Outcomes in patients with aortic stenosis and severely reduced ejection fraction following surgical aortic valve replacement and transcatheter aortic valve replacement.

BACKGROUND: Patients with severe aortic stenosis (AS) and left ventricular (LV) dysfunction demonstrate improvement in left ventricular injection fraction (LVEF) after aortic valve replacement (AVR). The timing and magnitude of recovery in patients with very low LVEF (≤ 25%) in surgical or transcatheter AVR is not well studied. OBJECTIVE: Determine clinical outcomes following transcatheter aortic valve replacement (TAVR) and surgical aortic valve repair (SAVR) in the subset of patients with severely reduced EF ≤ 25%. METHODS: Single-center, retrospective study with primary endpoint of LVEF 1-week following either procedure. Secondary outcomes included 30-day mortality and delayed postprocedural LVEF. T-test was used to compare variables and linear regression was used to adjust differences among baseline variables. RESULTS: 83 patients were enrolled (TAVR = 56 and SAVR = 27). TAVR patients were older at the time of procedure (TAVR 77.29 ± 8.69 vs. SAVR 65.41 ± 10.05, p < 0.001). One week post procedure, all patients had improved LVEF after both procedures (p < 0.001). There was no significant difference in LVEF between either group (TAVR 33.5 ± 11.77 vs. SAVR 35.3 ± 13.57, p = 0.60). Average LVEF continued to rise and increased by 101% at final follow-up (41.26 ± 13.70). 30-day mortality rates in SAVR and TAVR were similar (7.4% vs. 7.1%, p = 0.91). CONCLUSION: Patients with severe AS and LVEF ≤ 25% have a significant recovery in post-procedural EF following AVR regardless of method. LVEF doubled at two years post-procedure. There was no significant difference in 30-day mortality or mean EF recovery between TAVR and SAVR. TRIAL REGISTRATION: Indiana University institutional review board granted approval for above study numbered 15,322.

Heparin Dosing During Percutaneous Coronary Intervention and Obesity.

ABSTRACT: Unfractionated heparin is the most common anticoagulant used during percutaneous coronary intervention. Practice guidelines recommend an initial weight-based heparin bolus dose between 70 and 100 U/kg to achieve target activated clotting time (ACT) of 250-300 seconds. The impact of severe obesity on weight-based heparin dosing is not well studied. We performed a retrospective analysis of 424 patients undergoing percutaneous coronary intervention who received heparin for anticoagulation. We collected detailed data on cumulative heparin administration and measured ACT values in this cohort. We performed separate analyses to identify clinical predictors that may affect dose-response curves. There was significant variability in dosing with mean dose of 103.9 ± 32-U/kg heparin administered to achieve target ACT ≥ 250 seconds. Women received higher initial heparin doses when adjusted for weight than men (97.6 ± 31 vs. 89 ± 28 U/kg, P = 0.004), and only 49% of patients achieved ACT ≥ 250 s with the initial recommended heparin bolus dose (70-100 U/kg). Lower heparin dose (U/kg) was required in obese patients to achieve target ACT. In multivariate linear regression analysis with ACT as dependent variable, after inclusion of weight-based dosing for heparin, body mass index was the only significant covariate. In conclusion, there is significant variability in the therapeutic effect of heparin, with a lower weight-adjusted heparin dose required in obese patients.

Two-in-one aortic valve sizing and valvuloplasty conductance balloon catheter.

