Development Of Left Ventricular Hypertrophy Research Articles

Tlr2 deficiency does not limit the development of left ventricular hypertrophy in a model of transverse aortic constriction induced pressure overload.

BackgroundToll-like receptors (TLRs) are involved in a variety of cardiovascular disorders, including septic cardiomyopathy, ischemia/reperfusion, heart failure, and cardiac hypertrophy. Previous research revealed that TLR4 promotes cardiac hypertrophy in vivo. Therefore, we investigated whether TLR2 is also involved in the development of cardiac hypertrophy.MethodsTlr2 deficient and wild type mice were subjected to transverse aortic constriction (TAC) or sham operation procedure. Left ventricular, heart and lung weights as well as hemodynamic parameters were determined after 3, 14 or 28 days. Real-time RT PCR was used to evaluate left ventricular gene expression. Protein content was determined via ELISA.ResultsTAC increased systolic left ventricular pressure, contraction and relaxations velocities as well as the heart weight in both genotypes. Tlr2 deficiency significantly enhanced cardiac hypertrophy after 14 and 28 days of TAC. Left ventricular end-diastolic pressure and heart rate increased in Tlr2−/− TAC mice only. Fourteen days of TAC led to a significant elevation of ANP, BNP, TGFβ and TLR4 mRNA levels in Tlr2−/− left ventricular tissue.ConclusionThese data suggest that Tlr2 deficiency may promote the development of cardiac hypertrophy and ventricular remodeling after transverse aortic constriction.

PERSISTENCE OR DEVELOPMENT OF NEW ELECTROCARDIOGRAPHIC LEFT VENTRICULAR HYPERTROPHY BY BOTH CORNELL PRODUCT AND SOKOLOW-LYON VOLTAGE IS ASSOCIATED WITH MARKEDLY INCREASED RISK DURING ANTIHYPERTENSIVE THERAPY

Hypertensive patients with ECG left ventricular hypertrophy (LVH) are at increased risk, but single ECG criteria may underestimate risk. Whether the continued presence or new development of ECG LVH by two criteria can further concentrate risk during blood pressure (BP) lowering is unclear. Incident

KNOW-Ped CKD (KoreaN cohort study for outcomes in patients with pediatric CKD): Design and methods

BackgroundThe global prevalence of chronic kidney disease (CKD) is increasing. In children, CKD exhibits unique etiologies and can have serious impacts on children’s growth and development. Therefore, an aggressive approach to preventing the progression of CKD and its complications is imperative. To improve the understanding and management of Asian pediatric patients with CKD, we designed and launched KNOW-Ped CKD (KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease), a nationwide, prospective, and observational cohort study of pediatric CKD with funding from the Korean government.Methods/designFrom seven major centers, 450 patients <20 years of age with CKD stages I to V are recruited for the comprehensive assessment of clinical findings, structured follow-up, and bio-specimen collection. The primary endpoints include CKD progression, defined as a decline of estimated glomerular filtration rate by 50 %, and a requirement for renal replacement therapy or death. The secondary outcomes include the development of left ventricular hypertrophy or hypertension, impairment of growth, neuropsychological status, behavioral status, kidney growth, and quality of life.DiscussionWith this study, we expect to obtain more information on pediatric CKD, which can be translated to better management for the patients.Trial registrationNCT02165878 (ClinicalTrials.gov), submitted on June 11, 2014.

GPER is required for the age-dependent upregulation of the myocardial endothelin system

