Background—: A hallmark of heart failure is impaired cytoplasmic Ca ²⁺ handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca ²⁺ handling via altered excitation-transcription coupling contribute to the development and progression of heart failure. Methods and Results—: Using tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca ²⁺ handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca ²⁺ pumps and ryanodine receptors, increased expression of inositol-1,4,5-trisphosphate receptors, and differential orientation among these Ca ²⁺ transporters. These changes were associated with altered nucleoplasmic Ca ²⁺ handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca ²⁺ levels with diminished and prolonged nuclear Ca ²⁺ transients and slowed intranuclear Ca ²⁺ diffusion. Altered nucleoplasmic Ca ²⁺ levels were translated to higher activation of nuclear Ca ²⁺ /calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca ²⁺ alterations occurred early during hypertrophy and preceded the cytoplasmic Ca ²⁺ changes that are typical of heart failure. Conclusions—: During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca ²⁺ signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca ²⁺ regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling.

Hypertension is a major risk factor for atrial fibrillation. We hypothesized that arterial hypertension would alter atrial myocyte calcium (Ca²⁺) handling and that these alterations would serve to trigger atrial tachyarrhythmias. Left atria or left atrial (LA) myocytes were isolated from spontaneously hypertensive rats (SHR) or normotensive Wistar-Kyoto (WKY) controls. Early after the onset of hypertension, at 3 months of age, there were no differences in Ca²⁺ transients (CaTs) or expression and phosphorylation of Ca²⁺ handling proteins between SHR and WKY. At 7 months of age, when left ventricular (LV) hypertrophy had progressed and markers of fibrosis were increased in left atrium, CaTs (at 1 Hz stimulation) were still unchanged. Subcellular alterations in Ca²⁺ handling were observed, however, in SHR atrial myocytes including (i) reduced expression of the α1C subunit of and reduced Ca²⁺ influx through L-type Ca²⁺ channels, (ii) reduced expression of ryanodine receptors with increased phosphorylation at Ser2808, (iii) decreased activity of the Na⁺/Ca²⁺ exchanger (at unaltered intracellular Na⁺ concentration), and (iv) increased SR Ca²⁺ load with reduced fractional release. These changes were associated with an increased propensity of SHR atrial myocytes to develop frequency-dependent, arrhythmogenic Ca²⁺ alternans. In SHR, hypertension induces early subcellular LA myocyte Ca²⁺ remodelling during compensated LV hypertrophy. In basal conditions, atrial myocyte CaTs are not changed. At increased stimulation frequency, however, SHR atrial myocytes become more prone to arrhythmogenic Ca²⁺ alternans, suggesting a link between hypertension, atrial Ca²⁺ homeostasis, and development of atrial tachyarrhythmias.

Arterial hypertension affects ≈ 1 billion people worldwide. It is associated with increased morbidity and mortality and responsible for millions of deaths each year. Hypertension mediates damage of target organs including the heart. In addition to eliciting left ventricular hypertrophy, dysfunction and heart failure, hypertension also causes left atrial remodeling that may culminate in atrial contractile dysfunction and atrial fibrillation. Here, we will summarize data on the various aspects of left atrial remodeling in (essential) hypertension gathered from studies on patients with hypertension and from spontaneously hypertensive rats, an animal model that closely mimics cardiac remodeling in human hypertension. Analyzing the timeline of remodeling processes, i.e., distinguishing between alterations occurring in prehypertension, in early hypertension and during advanced hypertensive heart disease, we will derive the potential mechanisms underlying left atrial remodeling in (essential) hypertension. Finally, we will discuss the consequences of these remodeling processes for atrial and ventricular function. The data imply that left atrial remodeling is multifactorial, starts early in hypertension and is an important contributor to the progression of hypertensive heart disease, including the development of atrial fibrillation and heart failure.

Urocortin 2 (Ucn2) is a cardioactive peptide exhibiting beneficial effects in normal and failing heart. In cardiomyocytes, it elicits cAMP- and Ca²⁺-dependent positive inotropic and lusitropic effects. We tested the hypothesis that, in addition, Ucn2 activates cardiac nitric oxide (NO) signaling and elucidated the underlying signaling pathways and mechanisms. In isolated rabbit ventricular myocytes, Ucn2 caused concentration- and time-dependent increases in phosphorylation of Akt (Ser473, Thr308), endothelial NO synthase (eNOS) (Ser1177), and ERK1/2 (Thr202/Tyr204). ERK1/2 phosphorylation, but not Akt and eNOS phosphorylation, was suppressed by inhibition of MEK1/2. Increased Akt phosphorylation resulted in increased Akt kinase activity and was mediated by corticotropin-releasing factor 2 (CRF₂) receptors (astressin-2B sensitive). Inhibition of phosphatidylinositol 3-kinase (PI3K) diminished both Akt as well as eNOS phosphorylation mediated by Ucn2. Inhibition of protein kinase A (PKA) reduced Ucn2-induced phosphorylation of eNOS but did not affect the increase in phosphorylation of Akt. Conversely, direct receptor-independent elevation of cAMP via forskolin increased phosphorylation of eNOS but not of Akt. Ucn2 increased intracellular NO concentration ([NO]_i), [cGMP], [cAMP], and cell shortening. Inhibition of eNOS suppressed the increases in [NO]_iand cell shortening. When both PI3K-Akt and cAMP-PKA signaling were inhibited, the Ucn2-induced increases in [NO]_iand cell shortening were attenuated. Thus, in rabbit ventricular myocytes, Ucn2 causes activation of cAMP-PKA, PI3K-Akt, and MEK1/2-ERK1/2 signaling. The MEK1/2-ERK1/2 pathway is not required for stimulation of NO signaling in these cells. The other two pathways, cAMP-PKA and PI3K-Akt, converge on eNOS phosphorylation at Ser1177 and result in pronounced and sustained cellular NO production with subsequent stimulation of cGMP signaling.