The vasculature: a therapeutic target in heart failure?

It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.

NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo-DHF trial.

STUDY OBJECTIVE: This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) participants. DESIGN: Post-hoc genetic analysis. DATA SOURCE: Data and samples were derived from the multi-center, randomized, double-blind, placebo-controlled Aldo-DHF trial. PATIENTS: Aldo-DHF participants treated with spironolactone (n = 184) or placebo (n = 178) were included. INTERVENTION: Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing. MEASUREMENTS: In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area. MAIN RESULTS: Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to noncarriers (ß = 1.10; 95% confidence interval [CI]: 0.05-2.16; p = 0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (ß = 0.83; 95% CI: 0.17-1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (ß = -3.56; 95% CI: -6.73 to -0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes. CONCLUSIONS: Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.

Low-intensity pulsed ultrasound ameliorates cardiac diastolic dysfunction in mice: a possible novel therapy for heart failure with preserved left ventricular ejection fraction.

AIMS: Heart failure with preserved left ventricular ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice. METHODS AND RESULTS: Twelve-week-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy [1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2] or placebo procedure two times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive haemodynamic analysis showed that cardiac diastolic function parameters, such as e', E/e', end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, western blot showed that the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart. CONCLUSIONS: These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients.

Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs.

BACKGROUND: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. METHODS: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. RESULTS: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. CONCLUSION: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.

Adeno-associated virus 9-mediated RNA interference targeting SOCS3 alleviates diastolic heart failure in rats.

OBJECTIVE: To explore the effect of adeno-associated virus 9-mediated RNA interference targeting SOCS3 (AAV9-SOCS3 siRNA) on the treatment of diastolic heart failure (DHF). METHOD: A rat DHF model was established, and cardiac function and hemodynamic changes were measured. HE, Sirius red and TUNEL staining were applied to observe the pathological changes in the myocardium. Immunoblotting and immunohistochemical staining were utilized to detect SOCS3 expression. The expression levels of various factors, including fibrosis-related factors (collagen I, collagen II, α-SMA and TGF-ß), inflammatory-related factors (IL-1ß, IL-6, TNF-α, p-p65 and ICAM-1) and factors related to the JAK/STAT signal pathway were analyzed by immunoblotting and/or qPCR. The serum levels of IL-1ß, IL-6, and TNF-α were measured using ELISA. RESULTS: SOCS3 expression was significantly downregulated in the DHF rat model by SOCS3 siRNA delivery. In the successfully established DHF rat model, cardiac function was clearly decreased, and cardiomyocyte apoptosis and myocardial fibrosis were significantly increased. These changes were ameliorated by treatment with AAV9-SOCS3 siRNA. The expression levels of p-JAK2 and p-STAT3 were significantly upregulated in the AAV9-SOCS3 siRNA group compared with the sham and AAV9-siRNA control groups, indicating that SOCS3 is a negative regulator of this signaling pathway. The expression levels of collagen I/III, α-SMA and TGF-ß were also decreased at both the mRNA and protein levels. In addition, the serum and myocardial tissue expression levels of inflammatory-related factors, such as IL-6, IL-1ß, and TNF-α, were also reduced by the administration of AAV9-SOCS3 siRNA compared with the AAV9-siRNA control. CONCLUSIONS: SOCS3 gene silencing by AAV9-SOCS3 siRNA administration in a DHF rat model significantly reduced myocardial fibrosis and the inflammatory response and improved heart function. Therefore, this treatment is a potential therapeutic method for treating DHF.

Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice.

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.

The profile of selected single nucleotide polymorphisms in patients with hypertension and heart failure with preserved and mid-range ejection fraction.

The study aimed to assess the clinical significance of selected single nucleotide polymorphisms (SNPs) in patients with diastolic heart failure (HF): inflammation [-174 G/C Interleukin -6 (IL-6) rs1800795, tumor necrosis factor (TNF)-608 G/A rs1800629], fibrosis [Arg25Pro transforming growth factor ß (TGF ß) rs1800471], endothelial function [-786 T/C nitric oxide synthase (NOS) rs2070744], glucose and lipid metabolism [Pro12Ala peroxisome proliferator activated receptor (PPAR)γ rs1801282], and vitamin D metabolism [cytochrome P450 27B1 (CYP27B1) C-1260A].110 patients with HF with preserved and mid-range ejection fraction (HFpEF and HFmrEF) were recruited. GG homozygotes in 174 G/C of IL6 polymorphism are characterized by higher values of estimated glomerular filtration rate based on the study Modification of Diet in Renal Disease (eGFR MDRD) and C allele in the NOS polymorphism and AA profile in C-1260A of CYP27B1 polymorphism correlated with a lower eGFR (MDRD). In multivariate analysis the CG genotype for 174 G/C of IL-6 and allele A in C-1260A of CYP27B1 are the only SNPs independently associated with worse course of HFpEF and HFmrEF. These data confirm the importance of the selected SNPs in aggravation and complications of hypertension.

