Henriette Brinks

Clinical Outcomes of Patients With Severe Aortic Stenosis at Increased Surgical Risk According to Treatment Modality

OBJECTIVES The aim of this study was to assess the role of transcatheter aortic valve implantation (TAVI) compared with medical treatment (MT) and surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS) at increased surgical risk. BACKGROUND Elderly patients with comorbidities are at considerable risk for SAVR. METHODS Since July 2007, 442 patients with severe AS (age: 81.7 ± 6.0 years, mean logistic European System for Cardiac Operative Risk Evaluation: 22.3 ± 14.6%) underwent treatment allocation to MT (n = 78), SAVR (n = 107), or TAVI (n = 257) on the basis of a comprehensive evaluation protocol as part of a prospective registry. RESULTS Baseline clinical characteristics were similar among patients allocated to MT and TAVI, whereas patients allocated to SAVR were younger (p < 0.001) and had a lower predicted peri-operative risk (p < 0.001). Unadjusted rates of all-cause mortality at 30 months were lower for SAVR (22.4%) and TAVI (22.6%) compared with MT (61.5%, p < 0.001). Adjusted hazard ratios for death were 0.51 (95% confidence interval: 0.30 to 0.87) for SAVR compared with MT and 0.38 (95% confidence interval: 0.25 to 0.58) for TAVI compared with MT. Medical treatment (<0.001), older age (>80 years, p = 0.01), peripheral vascular disease (<0.001), and atrial fibrillation (p = 0.04) were significantly associated with all-cause mortality at 30 months in the multivariate analysis. At 1 year, more patients undergoing SAVR (92.3%) or TAVI (93.2%) had New York Heart Association functional class I/II as compared with patients with MT (70.8%, p = 0.003). CONCLUSIONS Among patients with severe AS with increased surgical risk, SAVR and TAVI improve survival and symptoms compared with MT. Clinical outcomes of TAVI and SAVR seem similar among carefully selected patients with severe symptomatic AS at increased risk.

Level of G protein–Coupled Receptor Kinase-2 Determines Myocardial Ischemia/Reperfusion Injury via Pro- and Anti-Apoptotic Mechanisms

Rationale: Activation of prosurvival kinases and subsequent nitric oxide (NO) production by certain G protein–coupled receptors (GPCRs) protects myocardium in ischemia/reperfusion injury (I/R) models. GPCR signaling pathways are regulated by GPCR kinases (GRKs), and GRK2 has been shown to be a critical molecule in normal and pathological cardiac function. Objective: A loss of cardiac GRK2 activity is known to arrest progression of heart failure (HF), at least in part by normalization of cardiac &bgr;-adrenergic receptor (&bgr;AR) signaling. Chronic HF studies have been performed with GRK2 knockout mice, as well as expression of the &bgr;ARKct, a peptide inhibitor of GRK2 activity. This study was conducted to examine the role of GRK2 and its activity during acute myocardial ischemic injury using an I/R model. Methods and Results: We demonstrate, using cardiac-specific GRK2 and &bgr;ARKct-expressing transgenic mice, a deleterious effect of GRK2 on in vivo myocardial I/R injury with &bgr;ARKct imparting cardioprotection. Post-I/R infarct size was greater in GRK2-overexpressing mice (45.0±2.8% versus 31.3±2.3% in controls) and significantly smaller in &bgr;ARKct mice (16.8±1.3%, P<0.05). Importantly, in vivo apoptosis was found to be consistent with these reciprocal effects on post-I/R myocardial injury when levels of GRK2 activity were altered. Moreover, these results were reflected by higher Akt activation and induction of NO production via &bgr;ARKct, and these antiapoptotic/survival effects could be recapitulated in vitro. Interestingly, selective antagonism of &bgr;2ARs abolished &bgr;ARKct-mediated cardioprotection, suggesting that enhanced GRK2 activity on this GPCR is deleterious to cardiac myocyte survival. Conclusion: The novel effect of reducing acute ischemic myocardial injury via increased Akt activity and NO production adds significantly to the therapeutic potential of GRK2 inhibition with the &bgr;ARKct not only in chronic HF but also potentially in acute ischemic injury conditions.

S100A1 Genetically Targeted Therapy Reverses Dysfunction of Human Failing Cardiomyocytes

OBJECTIVES This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs). BACKGROUND Depletion of the Ca²⁺-sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium. METHODS Enzymatically isolated HFCMs from hearts with severe systolic HF were subjected to S100A1 and control adenoviral gene transfer and contractile performance, calcium handling, signaling, and energy homeostasis were analyzed by video-edge-detection, FURA2-based epifluorescent microscopy, phosphorylation site-specific antibodies, and mitochondrial assays, respectively. RESULTS Genetically targeted therapy employing the human S100A1 cDNA normalized decreased S100A1 protein levels in HFCMs, reversed both contractile dysfunction and negative force-frequency relationship, and improved contractile reserve under beta-adrenergic receptor (β-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca²⁺ handling abnormalities basally and under β-AR stimulation shown by improved SR Ca²⁺ handling, intracellular Ca²⁺ transients, diastolic Ca²⁺ overload, and diminished susceptibility to arrhythmogenic SR Ca²⁺ leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosine-triphosphate ratio. CONCLUSIONS Our results demonstrate for the first time the therapeutic efficacy of genetically reconstituted S100A1 protein levels in HFCMs by reversing pathophysiological features that characterize human failing myocardium. Our findings close a gap in our understanding of S100A1s effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF.