AimsCardiac aging is associated with progressive structural changes and functional impairment, such as left ventricular hypertrophy, fibrosis and diastolic dysfunction. Aging also increases myocardial activity of endothelin-1 (ET-1), a multifunctional peptide with growth-promoting and pro-fibrotic activity. Because the G protein-coupled estrogen receptor (GPER) regulates vascular responsiveness to ET-1, we investigated whether GPER also plays a role in the regulation of the myocardial endothelin system with aging. Main methodsYoung (4month-old) and aged (24month-old) wild-type and Gper-deficient (Gper−/−) mice were studied. Gene expression levels of prepro-ET-1, endothelin converting enzymes ECE-1 and ECE-2, and endothelin ETA and ETB receptors were determined by qPCR in left ventricular myocardium. Key findingsAging markedly increased steady-state mRNA expression levels of ECE-1, ECE-2, ETA and ETB receptors (each p<0.001 vs. young mice). Deletion of Gper inhibited the age-dependent increase in ECE-2 and ETB receptor mRNA levels (57% and 40% reduction, respectively, each p<0.01 vs. wild-type mice), whereas gene expression of prepro-ET-1, ECE-1, and the ETA receptor was unaffected in Gper−/− mice. SignificanceWe identified a novel regulatory mechanism through which the endogenous Gper facilitates the age-dependent increase in myocardial expression of ECE-2 and the ETB receptor, which is compatible with an activating role of GPER for the local endothelin system with aging. Targeting GPER signaling by selective antagonists may therefore be considered a new therapeutic approach to reduce age-dependent increased ET-1 activity and the associated development of left ventricular hypertrophy, fibrosis and heart failure.

Beneficial effect of bilateral native nephrectomy as complete denervation on left ventricular mass and function in renal transplant recipients.

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular morbidity and mortality in renal transplant recipients. The development of LVH is connected with excessive activation of the sympathetic nervous system. A bilateral nephrectomy is an example of complete renal denervation. The aim of this study was to evaluate the effect of pretransplant bilateral native nephrectomy on left ventricular mass and function during a long-term follow-up of patients after kidney transplantation. The study group consisted of 32 renal transplant recipients who had previously undergone pretransplant bilateral native nephrectomy. The control group involved 32 recipients with preserved native kidneys, matched for age, sex, creatinine levels, estimated glomerular filtration rate, immunosuppressive treatment, and the time of renal replacement therapy. All patients were evaluated by echocardiography, and 16 patients--by cardiac magnetic resonance (CMR). In addition, all patients had their arterial blood pressure (BP) and metabolic markers measured. In comparison with controls, the study group had lower systolic BP (P = 0.048) and received a lower number of antihypertensive agents (P = 0.001). Lipid and hemoglobin levels were similar in both groups. The study group had a lower left ventricular mass index (LVMI; P = 0.001) and left atrial volume index (LAVI; P = 0.004). The left ventricular mass evaluated by CMR was also lower in the study group (P <0.001). Mild left ventricular diastolic dysfunction (LVDD) was more frequent in the study group compared with the control group ( P <0.001). In a long-term follow-up of patients after kidney transplantation, the bilateral native nephrectomy before transplantation was associated with a lower LVMI and LAVI as well as a lower grade of LVDD. These patients had lower systolic BP and used fewer antihypertensive drugs.

Association of ACE gene D polymorphism with left ventricular hypertrophy in patients with diastolic heart failure: a case–control study

ObjectivesTo explore the association between ACE gene insertion/deletion (I/D) polymorphism with left ventricular hypertrophy (LVH) in patients with hypertension who have developed heart failure with preserved ejection fraction (HFpEF). Being...

Factors Contributing to Development and Reversal of LVH: A Pilot Study.

