Jonathan Byrne

Contrasting Roles of NADPH Oxidase Isoforms in Pressure-Overload Versus Angiotensin II–Induced Cardiac Hypertrophy

Increased production of reactive oxygen species (ROS) is implicated in the development of left ventricular hypertrophy (LVH). Phagocyte-type NADPH oxidases are major cardiovascular sources of ROS, and recent data indicate a pivotal role of a gp91phox-containing NADPH oxidase in angiotensin II (Ang II)–induced LVH. We investigated the role of this oxidase in pressure-overload LVH. gp91phox−/− mice and matched controls underwent chronic Ang II infusion or aortic constriction. Ang II–induced increases in NADPH oxidase activity, atrial natriuretic factor (ANF) expression, and cardiac mass were inhibited in gp91phox−/− mice, whereas aortic constriction-induced increases in cardiac mass and ANF expression were not inhibited. However, aortic constriction increased cardiac NADPH oxidase activity in both gp91phox−/− and wild-type mice. Myocardial expression of an alternative gp91phox isoform, Nox4, was upregulated after aortic constriction in gp91phox−/− mice. The antioxidant, N-acetyl-cysteine, inhibited pressure-overload–induced LVH in both gp91phox−/− and wild-type mice. These data suggest a differential response of the cardiac Nox isoforms, gp91phox and Nox4, to Ang II versus pressure overload.

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.

Cardiac troponin T and I and creatine kinase-MB as markers of myocardial injury and predictors of outcome following percutaneous coronary intervention

AIMS This study was performed to determine the most sensitive biochemical marker for the detection of cardiac myocyte damage potentially sustained during percutaneous coronary intervention (PCI) and to assess whether such a marker can be used to identify patients at increased risk of poor subsequent clinical outcome. METHODS AND RESULTS We studied 109 consecutive patients presenting with clinical stable and unstable angina and undergoing PCI at our institution. Blood was sampled for creatine kinase-MB (CK-MB), cardiac Troponin T (cTnT) and I (cTnI) immediately before and at 6, 14 and 24 h post-PCI. Five patients with raised cardiac markers pre-PCI were excluded from further analysis. The occurrence of major adverse cardiac events (MACE) was documented in-hospital, at 30 days and at long-term clinical follow up of up to 20 months. MACE occurred in 26/109 (24%) patients: death=1, QWMI=4, NQWMI=5, repeat PCI=16 (nine target vessel revascularisations and seven de-novo lesions), CABG=5. cTnI had the highest detection rate for myocardial damage, with 58 cTnI-positive patients, 38 cTnT-positive patients and 28 CK-MB-positive patients in the 24 h following PCI (Pearsons Chi square test, P<0.01). The type of interventional strategy per se was not significantly associated with post-procedural cardiac marker concentrations (Kruskal-Wallis ANOVA, P>0.05). There was a significant association between post-procedural cardiac marker concentrations of CK-MB, cTnT and cTnI and the occurrence of procedural angiographic complications (P=0.0003, 0.0002, 0.001, respectively). All three markers, at each sampling time point between 6 and 24 h post-PCI, showed a significant predictive relationship with MACE in-hospital and at long-term follow up (ROC curve AUC analysis, P<0.05). All three markers provided equally predictive information at each of the three post-procedural sampling time points between 6 and 24 h following PCI. All levels of cardiac marker elevation above the clinically discriminant cut-off values were significantly predictive of outcome at long-term follow up. CONCLUSIONS cTnI proved to be the most sensitive marker in detecting myocardial necrosis following PCI. CK-MB, cTnT and cTnI all provided similarly reliable prognostic information, with cTnT and cTnI being marginally superior in predicting MACE at follow up.