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology.

Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.

Myocardial transcription factors in diastolic dysfunction: clues for model systems and disease.

There are multiple intrinsic mechanisms for diastolic dysfunction ranging from molecular to structural derangements in ventricular myocardium. The molecular mechanisms regulating the progression from normal diastolic function to severe dysfunction still remain poorly understood. Recent studies suggest a potentially important role of core cardio-enriched transcription factors (TFs) in the control of cardiac diastolic function in health and disease through their ability to regulate the expression of target genes involved in the process of adaptive and maladaptive cardiac remodeling. The current relevant findings on the role of a variety of such TFs (TBX5, GATA-4/6, SRF, MYOCD, NRF2, and PITX2) in cardiac diastolic dysfunction and failure are updated, emphasizing their potential as promising targets for novel treatment strategies. In turn, the new animal models described here will be key tools in determining the underlying molecular mechanisms of disease. Since diastolic dysfunction is regulated by various TFs, which are also involved in cross talk with each other, there is a need for more in-depth research from a biomedical perspective in order to establish efficient therapeutic strategies.

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

OBJECTIVES: To 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 a major contributor to the development of diastolic heart dysfunction, the renin angiotensin aldosterone system and its genetic variations are thought to induce LVH in hypertensive hearts apart from haemodynamic factors. DESIGN: Case control study. SETTING: An Iranian referral university hospital. PARTICIPANTS: 176 patients with hypertension and a diagnosis of HFpEF on presence of symptoms of heart failure plus Doppler echocardiographic documentation of left ventricular (LV) diastolic dysfunction and/or elevated NT-proBNP levels. Those with significant coronary, valvular, pericardial and structural heart diseases were excluded as well as patients with atrial fibrillation, renal failure and pulmonary causes of dyspnoea. They were divided into two cohorts of 88 cases with and 88 controls without LVH, after determination of LV mass index, using two-dimensional and M-mode echocardiography. The I/D polymorphism of the ACE gene was determined using the PCR method. RESULTS: The D allele was significantly more prevalent among cases with compared with controls without LVH (p=0.0007). Genotype distributions also differed significantly under additive (p=0.005, OR=0.53, 95% CI 0.34 to 0.84) and recessive (p=0.001, OR=0.29, 95% CI 0.13 to 0.66) models. CONCLUSIONS: In patients with hypertension who develop HFpEF, the D allele of the ACE gene is probably associated with the development of LVH. With the detrimental effects of LVH on the heart's diastolic properties, this can signify the role of genetic contributors to the development of HFpEF in patients with hypertension and may serve as a future risk predictor for the disease.

Genetics of systolic and diastolic heart failure.

Heart failure accounts for a significant portion of heart diseases. Molecular mechanisms gradually emerge that participate in pathways leading to left ventricular dysfunction in common systolic heart failure (SHF) and diastolic heart failure (DHF). A human genome-wide association study (GWAS) identified two markers for SHF and no GWAS on DHF has been documented. However, genetic analyses in rat models of SHF and DHF have begun to unravel the genetic components known as quantitative trait loci (QTLs) initiating systolic and diastolic function. A QTL for systolic function was detected and the gene responsible for it is identified to be that encoding the soluble epoxide hydrolase. Diastolic function is determined by multiple QTLs and the Ccl2/monocyte chemotactic protein gene is the strongest candidate. An amelioration on diastolic dysfunction is merely transient from changing such a single QTL accompanied by a blood pressure reduction. A long-term protection can be achieved only via combining alleles of several QTLs. Thus, distinct genes in synergy are involved in physiological mechanisms durably ameliorating or reversing diastolic dysfunction. These data lay the foundation for identifying causal genes responsible for individual diastolic function QTLs and the essential combination of them to attain a permanent protection against diastolic dysfunction, and consequently will facilitate the elucidation of pathophysiological mechanisms underlying hypertensive diastolic dysfunction. Novel pathways triggering systolic and diastolic dysfunction have emerged that will likely provide new diagnostic tools, innovative therapeutic targets and strategies in reducing, curing and even reversing SHF and DHF.

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition.

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction.