Regulation of GPCR signaling in Hypertension

Hypertension represents a complex, multifactorial disease and contributes to the major causes of morbidity and mortality in industrialized countries: ischemic and hypertensive heart disease, stroke, peripheral atherosclerosis and renal failure. Current pharmacological therapy of essential hypertension focuses on the regulation of vascular resistance by inhibition of hormones such as catecholamines and angiotensin II, blocking them from receptor activation. Interaction of G-protein coupled receptor kinases (GRKs) and regulator of G-protein signaling (RGS) proteins with activated G-protein coupled receptors (GPCRs) effect the phosphorylation state of the receptor leading to desensitization and can profoundly impair signaling. Defects in GPCR regulation via these modulators have severe consequences affecting GPCR-stimulated biological responses in pathological situations such as hypertension, since they fine-tune and balance the major transmitters of vessel constriction versus dilatation, thus representing valuable new targets for anti-hypertensive therapeutic strategies. Elevated levels of GRKs are associated with human hypertensive disease and are relevant modulators of blood pressure in animal models of hypertension. This implies therapeutic perspective in a disease that has a prevalence of 65million in the United States while being directly correlated with occurrence of major adverse cardiac and vascular events. Therefore, therapeutic approaches using the inhibition of GRKs to regulate GPCRs are intriguing novel targets for treatment of hypertension and heart failure.

Heart Failure Gene Therapy: The Path to Clinical Practice

Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies.

Transcatheter Aortic Valve Implantation or Surgical Aortic Valve Replacement as Redo Procedure After Prior Coronary Artery Bypass Grafting

BACKGROUND The perioperative risk for redo surgical aortic valve replacement (S-AVR) in patients with severe aortic stenosis and prior coronary artery bypass grafting (CABG) is increased. Transcatheter aortic valve implantation (TAVI) represents an alternative. We assessed the perioperative and mid-term clinical outcome of patients undergoing S-AVR or TAVI. METHODS In a retrospective observational, comparative study, 40 consecutive patients underwent redo operation with S-AVR or TAVI between April 2005 and April 2010. Median sternotomy and extracorporeal circulation were used for S-AVR; TAVI access was transfemoral (n = 27; 67.5%), transapical (n = 11; 27.5%), or transsubclavian (n = 2; 5.0%). Clinical and echocardiographic follow-up was at 30 days and 6 months. RESULTS TAVI patients were older (78.5 ± 6 vs 70.6 ± 8 years, p < 0.001) and presented higher logistic (33.5 ± 17 vs 20.2 ± 14, p < 0.001) European System for Cardiac Operative Risk Evaluation scores. All-cause mortality was 2.5% in both groups and major adverse cardiac and cerebrovascular event rates were comparable (7.5% TAVI vs 17.5% S-AVR, p = 0.311) after 30 days. TAVI was associated with a higher rate of permanent pacemaker implantation (30% vs 0%, p < 0.001) and grade II residual aortic regurgitation in 14%. Incidence of cerebrovascular events was 7.5% in S-AVR vs 2.5% in TAVI (p = 0.61). CONCLUSIONS In elderly, high-risk patients after prior CABG, conventional aortic valve replacement and TAVI are comparable treatment options with favorable clinical outcome. A redo operation itself does not sufficiently justify a TAVI approach.

The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition.

Rationale: The G&bgr;&ggr;-sequestering peptide &bgr;-adrenergic receptor kinase (&bgr;ARK)ct derived from the G-protein–coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased &bgr;-adrenergic receptor (&bgr;AR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by &bgr;ARKct and its impact on G&bgr;&ggr;-mediated signaling have yet to be fully elucidated. Objective: We sought to identify G&bgr;&ggr;-regulated targets and signaling mechanisms conveying &bgr;ARKct-mediated enhanced &bgr;AR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes. Methods and Results: Assessing viral-based &bgr;ARKct gene delivery with electrophysiological techniques, analysis of contractile performance, subcellular Ca2+ handling, and site-specific protein phosphorylation, we demonstrate that &bgr;ARKct enhances the cardiac L-type Ca2+ channel (LCC) current (ICa) both in NCs and FCs on &bgr;AR stimulation. Mechanistically, &bgr;ARKct augments ICa by preventing enhanced inhibitory interaction between the &agr;1-LCC subunit (Cav1.2&agr;) and liberated G&bgr;&ggr; subunits downstream of activated &bgr;ARs. Despite improved &bgr;AR contractile responsiveness, &bgr;ARKct neither increased nor restored cAMP-dependent protein kinase (PKA) and calmodulin-dependent kinase II signaling including unchanged protein kinase (PK)C&egr;, extracellular signal-regulated kinase (ERK)1/2, Akt, ERK5, and p38 activation both in NCs and FCs. Accordingly, although &bgr;ARKct significantly increases ICa and Ca2+ transients, being susceptible to suppression by recombinant G&bgr;&ggr; protein and use-dependent LCC blocker, &bgr;ARKct-expressing cardiomyocytes exhibit equal basal and &bgr;AR-stimulated sarcoplasmic reticulum Ca2+ load, spontaneous diastolic Ca2+ leakage, and survival rates and were less susceptible to field-stimulated Ca2+ waves compared with controls. Conclusion: Our study identifies a G&bgr;&ggr;-dependent signaling pathway attenuating cardiomyocyte ICa on &bgr;AR as molecular target for the G&bgr;&ggr;-sequestering peptide &bgr;ARKct. Targeted interruption of this inhibitory signaling pathway by &bgr;ARKct confers improved &bgr;AR contractile responsiveness through increased ICa without enhancing regular or restoring abnormal cAMP-signaling. &bgr;ARKct-mediated improvement of ICa rendered cardiomyocytes neither susceptible to &bgr;AR-induced damage nor arrhythmogenic sarcoplasmic reticulum Ca2+ leakage.