Chronic kidney injury in patients after cardiac catheterisation or percutaneous coronary intervention: a comparison of radial and femoral approaches (from the British Columbia Cardiac and Renal Registries)

Background Acute kidney injury (AKI) is a well-recognised complication of cardiac catheterisation and percutaneous coronary intervention (PCI). However, the incidence of chronic kidney disease (CKD) after catheterisation and PCI has not been fully evaluated. A number of risk factors have been implicated in the development of AKI following cardiac catheterisation. Transradial access could lead to a lower incidence of CKD after catheterisation or PCI because of less catheter contact with aortic atheroma, and reduced potential for atheroembolism. Objective To determine the incidence of CKD onset and its association with arterial access in patients after cardiac catheterisation or PCI. Methods and results Linkages between the British Columbia (BC) Cardiac Registry (N=69 214) patients who underwent catheterisation or PCI between 1999 and 2005 and the BC Renal Database were determined. Within 6 months after the cardiac procedure 0.4% of patients developed dialysis dependency, 0.2% in the transradial versus 0.4% in the transfemoral group (p<0.0001); 0.3% of patients developed stage 4 or 5 CKD, 0.1% in the transradial versus 0.4% in the transfemoral group (p<0.0001); 0.9% of patients developed new CKD, 0.2% in the transradial versus 1.2% in the transfemoral group (p<0.0001). After adjusting for baseline characteristics the femoral access site had an OR of 4.36 (95% CI 2.48 to 7.66) for the development of the composite end point of new dialysis, new stage 4 or 5 CKD or new CKD. Conclusions In this large database of current practice coronary catheterisation and PCI, the incidence of CKD onset within 6 months of the procedure was 0.9%. The transradial access site is associated with less CKD than the femoral approach.

Body Mass Index, Periprocedural Bleeding, and Outcome Following Percutaneous Coronary Intervention (from the British Columbia Cardiac Registry)

The incidence of obesity is increasing throughout the industrialized world and is a major public health concern. Some studies have shown a paradoxical protective effect of moderate obesity on outcome after percutaneous coronary intervention (PCI). The association between bleeding, body mass, and outcome is not well established and formed the basis for the present study, which examined major bleeding rates and mortality after PCI in British Columbia during a 6-year period. We identified 38,346 consecutive patients from the British Columbia Cardiac Registry who underwent PCI from 1999 to 2005. Data were cross-referenced to determine outcomes at 30 days and 1 year. Information about bleeding after PCI was obtained by cross-referencing the British Columbia Cardiac Registry with the Central Transfusion Registry. Baseline patient characteristics were compared among body mass index (BMI) categories. A clear bimodal (U-shaped) relation was seen between BMI and mortality. BMI was a potent independent predictor of mortality, particularly evident in the underweight (BMI <18.5 kg/m(2); odds ratio [OR] 1.98, 95% confidence interval [CI] 1.6 to 2.5, p <0.0001) and morbidly obese (> or =40 kg/m(2); OR 1.61, 95% CI 1.28 to 2.08, p <0.0001) groups. Periprocedural transfusion was also associated with adverse outcome (OR 2.86, 95% CI 2.52 to 3.25, p <0.0001). Transfusion adopted the same bimodal distribution across the entire cohort. Emergent PCI and femoral access were procedural factors associated with outcome. In conclusion, major bleeding conferred an adverse long-term prognosis after PCI. Identifying demographic and procedural factors that increase risk will facilitate more accurate risk scoring of patients undergoing PCI and allow targeted bleeding-avoidance strategies. Body mass and female gender identified subgroups at much higher risk of bleeding after PCI, an observation that merits further study.

Percutaneous Closure of Postinfarction Ventricular Septal Defect In-Hospital Outcomes and Long-Term Follow-Up of UK Experience

