Endovascular Treatment of Infrapopliteal Peripheral Artery Disease.

Endovascular treatment of infrapopliteal disease is focused on the treatment of patients with rest pain or critical limb ischemia (CLI) due to severe atherosclerotic disease. While the evidence base surrounding the comparative effectiveness of endovascular intervention vs. surgery is lacking, many operators have adopted an "endovascular first" approach to the treatment of infrapopliteal atherosclerotic disease due to the lower morbidity of these procedures. This manuscript reviews current data on the endovascular treatment of CLI, including a comparison of endovascular and surgical approaches, current indications for and outcomes with balloon angioplasty of infrapopliteal PAD, angiosome-guided revascularization, and emerging technologies to improve long-term vessel patency after endovascular intervention.

The role of hemodynamic catheterization in the evaluation of hypertrophic obstructive cardiomyopathy: A case series.

Confirmation of the presence and magnitude of left ventricular outflow tract (LVOT) obstruction is a critical component of the evaluation of symptoms in patients with hypertrophic cardiomyopathy (HCM). The presence of LVOT obstruction in patients with severe symptoms refractory to pharmacologic therapy identifies a subgroup of HCM patients who may benefit from septal reduction therapy. Two-dimensional echocardiography with continuous wave Doppler is the main tool for confirming the presence and severity of LVOT obstruction in HCM. However, when uncertainty remains following non-invasive evaluation, invasive hemodynamics studies are required to confirm and quantify LVOT obstruction. In this manuscript we describe a series of 6 cases in which hemodynamic catheterization is instrumental in supplementing non-invasive imaging in the assessment of LVOT obstruction in HCM.

Endovascular revascularization of a surgically ligated superficial femoral artery: A case report.

We present a case of a patient with left lower extremity ischemic rest pain who initially underwent surgical profundaplasty requiring ligation of his superficial femoral artery (SFA). The patient developed continued rest pain due to diffuse disease of his profunda and inadequate collaterals. Endovascular intervention was therefore performed to the oversewn SFA. Retrograde left SFA access was obtained and the origin of the SFA was recanalized with true lumen re-entry using an ultrasound guided re-entry catheter. Angioplasty was performed at the origin of the SFA and self-expanding stents were deployed in the proximal and mid left SFA. Hemostasis at the distal left SFA access site was obtained by balloon inflation at the access site and manual compression. This case illustrates the feasibility of endovascular repair of a ligated SFA.

Optimal treatment of extracranial carotid artery disease: carotid endarterectomy, carotid stenting, or optimal medical therapy.

The optimal treatment of extracranial carotid artery disease is more controversial for asymptomatic than for symptomatic patients. Early trials comparing carotid endarterectomy to medical therapy alone demonstrated clear benefit of surgery in both symptomatic and asymptomatic populations. However, some believe that advances in medical therapy now lead to similar outcomes with optimal medical therapy alone and revascularization in asymptomatic patients. The role of carotid stenting is heavily debated, and the evidence base comparing carotid stenting to endarterectomy is limited primarily by inadequate operator experience as well as paucity of data in high surgical risk patients. A useful clinical approach to carotid bifurcation disease is to categorize patients by symptomatic status and revascularization risk. For symptomatic patients, revascularization should be favored over medical therapy alone. For asymptomatic patients, medical therapy alone might be considered, particularly for patients at high risk of revascularization and with anticipated survival <3-5 years.

Acute heart failure with preserved ejection fraction: unique patient characteristics and targets for therapy.

Currently, there are 1.0 million annual hospital discharges for acute heart failure (AHF). The total cost of heart failure (HF) care in the United States is projected to increase to $53 billion in 2030, with the majority of costs (80 %) related to AHF hospitalizations. Approximately 50 % of AHF episodes occur in patients with preserved ejection fraction (HFpEF). There is a dearth of evidence-based guidelines for the management of AHF in HFpEF patients. Here, we briefly review the epidemiology, pathophysiology, and treatment of AHF patients with HFpEF.

Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo.

BACKGROUND: In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin. METHODS AND RESULTS: Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P<0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased. CONCLUSION: Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.

Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction.

BACKGROUND: Acute decompensated heart failure (ADHF) occurs with preserved (heart failure with preserved ejection fraction [HFpEF] ≥50%) or reduced (heart failure with reduced ejection fraction [HFrEF] <50%) ejection fraction. Natriuretic peptide (NP) levels are lower in HFpEF than HFrEF. We hypothesized that lower NP levels in HFpEF may be associated with other differences in biomarkers, specifically, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, and a biomarker that reflects collagen synthesis. METHODS: In this prespecified ancillary analysis of patients with ADHF enrolled in the Diuretic Optimization Strategies Evaluation study, clinical features and N-terminal pro-B-type NP, cystatin C, plasma renin activity, aldosterone, oxidative stress (uric acid), and procollagen type III N-terminal peptide were compared in HFpEF and HFrEF at enrollment and 60-day follow-up. RESULTS: Compared with HFrEF (n = 219), HFpEF (n = 81) patients were older, heavier, more commonly female, less treated with RAAS antagonists, but with similar New York Heart Association class, jugular venous pressure, and edema severity. N-terminal pro-B-type NP was lower, and systolic blood pressure and cystatin C were higher in HFpEF. Despite higher systolic blood pressure and less RAAS antagonist use in HFpEF, plasma renin activity and aldosterone levels were similar in HFpEF and HFrEF as were uric acid and procollagen type III N-terminal peptide levels. Changes in biomarker levels from enrollment to 60 days were similar between HFrEF (n = 149) and HFpEF (n = 50). CONCLUSION: Lower NP levels in decompensated HFpEF occur in association with similar ADHF severity, more impaired vascular and renal function but similar elevation of biomarkers that reflect RAAS activation, oxidative stress, and collagen synthesis as in HFrEF.

Cranial Dislocation of Infrarenal Aortic Endoprostheses During Transcatheter Aortic Valve Replacement.

This report describes the complexity of transcatheter aortic valve replacement in which rare complications sometimes occur, even at experienced centers. This is a case of cranial migration of an infrarenal aortic aneurysm endograft while advancing the balloon-expandable prosthesis through the infrarenal aorta, which was subsequently successfully treated by deploying a thoracic endoprosthesis after deployment of the aortic valve bioprosthesis.

Telephone titration of heart failure medications.

BACKGROUND: In clinical practice, heart failure (HF) medications are underused and prescribed at lower than recommended doses. Telephone care is an option that could help to titrate HF medication in a timely manner. We describe our experience of a nurse-run, cardiologist- or nurse practitioner-supervised clinic to up-titrate HF medications via telephone. METHODS: Patients with the diagnosis of HF, New York Heart Association classes I to III, were referred to a registered nurse-run, cardiologist-/nurse practitioner-supervised HF medication titration clinic. Clinical and medication data collected at enrollment to the clinic and at 3 to 6 months after optimization of HF medications in patients who did or did not reach the target doses were compared. Effect on left ventricular (LV) function was also evaluated. RESULTS: There were 79 patients in the evaluation: 64 with HF and LV systolic dysfunction (LVSD) and the remaining 15 with HF and preserved ejection fraction (EF). Seventy-two percent of patients with LVSD were on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 61% were on a ß-blocker at baseline, and this increased to 98% and 97%, respectively, after optimization. Target doses was achieved in 50% of patients for ACEI or ARB, and in 41% for ß-blockers. The median time to optimization was 54 days (interquartile range, 20-97 days). The average number of phone calls at the time of optimization were 5.4 (SD, 3.7), and the average number of clinic visits was 1.9 (SD, 1.3). Reasons for not reaching the target doses included hypotension, hyperkalemia, and renal dysfunction for ACEI and bradycardia for ß-blockers. Overall, the EF increased by 10% (SD, 10%) after 6 months, and 35% or greater in 42% of patients whose baseline EF was less than 35%. There were no adverse events related to the dose up-titration. CONCLUSION: Telephonic titration of HF medications was feasible and safe and was achieved in 97% patients on ACEI/ARB and ß-blockers. Medication titration was associated with significant improvement in LV function, avoiding the need for device therapy in many patients.

Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure.

BACKGROUND: Chronic kidney disease (CKD) is an established risk factor for poor outcomes in heart failure (HF). Whether proteinuria provides additional prognostic information is not known. Renin-angiotensin blockade medications improve outcomes in HF but are underutilized in HF patients with renal dysfunction because of safety concerns and a lack of evidence of their effectiveness. METHODS AND RESULTS: In the Valsartan in Heart Failure Trial (Val-HeFT), 5010 patients with class II, III, or IV heart failure were randomly assigned to receive valsartan or placebo. The 2 primary outcomes were death and first morbid event, defined as death, sudden death with resuscitation, hospitalization for HF, or administration of intravenous inotropic or vasodilator drugs for 4 hours or more without hospitalization. The study cohort was divided into subgroups according to the presence of CKD (estimated glomerular filtration rate <60 mL x min(-1) x 1.73 m(-2)) and proteinuria (positive dipstick). Multivariable Cox proportional hazards regression models were used to examine the relationships between study outcomes and proteinuria, including its interaction with CKD. The interaction between valsartan and CKD was also tested. The effect of valsartan on estimated glomerular filtration rate was estimated by generalized linear models, including tests of interactions between treatment and CKD. At baseline, CKD was found in 58% and dipstick-positive proteinuria in 8% of patients. Dipstick-positive proteinuria was independently associated with mortality (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.01 to 1.62, P=0.05) and first morbid event (HR 1.28, 95% CI 1.06 to 1.55, P=0.01). The increased risk of death associated with dipstick-positive proteinuria was similar for those with and without CKD (HR 1.26, 95% CI 0.96 to 1.66 versus HR 1.37, 95% CI 0.83 to 2.26; P=0.94), as was the hazard for first morbid event (HR 1.26, 95% CI 1.01 to 1.57 versus HR 1.42, 95% CI 0.98 to 2.07; P=0.71). Valsartan reduced estimated glomerular filtration rate compared with placebo to a similar extent (P=0.52) in the subgroups with CKD (mean reduction -3.6 mL x min(-1) x 1.73 m(-2)) and without CKD (mean reduction -4.0 mL x min(-1) x 1.73 m(-2)) and by -3.8 mL x min(-1) x 1.73 m(-2) in both groups combined. The beneficial effect of valsartan on first morbid events was similar in those with and without CKD (HR 0.86, 95% CI 0.74 to 0.99 versus HR 0.91, 95% CI 0.73 to 1.12; P=0.23) and was significant in the subgroup with CKD. The effect of valsartan on mortality did not differ in patients with and without CKD (HR 1.01, 95% CI 0.85 to 1.20 versus HR 0.91, 95% CI 0.69 to 1.25; P=0.08). CONCLUSIONS: CKD was common and dipstick-positive proteinuria was infrequent in this sample of patients with HF. After controlling for other risk factors, including CKD, the relatively small subgroup with dipstick-positive proteinuria did have worse outcomes. Valsartan reduced the estimated glomerular filtration rate by the same amount in patients with and without CKD and reduced the risk of the first morbid event in patients with CKD, which suggests its beneficial effects in patients with HF and CKD.

Supera self-expanding stents for endovascular treatment of femoropopliteal disease: a review of the clinical evidence.

Femoropopliteal lesions account for a significant proportion of endovascular interventions for peripheral artery disease in patients with disabling claudication or chronic limb ischemia. The femoropopliteal artery crosses two joint structures (hip and knee joints) and courses through the muscular adductor canal in the thigh, which places the artery at increased biomechanical stress. There is a critical need for stent platforms with a reduced risk of stent fracture while maintaining patency during long-term follow-up. The Supera peripheral stent system has a braided nickel-titanium alloy stent designed to withstand the unique stressors along the course of the femoropopliteal artery. This design may be associated with improved patency in association with reduced stent fracture rates on short- and medium-term follow-up. Further studies, including randomized controlled studies, comparing the Supera interwoven nickel-titanium alloy stent system with other stent platforms and angioplasty alone are needed.