BACKGROUND: Inaccurate aortic valve sizing and selection is linked to paravalvular leakage in transcatheter aortic valve replacement (TAVR). Here, a novel sizing valvuloplasty conductance balloon (SVCB) catheter is shown to be accurate, reproducible, unbiased, and provides real-time tool for aortic valve sizing that fits within the standard valvuloplasty procedure. METHODS AND RESULTS: The SVCB catheter is a valvuloplasty device that uses real-time electrical conductance measurements based on Ohm's Law to size the balloon opposed against the aortic valve at any given inflation pressure. Accuracy and repeatability of the SVCB catheter was performed on the bench in phantoms of known dimension and ex vivo in three domestic swine aortic annuli with comparison to computed tomography (CT) and dilator measurements. Procedural workflow and safety was demonstrated in vivo in three additional domestic swine. SVCB catheter measurements had negligible bias or error for bench accuracy considered as the gold standard (Bias: -0.11 ± 0.26 mm; Error: 1.2%), but greater disagreement in ex vivo versus dilators (Bias: -0.3 ± 1.1 mm; Error: 4.5%), and ex vivo versus CT (Bias: -1.0 ± 1.6 mm; Error: 8.7%). The dilator versus CT accuracy showed similar agreement (Bias: -0.9 ± 1.5 mm; Error: 7.3%). Repeatability was excellent on the bench (Bias: 0.02 ± 0.12 mm; Error: 0.5%) and ex vivo (Bias: -0.4 ± 0.9 mm; Error: 4.6%). In animal studies, the device fit well within the procedural workflow with no adverse events or complications. CONCLUSIONS: Due to the clinical relevance of this accurate, repeatable, unbiased, and real-time sizing measurement, the SVCB catheter may provide a useful tool prior to TAVR. These findings merit a future human study.

Conductance sizing balloon for measurement of peripheral artery minimal stent area.

BACKGROUND: Because stent underdeployment occurs frequently, accurate minimal stent area (MSA) measurement during postdilatation is necessary. This study investigated the accuracy and repeatability for MSA determination using a novel conductance balloon (CB) catheter for peripheral vessels. METHODS: The CB catheter is a standard balloon catheter that measures electrical conductance (ratio of current/voltage drop) in real-time during inflation, which directly relates to the balloon cross-sectional area through Ohm's law. CB measurements were made in 4- to 10-mm phantoms on the bench, ex vivo in stents fully deployed in diseased human peripheral arteries, and in vivo in stents fully deployed in peripheral vessels in six swine. CB measurement accuracy and repeatability were calculated and compared with the known dimension (bench phantoms) or with intravascular ultrasound (IVUS) measurement after stent deployment (ex vivo and in vivo). RESULTS: CB measurements were highly accurate (error: 1.8% bench, 5% ex vivo, and 5% in vivo) and repeatable (error: 0.9% bench, 1.8% ex vivo, and 1.3% in vivo), with virtually no bias (average difference in measurements: -0.05 mm bench CB vs known phantom diameters, -0.06 mm ex vivo CB vs IVUS, and -0.11 mm in vivo CB vs IVUS). CONCLUSIONS: The CB sizing capability can be integrated within a standard balloon catheter (two-in-one function) to provide accurate, real-time assessment of MSA to ensure full stent apposition rather than the use of pressure as a surrogate for size.

Mis-sizing of stent promotes intimal hyperplasia: impact of endothelial shear and intramural stress.

Stent can cause flow disturbances on the endothelium and compliance mismatch and increased stress on the vessel wall. These effects can cause low wall shear stress (WSS), high wall shear stress gradient (WSSG), oscillatory shear index (OSI), and circumferential wall stress (CWS), which may promote neointimal hyperplasia (IH). The hypothesis is that stent-induced abnormal fluid and solid mechanics contribute to IH. To vary the range of WSS, WSSG, OSI, and CWS, we intentionally mismatched the size of stents to that of the vessel lumen. Stents were implanted in coronary arteries of 10 swine. Intravascular ultrasound (IVUS) was used to size the coronary arteries and stents. After 4 wk of stent implantation, IVUS was performed again to determine the extent of IH. In conjunction, computational models of actual stents, the artery, and non-Newtonian blood were created in a computer simulation to yield the distribution of WSS, WSSG, OSI, and CWS in the stented vessel wall. An inverse relation (R(2) = 0.59, P < 0.005) between WSS and IH was found based on a linear regression analysis. Linear relations between WSSG, OSI, and IH were observed (R(2) = 0.48 and 0.50, respectively, P < 0.005). A linear relation (R(2) = 0.58, P < 0.005) between CWS and IH was also found. More statistically significant linear relations between the ratio of CWS to WSS (CWS/WSS), the products CWS × WSSG and CWS × OSI, and IH were observed (R(2) = 0.67, 0.54, and 0.56, respectively, P < 0.005), suggesting that both fluid and solid mechanics influence the extent of IH. Stents create endothelial flow disturbances and intramural wall stress concentrations, which correlate with the extent of IH formation, and these effects were exaggerated with mismatch of stent/vessel size. These findings reveal the importance of reliable vessel and stent sizing to improve the mechanics on the vessel wall and minimize IH.

