Reduction Of Left Ventricular Hypertrophy Research Articles

Left ventricular structure and function following renal sympathetic denervation in patients with HFpEF: an echocardiographic 9-year long-term follow-up.

High blood pressure is a major risk factor for cardiac remodeling and left ventricular hypertrophy, increasing cardiovascular risk and leading to heart failure with preserved ejection fraction (HFpEF). Since renal sympathetic denervation (RDN) reduces blood pressure in the long term, we aimed to investigate the long-term effect of RDN in patients with HFpEF in the present analysis. Patients previously enrolled in a local RDN registry who underwent high-frequency RDN with the use of the Symplicity Flex® renal denervation system between 2011 and 2014 were followed up. The patients were assessed by 24-h ambulatory blood pressure measurement, transthoracic echocardiography, and laboratory tests. We used the echocardiographic and biomarker criteria of the Heart Failure Association (HFA)-PEFF (Pre-test assessment, Echocardiography and Natriuretic Peptide Score, Funkctional testing, and Final aetiology) score to identify patients with HFpEF. Echocardiographic assessment was available for 70 patients at a 9-year long-term follow-up. Of these patients, 21 had HFpEF according to the HFA-PEFF score. We found a significant reduction of the HFA-PEFF score from 5.48 ± 0.51 points at baseline to 4.33 ± 1.53 points at the 9-year follow-up (P < 0.01). This decrease was due to a greater reduction in morphological and biomarker subcategories [from 1.95 ± 0.22 to 1.43 ± 0.51 points (P < 0.01) and from 1.52 ± 0.52 to 0.90 ± 0.63 points (P < 0.01), respectively] than in the functional one. Morphologically, there was a reduction in left ventricular hypertrophy and left atrial dilation. The present analysis suggests that RDN may lead to a regression of the extent of HFpEF beyond a reduction in blood pressure and thus possibly contribute to an improvement in prognosis. More detailed information will be provided by ongoing randomized sham-controlled trials.

Abstract 12927: Impact of AAV- MYBPC3 Gene Transfer on Heart Structure and Function in Human and Mouse Models of Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a life-threatening inherited heart disease characterized by left ventricular hypertrophy and diastolic dysfunction. The most common cause of HCM is genetic variants in MYBPC3 , encoding cardiac myosin binding protein C (cMyBP-C), a sarcomeric protein with structural and regulatory roles. The majority of MYBPC3 gene variants are truncating leading to protein haploinsufficiency. Hypothesis: Transfer of a functional copy of MYBPC3 to heart muscle deficient in cMyBP-C will lead to sustained improvements in cardiac function. Aims: To determine whether BMN 293 (AAV-hMYBPC3) can restore cMyBP-C levels in the sarcomere and halt and/or reverse disease progression in non-clinical models of genetic HCM due to MYPBC3 deficiency. Methods: BMN 293 is an adeno-associated virus (AAV) vector that encodes wild-type human MYBPC3 under the control of a cardiomyocyte-selective promoter. We transduced human iPSC-derived cardiomyocytes and engineered heart tissues (EHTs) carrying a compound heterozygous truncating MYBPC3 mutation (MYBPC3 -/- ) with BMN 293 and assessed cMyBP-C levels and contractile parameters. We also systemically administered BMN 293 to MYBPC3 -/- mice and assessed cardiac distribution of human cMyBP-C by molecular and histological methods and determined its impact on left ventricular hypertrophy and function by echocardiography and other imaging techniques. Results: BMN 293 transduction of human iPSC MYBPC3 -/- cardiomyocytes and EHTs resulted in high levels of human MYBPC3 mRNA and cMyBP-C protein, correct incorporation of cMyBP-C into the sarcomere, and complete normalization of contractile kinetics. BMN 293 was well tolerated in MYBPC3 -/- mice and resulted in uniform restoration of cMyBP-C expression throughout the heart and significant correction of structural and functional cardiac abnormalities. Conclusions: A single IV infusion of BMN 293 to MYBPC3 -/- mice resulted in early and sustained reduction in left ventricular hypertrophy and durable improvements in diastolic function.

Losartan Reduces Remodeling and Apoptosis in an Adriamycin-Induced Cardiomyopathy Rat Model.