The emperor's new clothes: PDE5 and the heart.

Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.

Prognostic impact of pulmonary artery systolic pressure in patients undergoing transcatheter aortic valve replacement for aortic stenosis.

Baseline pulmonary hypertension (PH) is a predictor of poor outcomes in patients with severe aortic stenosis (AS). Surgical aortic valve replacement is thought to alleviate PH. The aim of this study was to determine the prognostic impact of PH in patients who underwent transcatheter aortic valve replacement (TAVR). An observational cohort study was conducted using prospectively collected data on 277 consecutive patients with severe AS who underwent TAVR at the Mayo Clinic (Rochester, Minnesota) from November 1, 2008, to June 31, 2013. Clinical and echocardiographic data, pulmonary function characteristics, and outcomes stratified by tertiles of pulmonary artery systolic pressure (PASP) were analyzed. From 277 patients who underwent TAVR, 251 patients had PASP assessment at baseline. Those in the highest PASP tertile (PASP ≥49 mm Hg) had more severe chronic lung disease and worse diastolic dysfunction. Being in the highest PASP tertile was an independent predictor of long-term mortality (hazard ratio 2.88, 95% confidence interval 1.15 to 7.23). Patients in the highest PASP tertile had longer lengths of hospital stay, while other short-term outcomes (30-day mortality and readmission, stroke, prolonged ventilation, and reoperation for bleeding) were similar across PASP tertiles. TAVR was associated with a decrease in PASP in the highest PASP tertile at 1 week after the procedure (-8 ± 14 mm Hg) and at 3 months (-7 ± 15 mm Hg) compared with baseline. In conclusion, among patients with severe AS who underwent TAVR, higher baseline PASP was strongly associated with diastolic dysfunction and chronic lung disease. Patients with higher baseline PASP tolerated TAVR relatively well in the early postprocedural phase, with diminished long-term survival. PH should not disqualify patients with severe AS from consideration for TAVR.

Pregnancy and postpartum infective endocarditis: a systematic review.

The objective of this review was to describe the clinical characteristics, risk factors, and outcomes of infective endocarditis (IE) in pregnancy and the postpartum period. We conducted a systematic review of Ovid MEDLINE, Ovid Embase, Web of Science, and Scopus from January 1, 1988, through October 31, 2012. Included studies reported on women who met the modified Duke criteria for the diagnosis of IE and were pregnant or postpartum. We included 72 studies that described 90 cases of peripartum IE, mostly affecting native valves (92%). Risk factors associated with IE included intravenous drug use (14%), congenital heart disease (12%), and rheumatic heart disease (12%). The most common pathogens were streptococcal (43%) and staphylococcal (26%) species. Septic pulmonary, central, and other systemic emboli were common complications. Of the 51 pregnancies, there were 41 (80%) deliveries with survival to discharge, 7 (14%) fetal deaths, 1 (2%) medical termination of pregnancy, and 2 (4%) with unknown status. Maternal mortality was 11%. Infective endocarditis is a rare, life-threatening infection in pregnancy. Risk factors are changing with a marked decrease in rheumatic heart disease and an increase in intravenous drug use. The cases reported in the literature were commonly due to streptococcal organisms, involved the right-sided valves, and were associated with intravenous drug use.

Evaluation of apical subtype of hypertrophic cardiomyopathy using cardiac magnetic resonance imaging with gadolinium enhancement.