Selective autoretroperfusion preserves myocardial function during coronary artery ligation in swine.

BACKGROUND: External pumps have been previously used to minimize edema and hemorrhage caused by coronary retroperfusion. The objective of this study was to use a pump-less approach (selective autoretroperfusion, SARP) to preserve myocardial function after acute coronary artery ligation. METHODS: In five experimental pigs, the LAD artery was ligated distal to the first diagonal and retroperfusion was instituted for three hours from a brachiocephalic artery at 50 mmHg pressure through an adjustable occluder on the cannula. In eight control pigs, the LAD artery was ligated distal to the second diagonal for the same duration with no SARP. RESULTS: ECG showed more prominent S-T segment elevation in the untreated control group despite the more distal ligation. The degree of myocardial contraction was significantly attenuated in the control group but was largely preserved in the SARP treated group. The myocytes were well preserved in the SARP group with no rupture of venous microvessels. Myocyte edema and disruption was observed in the control group with only mild extracellular edema in the SARP treated group. CONCLUSION: SARP preserved myocardial function with no damage to the myocyte and venules during three hours of acute LAD ligation.

A novel system for the reconstruction of a coronary artery lumen profile in real time: a preclinical validation.

Accurate sizing of vessel diameter is important for understanding the physiology of blood vessels as well as the treatment of coronary and peripheral artery disease. The objective of this study was to validate a novel catheter-based system [the LumenRECON (LR) system] for the real-time reconstruction of lumen cross-sectional area (CSA) along the length of a vessel segment. A total of 22 swine (20 Yorkshire and 2 atherosclerotic Ossabaw swine) were used to evaluate the accuracy, reproducibility, and safety of the system compared with intravascular ultrasound (IVUS). The CSA of the right coronary artery, left anterior descending coronary artery, and left circumflex artery were determined by IVUS and the LR system over a 3- to 4-cm segment in 12 Yorkshire and 2 atherosclerotic Ossabaw swine and 2 postmortem atherosclerotic human hearts. In eight chronic animals, the effect of the LR catheter on the vessel wall was evaluated at 1 day and 2 wk (4 animals each) after the intervention. A Bland-Altman plot of the LR and IVUS data showed a mean difference between the two measurements of 0.055 mm in diameter, which was not statistically significant from zero, indicating a lack of bias in the comparison of the LR system with IVUS. The root mean square error of the two measurements was 10.2% of the mean IVUS diameter. The repeatability of the LR system was assessed using duplicate measurements. The mean of the difference between the two measurements was nearly zero, and the repeatability coefficient was within 4.5% of the mean of the two measurements. No injury or intimal hyperplasia was found acutely or chronically after the use of the LR system. This study establishes the accuracy, reproducibility, and safety of a nonimaging 2.7-Fr catheter for lumen sizing of coronary arteries. The system provides a continuous quantitative axial profile of the mean vessel lumen in real time and may have significant utility in vascular research and clinically in the catheterization laboratory.

Effects of stent sizing on endothelial and vessel wall stress: potential mechanisms for in-stent restenosis.

Stent sizing and apposition have been shown to be important determinants of clinical outcome. This study evaluates the mechanical effects of undersizing and oversizing of stents on endothelial wall shear stress (WSS) and vessel wall stress to determine a possible biomechanical mechanism of in-stent restenosis and thrombosis. Three-dimensional computational models of stents, artery, and internal fluid were created in a computer-assisted design package, meshed, and solved in finite element and computational fluid dynamic packages. The simulation results show that the effects of various degrees of undersizing on WSS, WSS gradient, and oscillatory shear index were highly nonlinear. As the degree of undersizing increased, the heterogeneity of WSS became smaller. The WSS distribution for the 20% undersizing was smooth and uniform, whereas the 5% case was very heterogeneous. The combination of lower WSS and higher WSS gradient and oscillatory shear index in the 5% undersized case may induce neointimal hyperplasia or thrombosis. Additionally, the oversizing simulation results show that the maximum intramural wall stress of the 20% oversizing case is significantly larger than the maximum stress for the 10% and zero oversizing cases. Edge stress concentration was observed, consistent with the restenosis typically observed in this region. This study demonstrates that proper sizing of stent is important for reducing the hemodynamic and mechanical disturbances to the vessel wall. Furthermore, the present findings may be used to improve stent design to reduce endothelial flow disturbances and intramural wall stress concentrations.