Left Ventricular Hypertrophy (LVH) often reflects as a physiological adaptation to chronic pressure overload. It has been identified as a strong independent risk factor of all-cause mortality and adverse cardiac events. Since not all subjects with hypertension develop LVH, understanding the clinical factors contributing to the development of LVH and the appropriate diagnostic and treatment strategies may help clinicians in conducting more definitive evaluation and managing the disease effectively. To assess the incidence of LVH in hypertensive subjects and the factors influencing its development and reversal. The study also evaluated the most effective diagnostic technique and therapy that could improve the disease symptoms and prognosis. The prospective study, conducted at Jagadguru Sri Shivarathreeshwara (JSS) Medical College JSS University, Mysore, India, included 50 patients with hypertension. Detailed history of the recruited subjects was collected from patient records and through physical examination. Demographic and clinical characteristics such as age, gender, BMI, and stage of hypertension (stage I HTN and stage II HTN) were also obtained. Funduscopic examination was done for all patients for evidence of hypertensive retinopathy. Echocardiography (ECHO), electrocardiography (ECG), and chest X-Ray were used for detection of LVH. The patients were reviewed after six months and reassessment of LVH was carried out. Statistical analysis was conducted using SPSS software and R 3.2 package. Angiotensin-Converting Enzyme (ACE) inhibitors were found to be more effective in the treatment of LVH when compared to calcium channel blockers and beta blockers. ECHO was found to be the best method to diagnose LVH. In patients with stage I HTN, 47.1% had normal LVM. Around 53% of the subjects with stage I HTN and all with stage II HTN had abnormal LVM. Retinal changes were noted in 96.2% of abnormal LVM patients and 50% of normal LVM patients. A positive association between BMI and LVH (OR: 1.39) was also noted. BMI may positively influence LVH regression. The presence of retinopathy, in addition to LVH, suggests an increased chance of regression with anti-hypertensive treatment.

Management of hypertension in patients with end-stage renal disease leading to haemodialysis: a challenge

The majority of the patients of end-stage renal disease (ESRD) leading to haemodialysis suffer from hypertension. Increase in blood pressure is both a cause and a consequence of chronic kidney disease and inadequate control of blood pressure in these patients increases the risk of development of left ventricular hypertrophy, congestive heart failure, stroke and other cardiovascular and neurological complications leading to high morbidity and mortality in these patients. In a meta-analysis of randomized controlled trials of antihypertensive therapy in haemodialysis patients, blood pressure lowering treatment was associated with a 29% lower relative risk of cardiovascular mortality and a 20% lower relative risk of all-cause mortality. While blood pressure control may improve cardiovascular mortality and morbidity, the management of hypertension is a big challenge in these patients especially in developing countries like India where the maintenance of optimal dry weight in between the dialysis therapy is inadequate due to high cost of hemodialysis and limited number of centers providing dialysis therapy. The aim of the present review the evidence on the optimal systolic and diastolic blood pressure in the patients on haemodialysis and the most effective drug or group of drugs that can provide adequate blood pressure control in all phases of dialysis (pre, post, intra and interdialytic phases) without complications like intradialytic hypotension or hypertension and good patient compliance.

The Role of Obesity in the Development of Left Ventricular Hypertrophy Among Children and Adolescents.

Both obesity and hypertension have increased substantially among children over the last several decades. At the same time, mounting evidence has pointed to the role of these and other cardiovascular disease risk factors on the development of end organ damage such as left ventricular hypertrophy in children. While traditionally thought to occur in response to an increased afterload as in systemic hypertension, evidence demonstrates that obesity is associated with left ventricular hypertrophy independent of blood pressure. Both hemodynamic and non-hemodynamic factors contribute to the pathogenesis of obesity-related left ventricular remodeling. However, more contemporary research suggests that adiposity and blood pressure have a greater effect on left ventricular geometry when present together than when present alone. Normalization of left ventricular mass in obese hypertensive individuals requires achievement of both normotension and weight loss. Additional strategies are needed to promote the cardiovascular health of children, with greater emphasis placed on obesity prevention.

Association of clinical and genetic factors with left ventricular hypertrophy in hypertension among the indigenous population Mountain Shoria

