Salim Hayek

Paravalvular Aortic Leak After Transcatheter Aortic Valve Replacement Current Knowledge

Transcatheter aortic valve replacement (TAVR) is now well-established as the standard of care for patients with severe symptomatic aortic stenosis who are deemed inoperable,1 and is seen as an alternative treatment option to surgical aortic valve replacement (SAVR) in a subset of patients with high postoperative mortality.2 The native valve is typically not removed but instead crushed by the superimposed bioprosthesis, which can result in an incomplete seal of the bioprosthetic valve and aortic annulus, with subsequent occurrence of paravalvular leak (PVL). Two types of Transcatheter Heart Valves (THV) that have been widely used, the balloon-expandable Edwards valve (Cribier-Edwards, Edwards SAPIEN and Edwards SAPIEN XT) by Edwards Lifesciences, and the self-expandable CoreValve by Medtronic, have been described in detail elsewhere.3,4 Despite the evolving technology of transcatheter valves, PVL post-TAVR is common, with a wide range of reported incidences (Table 1). Most importantly, PVL has been associated with increased short- and long-term mortality post-TAVR, and is seen as a barrier to more widespread use of this promising technique.5–13 This article describes the incidence, causes, and predictors of PVL, as well as its impact on clinical outcomes. Methods of prevention, diagnosis, and treatment of PVL are also reviewed. View this table: Table 1. TAVR Studies and Registries Reporting Incidence of PVL in >100 Patients Aortic regurgitation is characterized as either central or paravalvular. Pathological central regurgitation occurs in diseased native valves or damaged prosthetic valves, whereas minor central regurgitation is often a physiological feature of some bioprosthetic valves by virtue of their design. On the other hand, PVL is a complication only of aortic valve prostheses and occurs more commonly post-TAVR (Figure 1) than after SAVR. Figure 1. Parasternal longitudinal axis transthoracic echocardiography view showing mild paravalvular leak post–transcatheter heart valve deployment. Arrow indicates the site of paravalvular leak. Various multicenter …

Soluble Urokinase Receptor and Chronic Kidney Disease

BACKGROUND Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease. METHODS We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m(2) of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables. RESULTS A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was -0.9 ml per minute per 1.73 m(2) among participants in the lowest quartile of suPAR levels as compared with -4.2 ml per minute per 1.73 m(2) among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥ 90 ml per minute per 1.73 m(2)) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m(2), the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile. CONCLUSIONS An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.).

Infective Endocarditis After Transcatheter Aortic Valve Implantation Results From a Large Multicenter Registry

Background— We aimed to determine the incidence, predictors, clinical characteristics, management, and outcomes of infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI). Methods and Results— This multicenter registry included 53 patients (mean age, 79±8 years; men, 57%) who suffered IE after TAVI of 7944 patients after a mean follow-up of 1.1±1.2 years (incidence, 0.67%, 0.50% within the first year after TAVI). Mean time from TAVI was 6 months (interquartile range, 1–14 months). Orotracheal intubation (hazard ratio, 3.87; 95% confidence interval, 1.55–9.64; P=0.004) and the self-expandable CoreValve system (hazard ratio, 3.12; 95% confidence interval, 1.37–7.14; P=0.007) were associated with IE (multivariate analysis including 3067 patients with individual data). The most frequent causal microorganisms were coagulase-negative staphylococci (24%), followed by Staphylococcus aureus (21%) and enterococci (21%). Vegetations were present in 77% of patients (transcatheter valve leaflets, 39%; stent frame, 17%; mitral valve, 21%). At least 1 complication of IE occurred in 87% of patients (heart failure in 68%). However, only 11% of patients underwent valve intervention (valve explantation and valve-in-valve procedure in 4 and 2 patients, respectively). The mortality rate in hospital was 47.2% and increased to 66% at the 1-year follow-up. IE complications such as heart failure (P=0.037) and septic shock (P=0.002) were associated with increased in-hospital mortality. Conclusions— The incidence of IE at 1 year after TAVI was 0.50%, and the risk increased with the use of orotracheal intubation and a self-expandable valve system. Staphylococci and enterococci were the most common agents. Although most patients presented at least 1 complication of IE, valve intervention was performed in a minority of patients, and nearly half of the patients died during the hospitalization period.Background— We aimed to determine the incidence, predictors, clinical characteristics, management, and outcomes of infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI). Methods and Results— This multicenter registry included 53 patients (mean age, 79±8 years; men, 57%) who suffered IE after TAVI of 7944 patients after a mean follow-up of 1.1±1.2 years (incidence, 0.67%, 0.50% within the first year after TAVI). Mean time from TAVI was 6 months (interquartile range, 1–14 months). Orotracheal intubation (hazard ratio, 3.87; 95% confidence interval, 1.55–9.64; P =0.004) and the self-expandable CoreValve system (hazard ratio, 3.12; 95% confidence interval, 1.37–7.14; P =0.007) were associated with IE (multivariate analysis including 3067 patients with individual data). The most frequent causal microorganisms were coagulase-negative staphylococci (24%), followed by Staphylococcus aureus (21%) and enterococci (21%). Vegetations were present in 77% of patients (transcatheter valve leaflets, 39%; stent frame, 17%; mitral valve, 21%). At least 1 complication of IE occurred in 87% of patients (heart failure in 68%). However, only 11% of patients underwent valve intervention (valve explantation and valve-in-valve procedure in 4 and 2 patients, respectively). The mortality rate in hospital was 47.2% and increased to 66% at the 1-year follow-up. IE complications such as heart failure ( P =0.037) and septic shock ( P =0.002) were associated with increased in-hospital mortality. Conclusions— The incidence of IE at 1 year after TAVI was 0.50%, and the risk increased with the use of orotracheal intubation and a self-expandable valve system. Staphylococci and enterococci were the most common agents. Although most patients presented at least 1 complication of IE, valve intervention was performed in a minority of patients, and nearly half of the patients died during the hospitalization period. # CLINICAL PERSPECTIVE {#article-title-37}

Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease

Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic). Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD), such as focal segmental glomerulosclerosis (FSGS). The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction.

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

BACKGROUND Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

Arrhythmia Burden in Elderly Patients With Severe Aortic Stenosis as Determined by Continuous Electrocardiographic Recording Toward a Better Understanding of Arrhythmic Events After Transcatheter Aortic Valve Replacement

Background— This study sought to evaluate the prevalence of previously undiagnosed arrhythmias in candidates for transcatheter aortic valve replacement (TAVR) and to determine the impact on therapy changes and arrhythmic events after the procedure. Methods and Results— A total of 435 candidates for TAVR underwent 24-hour continuous ECG monitoring the day before the procedure. Newly diagnosed arrhythmias were observed in 70 patients (16.1%) before TAVR: paroxysmal atrial fibrillation (AF)/atrial tachycardia (AT) in 28, advanced atrioventricular block or severe bradycardia in 24, nonsustained ventricular tachycardia in 26, and intermittent left bundle-branch block in 3 patients. All arrhythmic events but one were asymptomatic and led to a therapy change in 43% of patients. In patients without known AF/AT, the occurrence of AF/AT during 24-hour ECG recording was associated with a higher rate of 30-day cerebrovascular events (7.1% versus 0.4%; P=0.030). Among the 53 patients with new-onset AF/AT after TAVR, 30.2% had newly diagnosed paroxysmal AF/AT before the procedure. In patients who needed permanent pacemaker implantation after the procedure (n=35), 31.4% had newly diagnosed advanced atrioventricular block or severe bradycardia before TAVR. New-onset persistent left bundle-branch block after TAVR occurred in 37 patients, 8.1% of whom had intermittent left bundle-branch block before the procedure. Conclusions— Newly diagnosed arrhythmias were observed in approximately a fifth of TAVR candidates, led to a higher rate of cerebrovascular events, and accounted for a third of arrhythmic events after the procedure. This high arrhythmia burden highlights the importance of an early diagnosis of arrhythmic events in such patients to implement the appropriate therapeutic measures earlier.

Assessment of Right Ventricular Function in Left Ventricular Assist Device Candidates