Percutaneous valve replacement: a paradigm shift.

PURPOSE OF REVIEW: Valvular heart disease is often associated with significant morbidity and mortality. Surgical treatment of stenotic or regurgitant valvular lesions can alter the natural history of the disease process, yielding excellent short and long-term results, meaning that this has been accepted as the gold standard for therapy of valvular disease. Surgical procedures can be associated with a significant rate of perioperative complications, however. These procedures are particularly associated with unacceptably high short and long-term morbidity and mortality in the elderly - a population group that has grown steadily over the years. Elderly patients often have significant comorbidities that preclude a safe and durable surgical correction of the valvular lesions in up to 31% of these high-risk cases. This review provides an overview of recent developments in percutaneous valve therapeutics. RECENT FINDINGS: Over the last decade, numerous technical developments in valvular interventions have focused on percutaneous valve replacement. There are percutaneous valve replacements on the horizon that promise to offer a novel approach to correct valvular lesions, especially in this high-risk surgical population. SUMMARY: Several devices are presently being evaluated in feasibility trials, and many new ones are being developed. Results with semilunar valves have generally been better than the atrioventricular valves. Long-term results of these treatment modalities are still unknown.

Modulation of atherosclerosis, blood pressure and arterial elasticity by statins.

It is well known that dyslipidemia and hypertension frequently coexist. There is increasing recognition of a mutually facilitative interaction between dyslipidemia and renin- angiotensin system (RAS) activation in the development of atherosclerosis. Both of these systems share many of the same properties in terms of activation of pro-inflammatory, pro-oxidant and pro-atherosclerosis pathways. Statins in particular have been shown to influence the biology of endothelial cells, vascular smooth muscle cells and constituents of the interstitial matrix, particularly fibroblasts. It is no wonder that concurrent therapy of dyslipidemia with statins enhances the effects of RAS inhibitors. Although the effects of statins on the regulation of determinants of vascular stiffness are not well defined, it is quite likely that these regulatory pathways will be influenced by dyslipidemia therapy, especially statins.

Single coronary artery with prepulmonic coursing left main coronary artery manifesting as prinzmetal's angina.

We report the case of a 32-year-old man who presented at the emergency department with severe chest pressure, left arm pain, and dizziness. These symptoms were described as intermittent, occurring after exercise and at rest. He had undergone several stress tests during the past 8 years, but no objective evidence of ischemia was produced. His history of hyperlipidemia and increasing frequency of symptoms prompted us to perform coronary angiography, which showed a single coronary artery with an ostium at the right sinus of Valsalva. The vessel had an initial, mixed common trunk that gave rise to both the right coronary artery proper and to the left coronary artery. The left main trunk followed a prepulmonic course. The anatomic features were eventually confirmed by computed tomographic angiography. The left main stem had a fixed 50% to 60% area narrowing, at baseline study. A treadmill stress myocardial perfusion study showed no evidence of ischemia. The patient was referred to a 2nd facility, where intravascular ultrasonography, at baseline, revealed 63% left main narrowing without evidence of atherosclerosis. Acetylcholine provocation demonstrated worsening of the stenosis to about 80%, with reproduction of angina and ST-segment depression, which indicated that medical management of spasm might provide symptomatic relief.

The role of statins in endothelial dysfunction in hypertension.