Objective. To determine the association of clinical and genetic factors with the left ventricular hypertrophy among indigenous patients with hypertension living in Mountain Shoria.Design and methods. A clinical-epidemiological study of Mountain Shoria indigenous populations at isolated regions was undertaken. Continuous method surveyed 547 people, consisted of a sample of the adult population (18 years and older). Studied anthropometric data, lipid spectrum of the blood polymorphisms of genes ADRB1 (Ser49Gly, A/G, rs1801252) ADRA2B (I/D), ACE (I/D), eNOS (4a/4b) and MTHFR (C677T, Ala222Val, rs1801133) and their association with left ventricular hypertrophy.Results. The left ventricular hypertrophy in patients with hypertension was detected in 47.3% of the respondents. The odds ratio found among patients with hypertension duration of 5 years with the respondents hypertrophied myocardium 0.5 times lower (38.2%) than people without this disease of the heart - 61.8%, while among those with hypertension long history of more than 10 years, 4.1 times higher: 73.3% vs 26.7%. In a population of Shor hypercholesterolemia and giperbetaholesterinemiya associated with exaggerated myocardial damage. The percentage of smokers in a cohort of patients with hypertensive cardiac disease was (37.8%) and was higher by 2.0 times than in hypertensive patients without left ventricular hypertrophy (22.0%). With the relative risk of hypertension with myocardial damage in a population Shor associated gene ACE I allele. The odds ratio of hypertension to identify patients with cardiac respondents with heterozygous genotype AG ADRB1 gene was 3.0 times higher compared to the surveyed individuals with homozygous genotypes AA and GG.Conclusion. Among Shor risk of hypertension with left ventricular hypertrophy was influenced by factors: prolonged duration of the disease more than 10 years, smoking, hypercholesterolemia, giperbetaholesterinemiya. Installed Association II genotype of ACE gene and gene genotype AG ADRB1s development of left ventricular hypertrophy in patients with arterial hypertension in the population of Shor.

Noninvasive Detection of Early Metabolic Left Ventricular Remodeling in Systemic Hypertension

Objectives: Hypertension (HTN) is a common cause of left ventricular hypertrophy (LVH). Sustained pressure overload induces a permanent myocardial switch from fatty-acid to glucose metabolism. In this study, we tested the hypothesis that metabolic remodeling, characterized by increased myocardial glucose uptake, precedes structural and functional remodeling in HTN-induced LVH. Methods: We recruited 31 patients: 11 with HTN only, 9 with HTN and LVH and 11 normotensive controls without LVH. Transthoracic echocardiography was performed to assess the function, mass, wall thickness and diastolic function of the left ventricle. Positron emission tomography imaging was performed, and the rate of myocardial 2-deoxy-2-[¹⁸F]fluoro-<smlcap>D</smlcap>-glucose uptake, Ki, was determined using a 3-compartment kinetic model. Results: The mean Ki values were significantly higher in HTN patients than in those with HTN and LVH (p < 0.001) and in controls (p = 0.003). The unexpected decrease in Ki with LVH may be secondary to a decreased Ki with diastolic dysfunction (DD), 0.039 ± 0.032 versus 0.072 ± 0.013 (p = 0.004). There was also a significant stepwise decrease in Ki with increasing DD grade (p = 0.04). Conclusion: Glucose metabolic remodeling is detectable in hypertensive patients before the development of LVH. Furthermore, lower glucose uptake rates are observed in patients with DD. The mechanism for this last finding requires further investigation.

Does low peritoneal glucose load protect from the development of left ventricular hypertrophy in peritoneal dialysis patients?

Left ventricular hypertrophy (LVH) is a major predictor of the development of cardiovascular events that is considered the main cause of morbidity and mortality in peritoneal dialysis (PD) patients. This study aimed to evaluate retrospectively the impact of low peritoneal glucose load on left ventricular mass (LVM) in PD patients. 36 patients who were on continuous ambulatory PD for at least a period of 2years enrolled in the study. Of them, 23 patients received only glucose-based solutions (GBS) [high peritoneal glucose load group (HPGL group)] from the start of PD, and 13 patients received AAS in combination with GBS when their serum albumin decreased to levels <3.5g/dl [low peritoneal glucose load group (LPGL group)]. AAS was substituted with 1.36% GBS when serum albumin rose to ≥3.5g/dl and restarted when serum albumin fell to <3.5g/dl. Medical history, physical findings, echocardiographic, laboratory and hydration status data from the first month of PD and after 24months, were obtained from each patient's medical records. Mean LVM index (LVMI) increased in both groups (p≤0.010). The increment in mean LVMI was higher in HPGL group compared to LPGL group (p=0.006). At 24months: peritoneal glucose load index (PGLI), fluid overload, mean arterial pressure (MAP), HbA1c and hsCRP were higher in HPGL group (p≤0.010), while 24h ultrafiltration, weekly Kt/V, serum albumin levels and RRF were higher in LPGL group (p≤0.025). The increment (Δ between the values of each parameter from the start of PD and after 24months) in PGLI, fluid overload, MAP, HbA1c and hsCRP values were higher in HPGL group (p<0.001). Low peritoneal glucose load may be associated with a protective effect from the development of LVH in PD patients.