The use of Adriamycin (ADR), also known as doxorubicin, as a chemotherapy agent is limited by its detrimental adverse effects, especially cardiotoxicity. Recent studies have emphasized the crucial role of angiotensin II (Ang-II) in the development of ADR-induced cardiomyopathy. This study aimed to explore the potential cardioprotective effects of losartan in a rat model of ADR-induced cardiomyopathy. Male Sprague-Dawley rats were randomly divided into 3 groups: a control group (group C), an ADR-treated group (ADR 5 mg/kg/wk for 3 weeks via intraperitoneal injections; group A), and co-treatment of ADR with losartan group (same dose of ADR and losartan; 10 mg/kg/day per oral for 3 weeks; group L). Western blot analysis was conducted to demonstrate changes in brain natriuretic peptide, collagen 1, tumor necrosis factor (TNF)-α, interleukin-6, matrix metalloproteinase (MMP)-2, B-cell leukemia/lymphoma (Bcl)-2, Bcl-2-associated X (Bax), and caspase-3 protein expression levels in left ventricular (LV) tissues from each group. Losartan administration reduced LV hypertrophy, collagen content, and the expression of pro-inflammatory factors TNF-α and MMP-2 in LV tissue. In addition, losartan led to a decrease in the expression of the pro-apoptotic proteins Bax and caspase-3 and an increase in the expression of the anti-apoptotic protein Bcl-2. Moreover, losartan treatment induced a reduction in the apoptotic area compared to group A. In an ADR-induced cardiomyopathy rat model, co-administration of ADR with losartan presented cardioprotective effects by attenuating LV hypertrophy, pro-inflammatory factors, and apoptosis in LV tissue.

Three-vessel coronary infusion of cardiosphere-derived cells for the treatment of heart failure with preserved ejection fraction in a pre-clinical pig model.

Heart failure with preserved ejection fraction (HFpEF) is a major public health concern. Its outcome is poor and, as of today, barely any treatments have been able to decrease its morbidity or mortality. Cardiosphere-derived cells (CDCs) are heart cell products with anti-fibrotic, anti-inflammatory and angiogenic properties. Here, we tested the efficacy of CDCs in improving left ventricular (LV) structure and function in pigs with HFpEF. Fourteen chronically instrumented pigs received continuous angiotensin II infusion for 5weeks. LV function was investigated through hemodynamic measurements and echocardiography at baseline, after 3weeks of angiotensin II infusion before three-vessel intra-coronary CDC (n = 6) or placebo (n = 8) administration and 2weeks after treatment (i.e., at completion of the protocol). As expected, arterial pressure was significantly and similarly increased in both groups. This was accompanied by LV hypertrophy that was not affected by CDCs. LV systolic function remained similarly preserved during the whole protocol in both groups. In contrast, LV diastolic function was impaired (increases in Tau, LV end-diastolic pressure as well as E/A, E/E'septal and E/E'lateral ratios) but CDC treatment significantly improved all of these parameters. The beneficial effect of CDCs on LV diastolic function was not explained by reduced LV hypertrophy or increased arteriolar density; however, interstitial fibrosis was markedly reduced. Three-vessel intra-coronary administration of CDCs improves LV diastolic function and reduces LV fibrosis in this hypertensive model of HFpEF.

Stricter blood pressure control reduces rate of left ventricular hypertrophy and diastolic dysfunction in ethnic minority groups in the UK:E-ECHOES study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation (PG/05/036) Primary Care Research Network-Central England. Background Blood pressure (BP, mmHg) targets have been mainly determined based on the white ethnic group. Optimal BP levels have been less established in people of South Asian and African Caribbean origin. There is less data on how different office BP values influence the presence of cardiac target organ damage, left ventricular hypertrophy (LVH) and diastolic dysfunction (DD). Methods This study is based on the large prospective UK community Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES, South Asian and African-Caribbean origin, age ≥45 years). Echocardiography was used to diagnose LVH and DD following British Echocardiographic Society criteria. Optimal receiver operator curves (ROC) cut-off values for predicting LVH and DD were determined using the Leu method. Multivariable logistic regression, adjusted for age and sex, was used to determine the effects of different BP values for LVH and DD, using SBP 130-&amp;lt;140 and DBP 80-&amp;lt;90 as comparators (STATA 13). Results The study included 3200 South Asians (age 59±10, 52% women), of whom 1568 (49%) had LVH, and 1497 (47%) had diastolic dysfunction. Of people with LVH, 869 (55%) had SBP &amp;gt;140, and 372 (24%) had DBP &amp;gt;90. The optimal BP cut-off for ROC analysis was 139/80.5 for LVH and 139/80.5 for diastolic dysfunction. SBP &amp;lt;130 and DBP &amp;lt;80 were both associated with a 31% reduction in diastolic dysfunction (Table). BP ≥140/90 was strongly predictive of LVH and DD. The study included 1922 African Caribbeans (62±12 age, 55% women), of whom 1186 (62%) had LVH and 1124 (58%) had DD. Of people with LVH, 778 (66%) had SBP &amp;gt;140, and 333 (28%) had DBP &amp;gt;90. The optimal BP cut-off for ROC analysis were 139/81.5 for LVH and 138/80.5 for DD. DBP &amp;lt;80 mmHg 27% reduction in LVH and 24% in DD (Table). BP ≥140/90 was strongly predictive of LVH and DD. Conclusions People of South Asian origin may benefit from stricter SBP (&amp;lt;130) control, and both ethnic groups may benefit from stricter DBP (&amp;lt;80) control.