PURPOSE OF REVIEW: Hypertension and dyslipidemia frequently coexist, and endothelial dysfunction is associated with the pathophysiology of both atherosclerosis and hypertension. Evidence is convincing for an overlapping role of oxidative stress, renin-angiotensin system activation, and dyslipidemia in the genesis of endothelial dysfunction. RECENT FINDINGS: Ample experimental and human data suggest that common cellular pathways are involved in the pathogenesis of hypertension, increased vascular resistance, and plaque formation. Multiple interventions such as dietary modification, exercise, antioxidants, and antihypertensive drugs improve endothelial dysfunction in hypertension. Statin drugs are a cornerstone of dyslipidemia therapy. Studies have demonstrated that statins correct endothelial function and vascular stiffening and may be useful in reducing blood pressure to target levels. SUMMARY: Statins may be a useful adjunct in the treatment of hypertension in patients with dyslipidemia and possibly those with normal cholesterol levels.

Suppression of atherogenesis by delivery of TGFbeta1ACT using adeno-associated virus type 2 in LDLR knockout mice.

TGFbeta(1) deficiency has been attributed to the development of atherosclerosis. There is, however, little direct evidence for this concept. To examine this hypothesis, low-density lipoprotein receptor knockout (LDLR(-/-)) mice were injected via tail vein with recombinant adeno-associated virus type 2 (rAAV) carrying a bioactive TGFbeta(1) mutant (AAV/TGFbeta1ACT, n=10) or granulocyte-macrophage-colony stimulating factor (AAV/GM-CSF, n=10, a negative control) or saline (n=9, control), and then put on a high cholesterol diet. At 18 weeks, blood lipids were found to be similarly elevated in all LDLR(-/-) mice. TGFbeta1ACT and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given TGFbeta1ACT or AAV/GM-CSF, respectively, showing sustained transfection following gene delivery by the systemic route. Saline-treated and AAV/GM-CSF-treated LDLR(-/-) mice showed extensive areas of atherosclerotic lesion formation. There was evidence of intense oxidative stress (nitrotyrosine staining), inflammation (CD68 staining), and expression of adhesion molecules and the ox-LDL receptor LOX-1 (gene array analysis) in the atherosclerotic tissues. Importantly, atherosclerotic lesion formation was markedly inhibited in the LDLR(-/-) mice given AAV/TGFbeta1ACT. Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given AAV/TGFbeta1ACT (P<0.05 vs. saline-treated or GM-CSF-treated LDLR(-/-) mice). These data for the first time demonstrate that systemic delivery of TGFbeta1ACT gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGFbeta(1) in atherogenesis and a potential new gene therapy for treatment of atherosclerosis.

Oxidative stress in diabetes: a mechanistic overview of its effects on atherogenesis and myocardial dysfunction.

Diabetes is a major risk factor for atherosclerosis. Atherogenesis involves endothelial dysfunction, activation and injury, inflammation, and smooth muscle cell migration and proliferation. Platelet activation in the narrowed arteries is the most proximate event in the culmination of an acute event such as acute myocardial infraction and stroke. Hyperglycemia is associated with all these adverse events in the process of genesis of atherosclerosis. The effect of diabetes (hyperglycemia) is mediated in large part by the state of enhanced oxidative stress, which is not counter-balanced by endogenous antioxidants. This paper reviews the ignition of oxidative stress in diabetes and the mediation of events leading to atherogenesis.

The effects of PPAR-gamma ligand pioglitazone on platelet aggregation and arterial thrombus formation.

BACKGROUND: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-gamma ligands reduce the development of atherosclerosis and myocardial ischemia-reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-gamma activation would inhibit platelet activation and intra-arterial thrombus formation. METHODS AND RESULTS: Sprague-Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl(3) was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% (P<0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP- as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding (P<0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day). CONCLUSION: These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.

Does carotid intima media thickness indicate coronary atherosclerosis?

Increased carotid intima media thickness (IMT) is relatively simple, inexpensive, and reproducible noninvasive marker of global atherosclerotic disease. It is a frequently used experimental tool in epidemiologic studies to identify and follow cardiovascular disease. There is evidence that early detection of atherosclerotic disease processes and subsequent therapeutic interventions significantly alter the natural course of the disease. Several large prospective studies have evaluated the usefulness of ultrasonographic measurement of IMT and have demonstrated its role in predicting future cardiovascular events. This article will focus on the relation between carotid artery IMT and coronary heart disease, and its utility and limitations in predicting cardiovascular events.