Abstract 17429: A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Sustained Severe Hypertension

Background: Currently, the lack of well-established large animal models of heart failure with preserved ejection fraction (HFpEF) is one of the major hurdles for developing effective therapies for HFpEF. Here, we describe a large animal model of HFpEF induced by sustained hypertension (HT) that mimics human diseases. Methods: We induced sustained severe hypertension in 9 adult pigs using a combination of intravenous Angiotensin-II (Ang-II, 0.015mg/hr) delivery with an osmotic infusion pump and subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets (100mg/kg) for 10 weeks. All animals underwent invasive blood pressure (BP) telemetry monitoring and serial invasive pressure-volume (PV) loop assessment as well as echocardiographic examination at baseline, 10 weeks and 18 weeks. Results: Mean systolic and diastolic BP at baseline was 88/61 mmHg which increased immediately after Ang-II infusion plus DOCA (Week 0,158/105 mmHg) and progressively elevated up to Week 10 (171/126mmHg) that persisted out to Week 18 (183/137mmHg) despite termination of Ang-II infusion. Serial echocardiograms showed the development of left ventricular hypertrophy with significant increase in left ventricular mass with preserved left ventricular ejection fraction (Figure, upper panel). PV loop showed progressive elevation of pulmonary artery capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure volume relationship (EDPVR) without change in end-systolic pressure volume relationship, suggestive of left ventricular diastolic dysfunction (Figure, lower panel). Conclusions: We successfully established a clinically relevant large animal model of HFpEF induced by sustained HT, which can be used for future investigation of new treatments for HFpEF.

Abstract 14278: The Impact of American-Style Football Participation on Left Ventricular Systolic Function

Introduction: Participation in American-Style Football (ASF) has been associated with the development of hypertension and left ventricular hypertrophy (LVH). To date, data defining the impact of ASF participation on myocardial function are lacking. We hypothesized that the LVH developed among ASF participants is accompanied by relative impairment in systolic function as measured by LV global longitudinal strain (GLS), a well-established marker of subclinical LV dysfunction. Methods: Collegiate ASF athletes were studied before (preseason) and after (postseason) a single competitive season with transthoracic echocardiography. LV systolic function was assessed using complementary parameters including GLS (speckle tracking) and ejection fraction (EF, 2D biplane). Analyses were stratified as a function of lineman (LM, n=30) versus non-lineman (NLM, n=57) field position. Results: Among 87 athletes analyzed, ASF participation was associated with significant increases in systolic blood pressure (SBP, 119±10 vs. 124±13 mmHg; p&lt;0.05), BSA-indexed LV mass (LVMI, 95±15 vs. 104±13 g/m2; p&lt;0.05), and prevalent LVH (8% vs. 25%, p&lt;0.05). The majority of LM with LVH (9/11, 82%) had concentric geometry while hypertrophied NLM (8/10, 80%) had eccentric geometry. In this context, LM demonstrated a significant decrease in GLS which was associated with changes in LV mass and SBP while NLM demonstrated an increase in GLS unrelated to either mass or SBP (Figure). Left ventricular EF was similar at both time points and did not differ by field position. Conclusions: The geometry and functional correlates of LVH among ASF participants vary by field position. Athletes at the LM position appear to be at risk for developing concentric LVH with relative impairment of GLS, while NLM athletes tend to harbor eccentric LVH without decrement in GLS. The underlying mechanisms, reversibility, and long-term prognostic significance of these findings represent important areas of future study.