Background— Postinfarction ventricular septal defect carries a grim prognosis. Surgical repair offers reasonable outcomes in patients who survive a healing phase. Percutaneous device implantation represents a potentially attractive early alternative. Methods and Results— Postinfarction ventricular septal defect closure was attempted in 53 patients from 11 centers (1997–2012; aged 72±11 years; 42% female). Nineteen percent had previous surgical closure. Myocardial infarction was anterior (66%) or inferior (34%). Time from myocardial infarction to closure procedure was 13 (first and third quartiles, 5–54) days. Devices were successfully implanted in 89% of patients. Major immediate complications included procedural death (3.8%) and emergency cardiac surgery (7.5%). Immediate shunt reduction was graded as complete (23%), partial (62%), or none (15%). Median length of stay after the procedure was 5.0 (2.0–9.0) days. Fifty-eight percent survived to discharge and were followed up for 395 (63–1522) days, during which time 4 additional patients died (7.5%). Factors associated with death after postinfarction ventricular septal defect closure included the following: age (hazard ratio [HR]=1.04; P=0.039), female sex (HR=2.33; P=0.043), New York Heart Association class IV (HR=4.42; P=0.002), cardiogenic shock (HR=3.75; P=0.003), creatinine (HR=1.007; P=0.003), defect size (HR=1.09; P=0.026), inotropes (HR=4.18; P=0.005), and absence of revascularization therapy for presenting myocardial infarction (HR=3.28; P=0.009). Prior surgical closure (HR=0.12; P=0.040) and immediate shunt reduction (HR=0.49; P=0.037) were associated with survival. Conclusions— Percutaneous closure of postinfarction ventricular septal defect is a reasonably effective treatment for these extremely high-risk patients. Mortality remains high, but patients who survive to discharge do well in the longer term.Background— Postinfarction ventricular septal defect carries a grim prognosis. Surgical repair offers reasonable outcomes in patients who survive a healing phase. Percutaneous device implantation represents a potentially attractive early alternative. Methods and Results— Postinfarction ventricular septal defect closure was attempted in 53 patients from 11 centers (1997–2012; aged 72±11 years; 42% female). Nineteen percent had previous surgical closure. Myocardial infarction was anterior (66%) or inferior (34%). Time from myocardial infarction to closure procedure was 13 (first and third quartiles, 5–54) days. Devices were successfully implanted in 89% of patients. Major immediate complications included procedural death (3.8%) and emergency cardiac surgery (7.5%). Immediate shunt reduction was graded as complete (23%), partial (62%), or none (15%). Median length of stay after the procedure was 5.0 (2.0–9.0) days. Fifty-eight percent survived to discharge and were followed up for 395 (63–1522) days, during which time 4 additional patients died (7.5%). Factors associated with death after postinfarction ventricular septal defect closure included the following: age (hazard ratio [HR]=1.04; P =0.039), female sex (HR=2.33; P =0.043), New York Heart Association class IV (HR=4.42; P =0.002), cardiogenic shock (HR=3.75; P =0.003), creatinine (HR=1.007; P =0.003), defect size (HR=1.09; P =0.026), inotropes (HR=4.18; P =0.005), and absence of revascularization therapy for presenting myocardial infarction (HR=3.28; P =0.009). Prior surgical closure (HR=0.12; P =0.040) and immediate shunt reduction (HR=0.49; P =0.037) were associated with survival. Conclusions— Percutaneous closure of postinfarction ventricular septal defect is a reasonably effective treatment for these extremely high-risk patients. Mortality remains high, but patients who survive to discharge do well in the longer term. # CLINICAL PERSPECTIVE {#article-title-23}

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.

Rare access site complications following transradial coronary intervention

Transradial access for coronary procedures dramatically reduces access site complications. A meta-analysis (1) found major access complications in 0.3% of cases that used the radial approach compared with 2.8% of cases that used the femoral approach (P<0.0001). A 59-year-old man developed a painless, pulsatile mass three weeks after transradial coronary intervention. There was no compromise to the hand and the Allen’s test was normal. An ultrasound scan (Figure 1) revealed a radial artery pseudoaneurysm containing some thrombus. Colour Doppler imaging (Figure 2) showed laminar flow entering and exiting the pseudoaneurysm. Prolonged compression failed to obliterate the pseudoaneurysm and the entrance was considered too wide for safe thrombin injection. The pseudoaneurysm was resected surgically and the patient remains asymptomatic. Figure 1 Figure 2 A 61-year-old man presented with an enlarging, painless pulsatile swelling with a thrill one year after transradial coronary intervention. There was no compromise to the hand and the Allen’s test was normal. An ultrasound (Figure 3) with colour Doppler imaging demonstrated an arteriovenous (AV) fistula with turbulent high-velocity flow at the site of communication. The patient was referred for surgical management of the AV fistula. An AV fistula is even less common than a radial pseudoaneurysm because only small veins are present in the vicinity of the radial artery. Figure 3