Superselective adrenal arterial embolization for primary aldosteronism without lateralized aldosterone secretion: an efficacy and safety, proof-of-principle study.

Superselective adrenal arterial embolization (SAAE) appears to be beneficial in primary aldosteronism (PA) patients with lateralized aldosterone secretion (unilateral PA). As confirmed by adrenal vein sampling (AVS), nearly 40% of PA patients would be PA without lateralized aldosterone secretion (bilateral PA). We aimed to investigate the efficacy and safety of SAAE on bilateral PA. We identified 171 bilateral PA patients from 503 PA patients who completed AVS. Thirty-eight bilateral PA patients received SAAE, and 31 completed a median 12-month clinical follow-up. The blood pressure and biochemical improvements of these patients were carefully analyzed. 34% of patients were identified as bilateral PA. Plasma aldosterone concentration, plasma renin activity, and aldosterone/renin ratio (ARR) were significantly improved 24-h after SAAE. SAAE was associated with 38.7% and 58.6% of complete/partial clinical and biochemical success within a median 12-month follow-up. A significant reduction in left ventricular hypertrophy was shown in patients who obtained complete biochemical success compared with partial/absent biochemical success. SAAE was associated with a more apparent nighttime blood pressure reduction than daytime blood pressure reduction in patients with complete biochemical success. No major adverse safety events related to SAAE were reported during the intraoperative, postoperative, and follow-up periods. SAAE was associated with blood pressure and biochemical improvements in part of bilateral PA and appeared safe. The biochemistry success was accompanied by improved cardiac remodeling and a more prominent decrease in nocturnal blood pressure. This study was part of a trial registered with the Chinese Clinical Trial Registry, number ChiCTR2100047689.

Differences in Cardiovascular Remodeling in Kidney Transplant Recipients and Peritoneal Dialysis Patients

Aims: Cardiovascular disease (CVD) is the leading cause of death in dialysis patients as well as in kidney transplant recipients (KTx). Left ventricular hypertrophy (LVH) starts early during the course of chronic kidney disease and is a strong predictor of CVD. We hypothesised that kidney transplant is significantly associated with improvement in cardiovascular reserve. We conducted a prospective study to compare changes in CV before and after kidney transplantation in patients with ESRD who received KTx to control individuals who received PD but did not receive a KTx.&#x0D; Study Design: A Case-Control Study.&#x0D; Place and Duration of Study: Clinic for nephrology Clinical Center University of Sarajevo, Bosnia and Herzegovina.&#x0D; Methodology: In this case-control study, we included 50 KTx from the Kidney Transplant Outpatient Clinic for nephrology Clinical Center. For each 50 KTx, PD outpatients matched for gender and age were recruited. All patients underwent transthoracic echocardiography, and LV (left ventricular) mass (LVM), LV mass index (LVMi), and indices of cardiac function were measured. In the small subgroup of 18 KTx, we retrospectively assessed and compared the LVMI measurements, during dialysis and the post-transplant period.&#x0D; Results: The prevalence of LVH was 24% in KTx patients and 72% in PD patients (NS). KTx had significantly lower LVM, LVMi levels, E/A ratio, FS, and LA diameter compared with the PD group, while the EF and other echocardiographic parameters did not differ. In the subgroup of 18 KTx, LVMi levels after transplantation were significantly lower than dialysis LVMi levels.&#x0D; Conclusion: LVH is the most frequent cardiac abnormality at the time of kidney transplantation. After KTx, the reduction of LVH and diastolic dysfunction was significant. CV remodelling after successful KTx is related to better kidney function, and can explain better outcomes for patients with kidney transplants over patients on long-term dialysis.

Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Cardiac Structural and Electrical Remodeling: From Myocardial Cytology to Cardiodiabetology.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have changed the clinical landscape of diabetes mellitus (DM) therapy through their favourable effects on cardiovascular outcomes. Notably, the use of SGLT2i has been linked to cardiovascular benefits regardless of DM status, while their pleiotropic actions remain to be fully elucidated. What we do know is that SGLT2i exert beneficial effects even at the level of the myocardial cell and that these are linked to an improvement in the energy substrate, resulting in less inflammation and fibrosis. SGLT2i ameliorates myocardial extracellular matrix remodeling, cardiomyocyte stiffness and concentric hypertrophy, achieving beneficial remodeling of the left ventricle with significant implications for the pathogenesis and outcome of heart failure. Most studies show a significant improvement in markers of diastolic dysfunction along with a reduction in left ventricular hypertrophy. In addition to these effects, there is electrophysiological remodeling, which explains initial data suggesting that SGLT2i have an antiarrhythmic action against both atrial and ventricular arrhythmias. However, future studies need to clarify not only the exact mechanisms of this beneficial functional, structural, and electrophysiological cardiac remodeling but also its magnitude to determine whether this is a class or a drug effect.

Cardioprotective Effects of Chronic Release Formulations of Subcutaneous Implants of Carvedilol in Spontaneously Hypertensive Rats

Background: In our laboratory, we have developed subcutaneous implants of carvedilol capable of maintaining stable concentrations of the β-blocker during 3 weeks. Objective: The aim of this study was to evaluate the in vivo release and the cardioprotective efficacy of subcutaneous implants of carvedilol developed with poly-epsilon-caprolactone (PCL) and Soluplus (SP) polymers in spontaneously hypertensive rats (SHR). Methods: Twelve spontaneously hypertensive male rats (250-300 g) underwent placement of subcutaneous implant of PCL:SP 100:50 mg (control group, n = 6) or carvedilol:PCL:SP (100mg:100mg:50mg) (carvedilol group, n = 6), every 3 weeks. The plasma profile of each implant and its effect on systolic blood pressure (SBP) was evaluated for 62 days. At the end of treatment, echocardiographic parameters were determined, and direct SBP and direct mean arterial pressure (MAP) were measured. Results: The group that received the implant containing 100 mg of carvedilol presented plasma concentrations of the drug in the range of 100- 500 ng/mL throughout 62 days of treatment, after which the SBP was 20 mmHg lower than in the control group (217±3 mm Hg vs. 237 ± 6 mm Hg; p &lt;0.05). Direct SBP and MAP were significantly lower in the treated group than in the control group. The implant loaded with carvedilol 100 mg reduced short-term blood pressure variability (BPV) in SHR compared with the control group. Echocardiographic parameters as left ventricular ejection fraction (LVEF), shortening fraction and E/A ratio were significantly greater in treated rats. Left ventricular weight was lower in the rats with carvedilol implant. Conclusion: Implants containing CAR/PCL/SP (100:100:50) mg provide therapeutic and stable plasma levels of carvedilol during treatment, which correlate with a significant and sustained decrease in indirect BP values. Treatment with carvedilol implants attenuated direct BP values and blood pressure variability in SHR. Treatment with implant produced cardioprotective effects evidenced in the echocardiogram by a reduction in left ventricular hypertrophy.

Differential impact of antihypertensive drugs on cardiovascular remodeling: a review of findings and perspectives for HFpEF prevention.

Heart failure (HF) is an important health problem worldwide whose stages have traditionally been classified from A to D. In addition, HF can be categorized as that with preserved ejection fraction (HFpEF) and that with reduced ejection fraction (HFrEF). Hypertension and arterial stiffness in stage A HF are major drivers of the progression to left ventricular hypertrophy (LVH), a criterion of stage B HF. Although the pathogenesis of HFpEF is heterogeneous, affected patients tend to be older than HFrEF patients and have a greater prevalence of hypertension, which is closely associated with arterial stiffness and LVH. Thus, to treat HFpEF, the optimal intervention for improving prognosis is an aggressive approach to early-stage, i.e., Stage A and B, HF. This paper reviews the findings on arterial stiffness and LVH using conventional antihypertensive drugs such as angiotensin receptor II blockers (ARBs) and a new drug class for HF, ARB/neprilysin inhibitor (ARNi). Previous studies have suggested that the combination of an ARB with an L-T-type calcium channel blocker might be recommended for the improvement of arterial stiffness and regression of LVH. More recent research has shown that ARNi also improves central BP, which leads to a reduced afterload and a significant reduction in LVH. For optimal treatment of HFpEF, drug therapy should directly address arterial stiffness as well as hypertension.