Cardiac G-Protein–Coupled Receptor Kinase 2 Ablation Induces a Novel Ca2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction

Background— G-protein–coupled receptor kinase 2 (GRK2) is a primary regulator of &bgr;-adrenergic signaling in the heart. G-protein–coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study. Methods and Results— Myocyte contractility, Ca2+ handling and excitation-contraction coupling were studied in isolated cardiomyocytes from wild-type and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed wild-type and GRK2KO hearts, myocyte contractions and Ca2+ transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca2+ content because of increased sodium-Ca2+ exchanger activity and inhibited SR Ca2+ ATPase by local protein kinase A–mediated activation of phosphodiesterase 4 resulting in hypophosphorylated phospholamban. This Ca2+ handling phenotype is explained by a higher fractional SR Ca2+ release induced by increased L-type Ca2+ channel currents. After &bgr;-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca2+ transients, which were not mediated through cardiac L-type Ca2+ channels but through an increased SR Ca2+. Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca2+ handling phenotype. The SR Ca2+ content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca2+ channel current density and no increase in sodium-Ca2+ exchanger in GRK2KO myocytes. An L-type Ca2+ channel blocker, verapamil, reversed some beneficial effects of GRK2KO. Conclusions— These data argue for novel differential regulation of L-type Ca2+ channel currents and SR load by GRK2. G-protein–coupled receptor kinase 2 ablation represents a novel beneficial Ca2+ handling phenotype resisting adverse remodeling after MI.

Contractile function is preserved in unloaded hearts despite atrophic remodeling

OBJECTIVE Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. MATERIAL AND METHODS Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. RESULTS Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). CONCLUSION Atrophic remodeling involves both the myocyte and interstitial tissue compartment. These data suggest that although there is decreased myocardial volume and increased stiffness, contractile capacity is preserved in the long-term unloaded heart.

Quality of life in high-risk patients: comparison of transcatheter aortic valve implantation with surgical aortic valve replacement

OBJECTIVES To compare health-related quality of life (QoL) in patients undergoing transcatheter aortic valve implantation via transapical access (TA TAVI) with patients undergoing surgical aortic valve replacement (SAVR). METHODS One hundred and forty-four high-risk patients referred for aortic valve replacement underwent TAVI screening and were assigned to either TA TAVI (n = 51, age 79.7 ± 9.2 years, logistic EuroSCORE 26.5 ± 16.1%, 51% males) or SAVR (n = 93, age 81.1 ± 5.3 years, logistic EuroSCORE 12.1 ± 9.3%, 42% males) by the interdisciplinary heart team. QoL was assessed using the Short Form 36 (SF-36) Health Survey Questionnaire and the Hospital Anxiety and Depression Scale. Furthermore, current living conditions and the degree of independence at home were evaluated. RESULTS Patients undergoing TA TAVI were at higher risk as assessed by EuroSCORE (26.5 ± 16 vs. 12.1 ± 9, P < 0.001) and STS score (6.7 ± 4 vs. 4.4 ± 3, P < 0.001) compared with SAVR patients. At the 30-day follow-up, the rate of mortality was similar and amounted to 7.8% for TA TAVI and 7.5% for SAVR patients and raised to 25.5% in TA TAVI and 18.3% in SAVR patients after a follow-up period of 15 ± 10 months. Assessment of QoL revealed no differences in terms of anxiety and depression between TA TAVI and SAVR patients. The SF-36 mental health metascore was similar in both groups (65.6 ± 19 vs. 68.8 ± 22, P = 0.29), while a significant difference was observed in the physical health metascore (49.7 ± 21 vs. 62.0 ± 21, P = 0.015). After adjustment for baseline characteristics, this difference disappeared. However, every added point in the preoperative risk assessment with the STS score decreased the SF-36 physical health dimension by two raw points at the follow-up assessment. CONCLUSIONS Selected high-risk patients undergoing TAVI by using a transapical access achieve similar clinical outcomes and QoL compared with patients undergoing SAVR. Increased STS scores predict worse QoL outcomes.