Abstract 11988: Waist Circumference and Systolic Blood Pressure Are Predictors of Left Ventricular Hypertrophy in Healthy Individuals

Introduction: Left ventricular hypertrophy (LVH) is considered to be a cause of heart failure. Previous studies indicated that patients with metabolic syndrome (MetS) and obesity might be at risk for cardiovascular disease (CVD). However, little is known about which MetS factors contribute to the development of LVH in healthy adults. Hypothesis: The aim of this study was to identify factors related to CVD and major organ dysfunction that could act as predictors of LVH based on thorough medical examinations of healthy subjects. Methods: A total of 1056 participants without diabetes mellitus, systolic dysfunction, chronic kidney disease, or other heart diseases underwent a thorough physical examination including transthoracic echocardiography. LV mass index (LVMI) ≥ 51 g/m2.7 was considered LVH. Single and multiple logistic regression analyses of LVMI and cardiovascular risk factors, including MetS factors and indicators of major organ dysfunction, were performed. Obese subjects (WC ≥ 85 cm in males and ≥ 90 cm in females) and non-obese subjects were also analyzed separately. Results: A total of 980 adults (age 62.8 ± 12.7 y, male 573) were analyzed, and LVH was observed in 21.5% of subjects (n = 211, male 155). Overall, 33.0% (43 of 434) of obese subjects had LVH. LVH was correlated with age, systolic blood pressure (SBP), diastolic BP, estimated glomerular filtration rate, total bilirubin, fasting blood sugar, HbA1c, and WC. Multiple logistic regression analysis indicated that age, high SBP (≥130 mmHg) and WC were independent predictors of LVMI (odds ratios 1.05, 1.99, 3.03; 95% confidence intervals 1.01-1.06, 1.42-2.79, 2.16-4.25, respectively, P&lt;0.01). In obese subjects, aging, WC, and high SBP were independent predictors of LVMI, but WC was not an independent predictor of LVMI in non-obese subjects. Moreover, the average WC was significantly higher in both males and females in obese (47.7 ± 13.5, 47.9 ± 14.1 g/m2.7) than in non-obese subjects (41.1 ± 10.3, 37.8 ± 10.1 g/m2.7). Conclusions: WC and SBP are independent risk factors for LHV in healthy individuals and, therefore, might be useful for predicting cardiovascular disease during routine physical checkups.

Molecular Mechanisms of Right Ventricular Failure

An abundance of data has provided insight into the mechanisms underlying the development of left ventricular (LV) hypertrophy and its progression to LV failure. In contrast, there is minimal data on the adaptation of the right ventricle (RV) to pressure and volume overload and the transition to RV failure. This is a critical clinical question, because the RV is uniquely at risk in many patients with repaired or palliated congenital heart disease and in those with pulmonary hypertension. Standard heart failure therapies have failed to improve function or survival in these patients, suggesting a divergence in the molecular mechanisms of RV versus LV failure. Although, on the cellular level, the remodeling responses of the RV and LV to pressure overload are largely similar, there are several key differences: the stressed RV is more susceptible to oxidative stress, has a reduced angiogenic response, and is more likely to activate cell death pathways than the stressed LV. Together, these differences could explain the more rapid progression of the RV to failure versus the LV. This review will highlight known molecular differences between the RV and LV responses to hemodynamic stress, the unique stressors on the RV associated with congenital heart disease, and the need to better understand these molecular mechanisms if we are to develop RV-specific heart failure therapeutics.

The prognostic legacy of left ventricular hypertrophy: cumulative evidence after the MAVI study.