AIMS: Tissue inhibitor of metalloproteinases (TIMPs) can mediate myocardial remodelling, hypertrophy, and fibrosis in heart disease. We investigated the impact of TIMP2 vs. TIMP3 deficiency in angiotensin II (Ang II)-induced myocardial remodelling and cardiac dysfunction. METHODS AND RESULTS: TIMP2(-/-), TIMP3(-/-), and wild-type (WT) mice received Ang II/saline (Alzet pump) for 2 weeks. Ang II infusion resulted in enhanced myocardial hypertrophy and lack of fibrosis in TIMP2(-/-), and conversely, excess fibrosis without hypertrophy in TIMP3(-/-) mice. Echocardiographic imaging revealed preserved ejection fraction in all groups; however, exacerbated left ventricular (LV) diastolic dysfunction was detected in Ang II-infused TIMP2(-/-) and TIMP3(-/-) mice, despite the suppressed Ang II-induced hypertension in TIMP3(-/-) mice. Enhanced hypertrophy in TIMP2(-/-) mice impaired active relaxation, while excess fibrosis in TIMP3(-/-) mice increased LV passive stiffness. Adult WT cardiomyocytes, only when co-cultured with cardiac fibroblasts, exhibited Ang II-induced hypertrophy which was suppressed in TIMP3(-/-) cardiomyocytes. In vitro studies on adult cardiofibroblasts (quiescent and cyclically stretched), and in vivo analyses, revealed that the increased fibrosis in TIMP3(-/-)-Ang II hearts is due to post-translational stabilization and deposition of collagen by matricellular proteins [osteopontin and Secreted Protein Acidic and Rich in Cysteine (SPARC)], which correlated with increased inflammation, rather than increased de novo synthesis. Reduced cross-linking enzymes, LOX and PLOD1, could underlie suppressed collagen deposition in TIMP2(-/-)-Ang II hearts. CONCLUSION: TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function. TIMP2(-/-) and TIMP3(-/-) mice provide a unique opportunity to study myocardial hypertrophy and fibrosis independently, and their impact on cardiac dysfunction.

Pitx2c is reactivated in the failing myocardium and stimulates myf5 expression in cultured cardiomyocytes.

BACKGROUND: Pitx2 (paired-like homeodomain 2 transcription factor) is crucial for heart development, but its role in heart failure (HF) remains uncertain. The present study lays the groundwork implicating Pitx2 signalling in different modalities of HF. METHODOLOGY/PRINCIPAL FINDINGS: A variety of molecular, cell-based, biochemical, and immunochemical assays were used to evaluate: (1) Pitx2c expression in the porcine model of diastolic HF (DHF) and in patients with systolic HF (SHF) due to dilated and ischemic cardiomyopathy, and (2) molecular consequences of Pitx2c expression manipulation in cardiomyocytes in vitro. In pigs, the expression of Pitx2c, physiologically downregulated in the postnatal heart, is significantly re-activated in left ventricular (LV) failing myocardium which, in turn, is associated with increased expression of a restrictive set of Pitx2 target genes. Among these, Myf5 was identified as the top upregulated gene. In vitro, forced expression of Pitx2c in cardiomyocytes, but not in skeletal myoblasts, activates Myf5 in dose-dependent manner. In addition, we demonstrate that the level of Pitx2c is upregulated in the LV-myocardium of SHF patients. CONCLUSIONS/SIGNIFICANCE: The results provide previously unrecognized evidence that Pitx2c is similarly reactivated in postnatal/adult heart at distinct HF phenotypes and suggest that Pitx2c is involved, directly or indirectly, in the regulation of Myf5 expression in cardiomyocytes.

Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin.

In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1(H-/-)), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1(H-/-) mice with rapamycin. Six to eight week old Acsl1(H-/-) mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1(H-/-) hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1(H-/-) hearts exhibited an 8-fold higher uptake of 2-deoxy[1-(14)C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-(14)C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1(H-/-) mice.

Genetics of diastolic heart failure.

Heart failure explains a large portion of heart diseases. Molecular mechanisms determining cardiac function, by inference dysfunction in heart failure, are incompletely understood, especially in the common (or congestive) systolic (SHF) and diastolic heart failure (DHF). Limited genome-wide association studies (GWASs) in humans are reported on SHF and no GWAS has been performed on DHF. Genetic analyses in a rodent model of true DHF, Dahl salt-sensitive (DSS) rats, have begun to unravel the genetic components determining diastolic function. Diastolic dysfunction of DSS rats can be ameliorated or even normalized by distinct quantitative trait loci (QTLs), designated as diastolic function/blood pressure QTLs (DF/BP QTLs), which also affect blood pressure (BP). However, an improvement in diastolic dysfunction is merely transitory from a single DF/BP QTL, despite a permanent lowering of BP. A long-term protection against diastolic dysfunction can be realized only through combining specific DF/BP QTLs. Moreover, the worsening diastolic dysfunction with age can also be reversed in a different combination of DF/BP QTLs. Thus, distinct genes in combinations must be involved in the physiological mechanisms ameliorating or reversing diastolic dysfunction. As not all the QTLs that influence BP can affect diastolic function, it is not BP reduction itself that restores diastolic function, but rather specific genes that are uniquely integrated into the pathways of blood pressure homeostasis as well as diastolic function. Thus, the elucidation of pathophysiological mechanisms causal to hypertensive diastolic dysfunction will not only provide new diagnostic tools, but also novel therapeutic targets and strategies in reducing, curing, and even reversing DHF.