Effect of amlodipine on ventricular hypertrophy in hypertension patients: a systematic review and meta-analysis.

Left ventricular (LV) hypertrophy predicts worse cardiac outcomes. Blood pressure lowering is associated with the reduction of LV hypertrophy. This study evaluated the effect of a calcium channel blocker, amlodipine, on LV hypertrophy in patients with hypertension. Studies were identified by conducting a literature survey in electronic databases, and study selection was carried out according to precise eligibility criteria. Meta-analyses of mean change between the follow-up and baseline values of systolic/diastolic blood pressure (SBP/DBP) and LV hypertrophy indices were performed. Meta-regression analyses were performed to examine the factors affecting changes in these indices. Twenty-three studies [involving 737 patients; age 56.4 years, 95% confidence interval (CI): 53.5-59.2; females 34%, 95% CI: 25-44%; body mass index 26.4 kg/m2, 95% CI: 24.6-28.1] were included. Amlodipine treatment led to a significant reduction in SBP (-24.9 mmHg; 95% CI: -28.3 to -21.6; P<0.0001) and DBP (-14.8; 95% CI: -16.4 to -13.3; P<0.0001), without affecting the heart rate. Amlodipine treatment also significantly reduced the LV mass index. The mean difference (MD) between the follow-up and baseline LV mass index was -12.9; 95% CI: -15.4 to -10.4 (P<0.001). This decrease in LV mass index was positively associated with the follow-up duration [meta-regression coefficient (MC): 0.392; 95% CI: 0.050-0.733; P=0.026] and baseline LV mass index (MC: 0.139; 95% CI: 0.007-0.271; P=0.040). Amlodipine treatment significantly reduced the LV posterior wall thickness, which was also positively associated with the follow-up duration. There was no significant decrease in the LV end-diastolic diameter following amlodipine treatment. Amlodipine treatment in patients with hypertension significantly reduced the LV mass index and LV posterior wall thickness, without notably affecting the LV end-diastolic diameter. Since many of the included studies were non-randomized, open-label, or lacking appropriate comparability, we therefore performed pooled analyses of the changes from baseline, and a comparative account could not be carried out.

CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in mice upon transverse aortic constriction.

The CX3CL1/CX3CR1 axis mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and plays a pivotal role in the inflammation-driven pathology of cardiovascular disease. The cardiac immune response differs depending on the underlying causes. This suggests that for the development of successful immunomodulatory therapy in heart failure due to chronic pressure overload induced left ventricular (LV) hypertrophy, the underlying immune patterns must be examined. Here, the authors demonstrate that Fraktalkine-receptor CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in a mouse model of transverse aortic constriction (TAC). The comparison of C57BL/6 mice with CX3CR1 deficient mice displayed reduced LV hypertrophy and preserved cardiac function in response to pressure overload in mice lacking CX3CR1. Moreover, the normal immune response following TAC induced pressure overload which is dominated by Ly6Clow macrophages changed to an early pro-inflammatory immune response driven by neutrophils, Ly6Chigh macrophages and altered cytokine expression pattern in CX3CR1 deficient mice. In this early inflammatory phase of LV hypertrophy Ly6Chigh monocytes infiltrated the heart in response to a C-C chemokine ligand 2 burst. CX3CR1 expression impacts the immune response in the development of LV hypertrophy and its absence has clear cardioprotective effects. Hence, suppression of CX3CR1 may be an important immunomodulatory therapeutic target to ameliorate pressure-overload induced heart failure.