Apical hypertrophic cardiomyopathy (HC) is an uncommon variant of HC. We sought to characterize cardiac magnetic resonance imaging (MRI) findings among apical HC patients. This was a retrospective review of consecutive patients with a diagnosis of apical HC who underwent cardiac MRI examinations at the Mayo Clinic (Rochester, MN) from August 1999 to October 2011. Clinical and demographic data at the time of cardiac MRI study were abstracted. Cardiac MRI study and 2-dimensional echocardiograms performed within 6 months of the cardiac MRI were reviewed; 96 patients with apical HC underwent cardiac MRI examinations. LV end-diastolic and end-systolic volumes were 130.7 ± 39.1 ml and 44.2 ± 20.9 ml, respectively. Maximum LV thickness was 19 ± 5 mm. Hypertrophy extended beyond the apex into other segments in 57 (59.4%) patients. Obstructive physiology was seen in 12 (12.5%) and was more common in the mixed apical phenotype than the pure apical (19.3 vs 2.6%, p = 0.02). Apical pouches were noted in 39 (40.6%) patients. Late gadolinium enhancement (LGE) was present in 70 (74.5%) patients. LGE was associated with severe symptoms and increased maximal LV wall thickness. In conclusion, cardiac MRI is well suited for studying the apical form of HC because of difficulty imaging the cardiac apex with standard echocardiography. Cardiac MRI is uniquely suited to delineate the presence or absence of an apical pouch and abnormal myocardial LGE that may have implications in the natural history of apical HM. In particular, the presence of abnormal LGE is associated with clinical symptoms and increased wall thickness.

Evaluation of apical pouches in hypertrophic cardiomyopathy using cardiac MRI.

The presence of apical pouches in hypertrophic cardiomyopathy (HCM) may portend poor prognosis. We sought to study if the use cardiac magnetic resonance imaging (CMR) improves the detection of apical pouches in HCM compared to echocardiography. A retrospective review was performed of all consecutive HCM patients with an apical pouch identified by CMR at Mayo Clinic from May 2004 to Sept 2011. Clinical data was abstracted and CMR and echocardiographic images were analyzed. There were 56 consecutive HCM patients with an apical pouch identified by CMR. The predominant morphological type was apical in 41 (73.2 %), followed by sigmoid in 6 (10.7 %), reversed curve in 6 (10.7 %) and neutral in 3 (5.4 %). Obstructive physiology or systolic anterior motion of the mitral valve leaflet was evident in 23 (41.1 %). Late gadolinium enhancement was present in 47 (87.0 %) patients. Apical pouches were detected in only 18 (32.1 %) patients on echocardiography. Even when intravenous contrast was used (29/56 patients), in 16/29 (55.2 %) pouches were missed on echocardiography. Pouch length and neck dimensions in systole and diastole, measured on CMR, were larger among those patients in whom pouches were detected on echocardiography suggesting only larger pouches can be identified on echocardiography. In the largest CMR series to date of apical pouches in HCM, we show that while apical pouches are most commonly seen in apical HCM, they can be found in other phenotypic variants. CMR is better suited for the evaluation of apical pouches compared to echocardiography even with the use of intravenous contrast. CMR is likely a better tool for evaluating the cardiac apical structures including apical pouches when clinically indicated.

Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Key alterations in HFpEF include increased left ventricular (LV) stiffness and abnormal relaxation. We hypothesized that myofilament protein phosphorylation and function are deranged in experimental HFpEF vs. normal myocardium. Such alterations may involve the giant elastic protein titin, which contributes decisively to LV stiffness. METHODS AND RESULTS: LV tissue samples were procured from normal dogs (CTRL) and old dogs with hypertension-induced LV hypertrophy and diastolic dysfunction (OHT/HFpEF). We quantified the expression and phosphorylation of myofilament proteins, including all-titin and site-specific titin phosphorylation, and assessed the expression/activity of major protein kinases (PKs) and phosphatases (PPs), myofilament calcium sensitivity (pCa(50)), and passive tension (F(passive)) of isolated permeabilized cardiomyocytes. In OHT vs. CTRL hearts, protein kinase-G (PKG) activity was decreased, whereas PKCα activity and PP1/PP2a expression were increased. Cardiac MyBPC, TnT, TnI and MLC2 were less phosphorylated and pCa(50) was increased in OHT vs. CTRL. The titin N2BA (compliant) to N2B (stiff) isoform-expression ratio was lowered in OHT. Hypophosphorylation in OHT was detected for all-titin and at serines S4010/S4099 within titin-N2Bus, whereas S11878 within proline, glutamate, valine, and lysine (PEVK)-titin was hyperphosphorylated. Cardiomyocyte F(passive) was elevated in OHT, but could be normalized by PKG or PKA, but not PKCα, treatment. CONCLUSIONS: This patient-mimicking HFpEF model is characterized by titin stiffening through altered isoform composition and phosphorylation, both contributing to increased LV stiffness. Hypophosphorylation of myofilament proteins and increased calcium sensitivity suggest that functional impairment at the sarcomere level may be an early event in HFpEF.