As a result of the improved survival of patients with heart failure (HF) and the overall rise in the prevalence of HF,1 the number of patients in advanced (stage D) HF continues to increase, thus exceeding the limited availability of donor organs by a wide margin.2 Initially used primarily as a bridge to heart transplantation, mechanical circulatory support is now increasingly offered as a destination therapy to patients with advanced HF in clinical deterioration who are not candidates for transplantation. Improvement in survival to 80% at 1-year postimplantation3 has steadily followed the development of new technologies such as the continuous-flow pump, which now encompasses 99% of left ventricular assist devices (LVADs),3 and improvements in patient and device management. Far from being a panacea, mechanical circulatory support is still fraught with challenges. Among them, post-LVAD right ventricular failure (RVF) is a major cause of morbidity and mortality. Despite (1) overall improved outcomes and lower rates of RVF with the use of the newer, continuous-flow LVADs over pulsatile-flow devices,4 and (2) development of clinical prediction scores to facilitate preoperative identification of patients at risk for RVF after implantation,5–9 RVF still occurs in 13% to 40% of continuous-flow device.10 LVAD function relies heavily on right ventricular (RV) function for adequate preload. Severe RVF cannot only lead to systemic hypoperfusion, multiorgan failure, and death but also to prolonged or recurrent hospitalization and poor quality of life even in less extreme cases. LVAD recipients who develop RVF have poor outcomes,11–13 including higher perioperative, short- and long-term mortality,5,14,15 and reduced survival to transplantation.11,13–20 RVF has also been associated with higher risk of bleeding, renal failure, and hypotension,13,14,19 and longer …

Arrhythmia Burden in Elderly Patients with Severe Aortic Stenosis as Determined by Continuous ECG Recording: Towards a Better Understanding of Arrhythmic Events Following Transcatheter Aortic Valve Replacement

Background— This study sought to evaluate the prevalence of previously undiagnosed arrhythmias in candidates for transcatheter aortic valve replacement (TAVR) and to determine the impact on therapy changes and arrhythmic events after the procedure. Methods and Results— A total of 435 candidates for TAVR underwent 24-hour continuous ECG monitoring the day before the procedure. Newly diagnosed arrhythmias were observed in 70 patients (16.1%) before TAVR: paroxysmal atrial fibrillation (AF)/atrial tachycardia (AT) in 28, advanced atrioventricular block or severe bradycardia in 24, nonsustained ventricular tachycardia in 26, and intermittent left bundle-branch block in 3 patients. All arrhythmic events but one were asymptomatic and led to a therapy change in 43% of patients. In patients without known AF/AT, the occurrence of AF/AT during 24-hour ECG recording was associated with a higher rate of 30-day cerebrovascular events (7.1% versus 0.4%; P=0.030). Among the 53 patients with new-onset AF/AT after TAVR, 30.2% had newly diagnosed paroxysmal AF/AT before the procedure. In patients who needed permanent pacemaker implantation after the procedure (n=35), 31.4% had newly diagnosed advanced atrioventricular block or severe bradycardia before TAVR. New-onset persistent left bundle-branch block after TAVR occurred in 37 patients, 8.1% of whom had intermittent left bundle-branch block before the procedure. Conclusions— Newly diagnosed arrhythmias were observed in approximately a fifth of TAVR candidates, led to a higher rate of cerebrovascular events, and accounted for a third of arrhythmic events after the procedure. This high arrhythmia burden highlights the importance of an early diagnosis of arrhythmic events in such patients to implement the appropriate therapeutic measures earlier.

Prevalence of Resistant Hypertension and Eligibility for Catheter-Based Renal Denervation in Hypertensive Outpatients

BACKGROUND Studies of endovascular renal denervation (RDN) have demonstrated significant blood pressure reduction in eligible patients with resistant hypertension. These trials have used stringent inclusion and exclusion criteria in patient enrollment, potentially selecting for a small subset of patients with resistant hypertension. In this study, we examined the changes in estimated prevalence of resistant hypertension when using increasingly stringent definitions of resistant hypertension in a fixed population and assessed the generalizability of RDN when applying study criteria to a community-based hypertensive population. METHODS A retrospective chart review was done of hypertensive outpatients. Four increasingly stringent interpretations of the American Heart Association definition of resistant hypertension were used to calculate prevalence estimates. Patients eligible for RDN were identified using criteria from SYMPLICITY HTN-3. Demographic and clinical characteristics were compared. RESULTS We identified 1,756 hypertensive outpatients; 55.0% were male, 53.9% were white, and subjects had a mean age of 66.6 ± 12.5 years and a body mass index (BMI) of 30.1 ± 10.7 kg/m(2). Only 14 (0.8%) were eligible for RDN. Among these patients, 10 (71.4%) were female and all were black, with a mean age of 69.9 ± 8.8 and BMI of 35.7 ± 6.6. Congestive heart failure was more common in patients eligible for RDN. CONCLUSIONS Patients eligible for RDN based on published studies represent an exceedingly small proportion of the total hypertensive population. Further studies are necessary to determine if the benefits of RDN can be generalized to a broader range of hypertensive patients than those included in previous trials.