P0693THE MATRIX PROTEIN THROMBOSPONDIN-1 CONTRIBUTES TO THE DEVELOPMENT OF CARDIOVASCULAR PATHOLOGY IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Patients with chronic kidney disease (CKD) are at significantly greater risk of cardiovascular disease (CVD), which remains the leading cause of hospitalisation and mortality. Cardiovascular complications are 20-30 times more likely to occur in these patients than progression to end-stage kidney disease. Traditional cardiovascular risk factors are prevalent in patients with CKD, but clinical trials targeting standard cardiovascular risks have failed to improve outcomes in patients with CKD. This has led to the investigation of non-traditional pathways that drive the development of the CVD in CKD. The matrix protein thrombospondin-1 (TSP1), and its receptor CD47, regulates cell responses and we recently identified their role in acute kidney injury. We now investigate this pathway in vascular changes in CKD. Method Human plasma TSP1 was collected from n=120 patients attending outpatient clinics and measured by ELISA. Age matched male C57BL/6 (WT) and TSP1KO mice (on a C57BL/6 background) were used to develop a model of CKD employing a 5/6 nephrectomy technique (5/6Nx). Blood pressure and weight were checked weekly, and echocardiography analysed cardiac function at baseline. After 12 weeks, we performed echocardiography and biomolecular phenotyping on tissues. Human cardiomyocytes were used to assess the effect of TSP1 and the uremic toxin indoxyl sulfate on cell proliferation and senescence. Results Linear regression analysis demonstrate that plasma TSP1 correlated inversely with eGFR (r2=-0.556, p&amp;lt;0.001). WT mice undergoing 5/6Nx developed renal interstitial fibrosis, hypertension, and left ventricular (LV) hypertrophy after 12 weeks. Echocardiography confirmed LV thickness with a concurrent reduction in LV ejection fraction compared to baseline. Histologic examination of WT myocardium revealed interstitial and perivascular fibrosis, and increased myocardial TSP1 expression. These findings were mitigated in TSP1KO mice who had preserved LV function, reduced LV hypertrophy and reduced cardiac fibrosis despite equivalent changes in renal mass and blood pressure. mRNA levels of cardiac-based TNF-α, IL-6, collagen-1, fibronectin and α-smooth muscle actin were increased in WT 5/6Nx mice compared to sham-operated controls, and transcript expression was robustly reduced in TSP1KO mice. In vitro, the addition of uremic toxin (indoxyl sulfate) to cardiomyocytes robustly upregulated expression of TSP1, and this was dependent upon activation of the aryl hydrocarbon receptor. TSP1 significantly down-regulated cardiomyocte proliferation and increased β-galactosidase activity. Pre-incubation with a blocking antibody reversed the proliferative and senescent effects of indoxyl sulfate and TSP1. Conclusion Our findings show that TSP1 is elevated in CKD and may drive the cardiovascular manifestations of uremia. TSP1KO mice were protected from disease, suggestion this protein has a crucial role in the development of CVD. Manipulation of TSP1 signaling is an attractive target to potentially reduce the excessive burden of CVD seen in the CKD population.

Lyso−Gb3is not a predictive biomarker of treatment response in migalastat-treated patients with migalastat-amenable variants

Fabry disease (FD) is an X-linked disorder caused by mutations in GLA gene responsible for coding of the lysosomal enzyme alpha-galactosidase A(α-GAL). The resultant accumulation of globotriaosylceramide (Gb-3) leads to multisystemic disease including progressive chronic kidney disease, hypertrophic cardiomyopathy, stroke, angiokeratomas and corneal whorls. Current treatments include enzyme replacement therapy (ERT), along with recent advent of chaperone therapy. ERT has not shown to have dramatic improvement in outcomes for all organ systems, with benefit mostly seen in kidney disease and reduction in left ventricular hypertrophy. ERT, however, is associated with formation of anti-drug antibodies and requirement of long-term venous access, while chaperone therapy can only be used in amenable mutations. A multitude of therapies are now under investigation in various phases of clinical trials. These include pegylated form of α-GAL (pegunigalsidase alpha), gene therapy (both in-vivo and ex-vivo methods), mRNA therapy (inducing production of α-GAL) and substrate reduction therapy (inhibitors of glucosylceramide synthase leading to reduction of Gb-3). This review encapsulates literature pertaining to current and investigational therapies for FD.

Changes in Left Ventricular Mass and Cardiovascular Risk Factors after Kidney Transplantation.

Left ventricular hypertrophy (LVH), the most common structural cardiac complication, is the single most important cause for sudden cardiac death. There are no published data from India looking at the changes in left ventricular mass and cardiac dysfunction after kidney transplantation. We aimed to determine the changes in the left ventricular mass and other cardiovascular risk factors in kidney transplant recipients. This was a prospective observational study. All patients who underwent kidney transplantation at Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, during the study period were included in the study. Measurement of clinical and biochemical parameters and echocardiography were done before, six months, and one year after transplantation. There was significant reduction in LV mass index (124.8 ± 39 vs. 102.2 ± 24.4 g/m2, P <0.001) and improvement in ejection fraction (57.8 ± 7 vs. 60.1 ± 1.9, P = 0.015) at the end of six months. There were significant differences in the mean hemoglobin, systolic, and diastolic blood pressures (P <0.001) during the study. There was also a significant reduction in the number of antihypertensive drugs required for blood pressure control. There was a significant reduction in LVH in the study group. There was also improvement in systolic and diastolic functions of the heart. There was also a significant improvement in blood pressure control both in terms of mean blood pressure levels as well as in terms of the number of anti-hypertensive drugs needed for blood pressure control. Renal transplantation ameliorates cardiovascular risk in renal transplant recipients.

