival analyses, baseline RDW≥15.5% predicted death (adjusted HR 2.70, 95% CI 1.40 to 5.22, p=0.003) independently of LVEF, transfemoral approach, baseline pulmonary artery systolic pressure, moderate/severe mitral regurgitation and body mass index. A greater rate of increase in RDW over time was associated with increased mortality (adjusted HR 1.11, 95% CI 1.04 to 1.18, p=0.001) independently of baseline RDW and other significant temporal variables including a change in creatinine, bilirubin, mean cell haemoglobin concentration or urea. An increase in RDW>0.1%/month was associated with a twofold increased risk of mortality. Conclusions Baseline RDW≥15.5% and a rising RDW over time strongly correlate to an increased risk of death post-TAVI, and could be used to refine risk stratification. Investigating and ameliorating the causes of RDW expansion may improve survival.

Device-dependent association between paravalvar aortic regurgitation and outcome after TAVI

Objective The aim of the current study was to identify predictors of paraprosthetic aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) and examine its influence on short/medium-term mortality using the UK TAVI Registry. TAVI is an effective treatment for high-risk patients with severe symptomatic aortic stenosis (AS), but paraprosthetic AR has been associated with increased in-hospital and mid-term mortality. Methods Between January 2007 and December 2011, 2584 TAVI procedures were performed in the UK. Patients undergoing ‘valve-in-valve’ procedures, patients with aortic regurgitation as the primary pathology and with no recorded severity of AR were excluded from this analysis (n=144). In total, therefore, 2440 patients were included. Balloon-expandable and self-expanding devices were implanted in 52.7 and 47.2%, respectively, using either transfemoral (67.7%) or non-transfemoral, surgical access (32.3%). Results Postprocedural AR was observed in 68%, mild AR in 57% and moderate-severe in 10%. A large aortic annulus, high preprocedural transaortic gradient, and use of self-expanding valve were independent predictors of moderate-severe AR. Moderate-severe (but not mild) AR was associated with increased mortality, and this relationship appeared significant for the balloon-expandable but not the self-expanding device. Conclusions Our data suggest that a large aortic annulus, high preprocedural transaortic gradient, and use of the self-expanding valve predict moderate-severe AR after TAVI. Such a degree of AR is associated with a significantly worse outcome with the balloon-expandable, but not with the self-expanding valve. Further studies are needed to verify this and explore potential mechanisms.