Anti-remodeling effects of rapamycin in experimental heart failure: dose response and interaction with angiotensin receptor blockade.

While neurohumoral antagonists improve outcomes in heart failure (HF), cardiac remodeling and dysfunction progress and outcomes remain poor. Therapies superior or additive to standard HF therapy are needed. Pharmacologic mTOR inhibition by rapamycin attenuated adverse cardiac remodeling and dysfunction in experimental heart failure (HF). However, these studies used rapamycin doses that produced blood drug levels targeted for primary immunosuppression in human transplantation and therefore the immunosuppressive effects may limit clinical translation. Further, the relative or incremental effect of rapamycin combined with standard HF therapies targeting upstream regulators of cardiac remodeling (neurohumoral antagonists) has not been defined. Our objectives were to determine if anti-remodeling effects of rapamycin were preserved at lower doses and whether rapamycin effects were similar or additive to a standard HF therapy (angiotensin receptor blocker (losartan)). Experimental murine HF was produced by transverse aortic constriction (TAC). At three weeks post-TAC, male mice with established HF were treated with placebo, rapamycin at a dose producing immunosuppressive drug levels (target dose), low dose (50% target dose) rapamycin, losartan or rapamycin + losartan for six weeks. Cardiac structure and function (echocardiography, catheterization, pathology, hypertrophic and fibrotic gene expression profiles) were assessed. Downstream mTOR signaling pathways regulating protein synthesis (S6K1 and S6) and autophagy (LC3B-II) were characterized. TAC-HF mice displayed eccentric hypertrophy, systolic dysfunction and pulmonary congestion. These perturbations were attenuated to a similar degree by oral rapamycin doses achieving target (13.3±2.1 ng/dL) or low (6.7±2.5 ng/dL) blood levels. Rapamycin treatment decreased mTOR mediated regulators of protein synthesis and increased mTOR mediated regulators of autophagy. Losartan monotherapy did not attenuate remodeling, whereas Losartan added to rapamycin provided no incremental benefit over rapamycin alone. These data lend support to investigation of low dose rapamycin as a novel therapy in human HF.

Index of biventricular interdependence calculated using cardiac MRI: a proof of concept study in patients with and without constrictive pericarditis.

We sought to propose a magnetic resonance (MR) imaging-derived index of biventricular interdependence as a diagnostic parameter to distinguish patients with surgically-confirmed pericardial constriction from those without. Free-breathing real time MR pulse sequences of seventeen subjects with surgically proven constrictive pericarditis and thirty-five patients referred for clinically-indicated cardiac MR examinations but without documented constriction were analyzed using a novel index of biventricular interdependence. Cross-sectional biventricular areas at end diastole using the epicardial surface were traced at the mid left ventricular level at end-inspiration and end-expiration and an index of biventricular interdependence, defined as the ratio of (biventricular end-diastolic area at end-inspiration)/(biventricular end-diastolic area at end-expiration) was calculated for each subject. The mean index for both groups was calculated and results were statistically compared. The index of biventricular interdependence approximated unity (mean index 1.03 ± 0.03 SD) in patients with surgically confirmed pericardial constriction, indicating similar biventricular area at end-inspiration and end-expiration, and was significantly lower than in individuals without constrictive pericarditis (mean index 1.28 ± 0.10 SD; p < 0.0001). The MR-derived index of biventricular interdependence was significantly different between subjects with surgically-confirmed pericardial constriction and subjects where pericardial constraint was not suspected and may serve as a useful metric in the hemodynamic assessment of patients with a potential diagnosis of constrictive pericarditis.