Long-term effects of Na+ /Ca2+ exchanger inhibition with ORM-11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but there is currently no established pharmacological therapy. We hypothesized that ORM-11035, a novel specific Na+ /Ca2+ exchanger (NCX) inhibitor, improves cardiac function and remodelling independent of effects on arterial blood pressure in a model of cardiorenal HFpEF. Rats were subjected to subtotal nephrectomy (NXT) or sham operation. Eight weeks after intervention, treatment for 16 weeks with ORM-11035 (1mg/kg body weight) or vehicle was initiated. At 24 weeks, blood pressure measurements, echocardiography and pressure-volume loops were performed. Contractile function, Ca2+ transients and NCX-mediated Ca2+ extrusion were measured in isolated ventricular cardiomyocytes. NXT rats (untreated) showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV end-diastolic pressure (LVEDP) elevation, increased brain natriuretic peptide (BNP) levels, preserved ejection fraction and pulmonary congestion. In cardiomyocytes from untreated NXT rats, early relaxation was prolonged and NCX-mediated Ca2+ extrusion was decreased. Chronic treatment with ORM-11035 significantly reduced LV hypertrophy and cardiac remodelling without lowering systolic blood pressure. LVEDP [14 ± 3 vs. 9± 2 mmHg; NXT (n= 12) vs. NXT + ORM (n= 12); P= 0.0002] and BNP levels [71 ± 12 vs. 49 ± 11 pg/mL; NXT (n= 12) vs. NXT + ORM (n= 12); P< 0.0001] were reduced after ORM treatment. LV cardiomyocytes from ORM-treated rats showed improved active relaxation and diastolic cytosolic Ca2+ decay as well as restored NCX-mediated Ca2+ removal, indicating NCX modulation with ORM-11035 as a promising target in the treatment of HFpEF. Chronic inhibition of NCX with ORM-11035 significantly attenuated cardiac remodelling and diastolic dysfunction without lowering systemic blood pressure in this model of HFpEF. Therefore, long-term treatment with selective NCX inhibitors such as ORM-11035 should be evaluated further in the treatment of heart failure.

Alpha-calcitonin gene-related peptide prevents pressure-overload induced heart failure: role of apoptosis and oxidative stress.

Alpha‐calcitonin gene‐related peptide (α‐CGRP) is a 37‐amino acid neuropeptide that plays an important protective role in modulating cardiovascular diseases. Deletion of the α‐CGRP gene increases the vulnerability of the heart to pressure‐induced heart failure and the administration of a modified α‐CGRP agonist decreases this vulnerability. Systemic administration of α‐CGRP decreases blood pressure in normotensive and hypertensive animals and humans. Here we examined the protective effect of long‐term administration of native α‐CGRP against pressure‐overload heart failure and the likely mechanism(s) of its action. Transverse aortic constriction (TAC) was performed to induce pressure‐overload heart failure in mice. We found that TAC significantly decreased left ventricular (LV) fractional shortening, ejection fraction, and α‐CGRP content, and increased hypertrophy, dilation, and fibrosis compared to sham mice. Administration of α‐CGRP‐filled mini‐osmotic pumps (4 mg/kg bwt/day) in TAC mice preserved cardiac function and LV α‐CGRP levels, and reduced LV hypertrophy, dilation, and fibrosis to levels comparable to sham mice. Additionally, TAC pressure‐overload significantly increased LV apoptosis and oxidative stress compared to the sham mice but these increases were prevented by α‐CGRP administration. α‐CGRP administration in TAC animals decreased LV AMPK phosphorylation levels and the expression of sirt1, both of which are regulatory markers of oxidative stress and energy metabolism. These results demonstrate that native α‐CGRP is protective against pressure‐overload induced heart failure. The mechanism of this cardio‐protection is likely through the prevention of apoptosis and oxidative stress, possibly mediated by sirt1 and AMPK. Thus, α‐CGRP is a potential therapeutic agent in preventing the progression to heart failure, and the cardio‐protective action of α‐CGRP is likely the result of a direct cellular effect; however, a partial vasodilatory blood pressure‐dependent mechanism of α‐CGRP cannot be excluded.