Although regression of left ventricular hypertrophy (LVH) confers a marked prognostic benefit, it is unknown whether cardiovascular risk in these patients is comparable to those who never developed LVH. We analyzed the 'Massa Ventricolare sinistra nell'Ipertensione' (MAVI) study, a prospective study in which serial changes in left ventricular mass at echocardiography were associated with subsequent cardiovascular events. We also conducted a cumulative meta-analysis in order to investigate how evidence progressed in this field. We defined three phenotypes: persistently normal left ventricular mass; LVH regression; persistence/new development of LVH. Left ventricular mass was measured at baseline and 2 years after the initial assessment in 374 patients (64% women). Clinical outcomes were ascertained after the 2-year echocardiographic evaluation (mean follow-up 3.2 years). Persistence or new development of LVH was associated with an increased risk of cardiovascular events (odds ratio 1.96, 95% confidence interval 1.07-3.57, P = 0.029). In a cumulative meta-analyses that included MAVI and six comparable studies for a total of 2954 patients and 339 cardiovascular events, when a persistently normal left ventricular mass was taken as reference, regression of LVH was associated with 56% higher risk of cardiovascular events (odds ratio 1.56, 95% confidence interval 1.04-2.36, absolute risk increase 3%, P = 0.033). Conversely, evidence accrued from previous studies that persistence or new development of LVH predicts an adverse outcome did not change after MAVI. Cardiovascular risk is higher in patients with LVH regression than in those with persistently normal left ventricular mass. Preventing development of LVH is thus an important target.

Feasibility and significance of preclinical diagnosis in hypertrophic cardiomyopathy.

Preclinical diagnosis in hypertrophic cardiomyopathy (HCM) refers to the detection of functional or histopathological abnormalities in subjects who carry any HCM-causing gene mutation, before or even without the development of left ventricular hypertrophy [genotype(+)/phenotype(-)subjects]. The concept that HCM pathology may exist in the absence of left ventricular hypertrophy is quite old but the ability to recognize the presence of early myocardial changes is quite new. Lessons from animal models have shown that in experimental human HCM, myocardial cell mechanical dysfunction precedes histopathological changes, such as myocyte disarray, fibrosis, and hypertrophy. Several clinical reports have demonstrated that the majority of HCM genotype(+)/phenotype(-) subjects display myocardial functional or histopathological changes, such as reduced tissue Doppler imaging-derived systolic and diastolic velocities, abnormal electrocardiogram, cardiac magnetic resonance-visualized myocardial crypts, mitral leaflet elongation, and evidence of a fibrotic state, such as increased type I procollagen synthesis, cardiac magnetic resonance-increased myocardial extracellular volume, and late gadolinium myocardial enhancement. All these signs have been proposed as preclinical markers of HCM. At present the separation of such a group of subjects in the early phase of their disease provides the opportunity to test new therapies to prevent the development of fibrosis, hypertrophy, and dysfunction.

Macrophages dictate the progression and manifestation of hypertensive heart disease

Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling. We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p<0.05), and reduced cardiac fibrosis by 75%, compared with controls (p=0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p<0.05), and a 13% in LV mass (p=0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p=0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%). Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.

Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate

Endurance exercise training induces substantial adaptive cardiac modifications such as left ventricular hypertrophy (LVH). Simultaneously to the development of LVH, adipose tissue (AT) lipolysis becomes elevated upon endurance training to cope with enhanced energy demands. In this study, we investigated the impact of adipose tissue lipolysis on the development of exercise-induced cardiac hypertrophy. Mice deficient for adipose triglyceride lipase (Atgl) in AT (atATGL-KO) were challenged with chronic treadmill running. Exercise-induced AT lipolytic activity was significantly reduced in atATGL-KO mice accompanied by the absence of a plasma fatty acid (FA) increase. These processes were directly associated with a prominent attenuation of myocardial FA uptake in atATGL-KO and a significant reduction of the cardiac hypertrophic response to exercise. FA serum profiling revealed palmitoleic acid (C16:1n7) as a new molecular co-mediator of exercise-induced cardiac hypertrophy by inducing nonproliferative cardiomyocyte growth. In parallel, serum FA analysis and echocardiography were performed in 25 endurance athletes. In consonance, the serum C16:1n7 palmitoleate level exhibited a significantly positive correlation with diastolic interventricular septum thickness in those athletes. No correlation existed between linoleic acid (18:2n6) and diastolic interventricular septum thickness. Collectively, our data provide the first evidence that adipose tissue lipolysis directly promotes the development of exercise-induced cardiac hypertrophy involving the lipokine C16:1n7 palmitoleate as a molecular co-mediator. The identification of a lipokine involved in physiological cardiac growth may help to develop future lipid-based therapies for pathological LVH or heart failure.