Analysis of ex vivo left ventricular pressure–volume relations in the isolated murine ejecting heart

The development of microconductance technology to study cardiac pressure–volume relations in mice in vivo has significantly advanced the haemodynamic assessment of gene‐modified models of cardiovascular disease. In this study, we describe the application of microconductance analysis of cardiac function to the isolated murine ejecting heart. This ex vivo model is complementary to the previously described in vivo preparation, allows assessment without confounding effects of anaesthetic or neurohumoral influences and enables careful control of cardiac loading (particularly preload). Ex vivo pressure–volume relations in the isolated murine heart are sensitive to changes in myocardial contractility induced by β‐adrenoceptor stimulation or β‐adrenoceptor blockade, as well as the effects of chronic pressure overload induced by aortic banding. We present data for both steady‐state analyses of the Frank–Starling relation and for assessment of the left ventricular pressure–volume relation over variably loaded beats, which allows investigation of the end‐systolic and end‐diastolic pressure–volume relations. The measurement of ventricular volume in addition to pressure under carefully controlled loading conditions in the isolated ejecting heart allows a comprehensive analysis of cardiac contractile function, and provides a useful complementary model for the assessment of cardiac performance in murine models of heart disease.

Fractional Flow Reserve in the Transradial Era: Will Hand Vein Adenosine Infusion Suffice?: A Comparative Study of the Extent, Rapidity, and Stability of Hyperemia From Hand and Femoral Venous Routes of Adenosine Administration

OBJECTIVES The aim of this study was to assess adenosine infusion via a cannula in the back of the hand compared with central venous access to achieve peak hyperemia during fractional flow reserve (FFR). BACKGROUND Adenosine is often used to induce maximal hyperemia when measuring FFR. The gold standard is continuous infusion via a large central vein; however, the increasing use of the transradial route for angiography makes it desirable to have an alternative route for adenosine. Peripheral venous access is frequently obtained in the hand, but concern exists as to whether adenosine delivery from this site can achieve adequate vasodilation for accurate FFR measurement. Our aim was to address this. METHODS Subjects were selected from patients presenting for coronary angiography/intervention who required a pressure-wire study. Subjects received intravenous adenosine infusion sequentially via 2 routes: first, via a 20-gauge hand cannula, and then, after a washout period, via a 5- or 6-F femoral venous sheath. Adenosine was administered at 140 μg/kg/min from each site. Data interpretation was blinded. Minimal FFR achieved with intravenous adenosine from each infusion site was recorded as was the time to peak hyperemia. RESULTS Paired (hand and femoral adenosine) recordings taken from 84 vessels in 61 patients were suitable for blinded analysis. The mean FFR measured using adenosine administered via hand and femoral routes was 0.85 with an SD of 0.08 (intraclass correlation=0.986). Time to peak hyperemia was longer on average with hand-administered adenosine compared with femoral adenosine administration (63 s vs. 43 s; mean difference, 22 s with a 95% confidence interval: 18 s to 27 s; p<0.0001). Formal comparison of FFR stability using Mann-Whitney analysis (2 tailed) gives p=0.43, indicating no significant evidence of a difference in stability between the 2 routes. CONCLUSIONS Hand vein adenosine infusion produced FFR values very similar to those obtained using central femoral vein adenosine administration, with no systematic bias toward higher or lower reading from 1 site. This has important practical implications for radial access cases involving pressure-wire studies.