La réadaptation du patient valvulaire

Valvular disease is the second indication of cardiac rehabilitation (CR) after coronary artery disease. Patients suffering valvular disease are addressed to CR after valvular repair, and are usually old. Valvular replacement are the most frequent, and more and more patients being treated by TAVI are addressed to CR. CR takes place on two phases: From the seventh (day 7) to the fifteenth (day 15) day: management of complications, respiratory physio, and help to autonomy if necessary. From the fifteenth day (day 15): rehabilitation to exercise after an exercise stress test with or without MVO2 measurement. Because the patients are taking anticoagulants and are at risk of endocarditis, therapeutic education takes an important place during the stage. CR of patients suffering valvular disease has demonstrated its usefulness with: An increase of exercise capacity in all kind of valvular disease; A reduction of left ventricular hypertrophy in patients with aortic valve stenosis. No serious complication was observed in all studies regarding CR in patients with valvular disease.

P5996HDAC inhibition improves myofibrillar relaxation and metabolism in a feline model of HFpEF

Abstract Background Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for about 50% of all cases of HF and there are currently no effective therapies. Purpose To assess the effects of histone deacetylase (HDAC) inhibition on cardiac and mitochondrial function and the plasma metabolome in a large mammalian model of slow-progressive pressure overload with features of HFpEF. Methods Male domestic short hair cats (n=26, aged 2mo), underwent either sham (S) procedures (n=5) or aortic constriction with a customized pre-shaped band (n=21), resulting in slow progressive pressure overload during growth. 2 months post-banding, animals were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), a pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Serial in-vivo cardiopulmonary phenotyping was performed monthly, and invasive hemodynamic and gas exchange parameters were evaluated 4 months post-banding. Ex-vivo myofibril mechanical studies and blood-based metabolomic profiling were performed. Data is presented as mean±SEM. Results Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs. b+veh animals. Left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly lower in b+SAHA vs. b+veh. SAHA treatment also improved ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, and improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness and intrapulmonary shunt. SAHA treatment also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Treatment with SAHA caused an increase in both oxygen consumption in-vivo and the percentage of type 1 skeletal muscle fibers (higher oxidative capacity). SAHA also increased mRNA levels of coactivators that regulate mitochondrial function and induced metabolic reprogramming towards mitochondrial oxidation preferentially utilizing fatty acids. SAHA treated HeLa cells showed a significant increase in oxidative phosphorylation and ATP production. Effects of SAHA Conclusion These results show that slow-progressive pressure overload mimics critical features of HFpEF. SAHA can improve cardiac, pulmonary, and metabolic derangements caused by chronic pressure overload. Therefore, HDAC inhibition may be an interesting therapeutic strategy to treat the ever growing HFpEF population. Acknowledgement/Funding NIH [HL33921 to S.R.H, HL116848, HL127240 to T.A.M]; AHA [16SFRN31400013 to T.A.M.]; Medical University of Graz [M.W.], Stadt Graz [M.W.]

The mechanism of adaptation of the organism of patients with chronic heart failure combined with vitamin D deficiency and the morphofunctional state of peripheral blood erythrocytes

The problem of structural changes in peripheral blood erythrocytes in patients with chronic heart failure in combination with vitamin D deficiency during exercise stress remains insufficiently studied. Vitamin receptors are located on smooth myocytes, endothelial cells, cardiomyocytes and blood cells. It affects the state of the cell membrane, the contractile function of the myocardium, the regulation of blood pressure, cardiac remodeling and reduction of left ventricular hypertrophy. Therefore, it is important to assess the level of vitamin D in blood plasma in individuals with chronic heart failure and to identify the effect of its deficiency on the state of peripheral red blood cells when performing a 6-minute walk test. A total of 75 patients of the main group with chronic heart failure stage II A, I–II functional class with different levels of vitamin D deficiency were examined. The control group included 25 patients with chronic heart failure stage II A, functional class I–II without signs of vitamin D deficiency. The average age of patients was 57.5 ± 7.5 years. All patients were asked to undergo the 6 minutes walking test. The level of total vitamin D in plasma was determined by enzyme immunoassay. Morphological studies of erythrocytes were performed on the light-optical and electron-microscopic level. The obtained results showed that patients of the main group with chronic heart failure had a decrease in vitamin D by 2.2 times compared with the control group. Correlation analysis showed a directly proportional relationship between vitamin D deficiency and the number of red blood cells of a modified form and red blood cells with low osmotic resistance. Dosed exercise stress in patients with chronic heart failure against a background of vitamin D deficiency leads to an increase in the number of reversibly and irreversibly deformed erythrocytes and a decrease in their osmotic stability. This indicates a disorder in the structural integrity of their membrane and can have negative consequences for the somatic health of such patients.