The Pathophysiology of Left Ventricular Hypertrophy, beyond Hypertension, in Autosomal Dominant Polycystic Kidney Disease

Heart disease is one of the leading causes of death in autosomal dominant polycystic kidney disease (ADPKD) patients. Left ventricular hypertrophy (LVH) is an early and severe complication in ADPKD patients. Two decades ago, the prevalence of LVH on echocardiography in hypertensive ADPKD patients was shown to be as high as 46%. Recent studies using cardiac magnetic resonance imaging have shown that the prevalence of LVH in ADPKD patients may be lower. The true prevalence of LVH in ADPKD patients is controversial. There is evidence that factors other than hypertension contribute to LVH in ADPKD patients. Studies have shown that young normotensive ADPKD adults and children have a higher left ventricular mass index compared to controls and that the prevalence of LVH is high in patients with ADPKD whose blood pressure is well controlled. Polycystin-1 (PC-1) and polycystin-2 (PC-2) control intracellular signaling pathways that can influence cardiac function. Perturbations of PC-1 or PC-2 in the heart can lead to profound changes in cardiac structure and function independently of kidney function or blood pressure. PC-1 can influence mammalian target of rapamycin and mitophagy and PC-2 can influence autophagy, processes that play a role in LVH. Polymorphisms in the angiotensin-converting enzyme gene may play a role in LVH in ADPKD. This review will detail the pathophysiology of LVH, beyond hypertension, in ADPKD.

© 2022 S. Karger AG, Basel

Cardiac Hypertrophy in Autosomal Dominant Polycystic Kidney Disease Patients

Heart disease is one of the leading causes of death in autosomal dominant polycystic kidney disease (ADPKD) patients [1]. Left ventricular hypertrophy (LVH) is an early and severe complication in ADPKD patients. LVH predisposes to heart failure and arrhythmias, essential components of cardiovascular mortality and adverse outcomes [2]. Two decades ago, the prevalence of LVH in hypertensive ADPKD patients not yet on dialysis was shown on echocardiography to be as high as 46% [3]. Echocardiography is the most frequently used test to assess left ventricular mass (LVM), but it has technical, observer, and patient-dependent variables that interfere with accuracy. Cardiac magnetic resonance imaging (MRI) measurements of LVM closely correlate with actual heart weight determined at autopsy in both animals and humans. Cardiac MRI is considered the gold standard for determining ventricular dimensions in hypertensive adult patients. Recently, cardiac MRI scans in a large group of ADPKD patients from the HALT Progression of Polycystic Kidney Disease (HALT-PKD) study were performed and showed an LVH prevalence of less than 4% [4]. However, cardiac MRI scans in these ADPKD patients were not compared to exact age-matched controls without ADPKD or hypertension. Potential changes in the prevalence of LVH in ADPKD patients over the last 2 decades may be related to differences in imaging modalities, differences in parameters used to define LVH, lack of matching normal control groups, demographic differences in the study populations, the earlier detection and rigorous treatment of hypertension, increased use of angiotensin-converting enzyme (ACE) inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Thus the exact prevalence of LVH in ADPKD patients remains controversial. The prevalence of LVH in ADPKD as measured by cardiac MRI scan is not known before the onset of hypertension or treatment with inhibitors such as ACEIs or ARBs. It is not known whether LVH in ADPKD can be normalized with ACEI/ARB treatment.

Hypertension and LVH in ADPKD

The pathogenesis of hypertension in ADPKD is multifactorial [5]. Abnormal Polycystin-1 (PC-1) and Polycystin-2 (PC-2) expression in blood vessels results in abnormal vascular structure and function, reduced nitric oxide (NO), and abnormal endothelial response. Activation of the renin-angiotensin-aldosterone system (RAAS) due to cyst growth results in hypertension in ADPKD [5]. The high incidence of hypertension at an early age in ADPKD correlates with kidney cyst volume.

There is no doubt that hypertension contributes to LVH in ADPKD patients. Hypertension is the most common initial presentation of ADPKD patients, and unlike other kidney diseases, the majority of patients (50–70%) have normal renal function when hypertension develops. The presence of hypertension increases the prevalence of LVH. Chapman et al. [6] found the frequency of LVH to be 48% in hypertensive patients with ADPKD. In one study, the prevalence of LVH with ADPKD is 43% in hypertensive patients [7]. In a study comparing ADPKD patients and age- and sex-matched patients with essential hypertension, the LVM index (LVMI) is higher in male ADPKD patients than in the control group [8]. Circadian blood pressure changes affect LVM. It was shown that the nocturnal reduction in blood pressure in patients with ADPKD is less than in hypertensive patients without ADPKD [9]. Effective treatment of hypertension in patients with ADPKD is essential to slow the progressive increase in LVMI. A 7-year prospective randomized study to investigate the cardiac and renal effects of rigorous (<120/80 mm Hg) and standard (135–140/85–90 mm Hg) blood pressure control in ADPKD found that the LVMI decreased by 21% in the standard group and by 35% in the rigorous group. A mixed model longitudinal data analysis revealed that rigorous blood pressure control is significantly more effective in decreasing LVMI [10].

In patients from the HALT-PKD study, LVM measurements were performed using cardiac MRI [4]. In these ADPKD patients, although blood pressure is well controlled with ACEI and ARBs, most patients had LVMI at the upper limit on MRI scans and no direct comparison was made with age-matched healthy controls. The low prevalence of LVH (4%) in this study population may also be explained by improved blood pressure control, earlier diagnosis of hypertension, and more common and earlier use of ACEI and ARBs and different imaging techniques compared to previous studies [4].

In a subsequent study, in the same HALT-PKD patients, ADPKD patients were randomized to either a standard blood pressure target (120/70–130/80 mm Hg) or a low blood pressure target (95/60–110/75 mm/Hg) [11]. Rigorous blood pressure versus standard blood pressure control resulted in a slower increase in total kidney volume and no overall change in the estimated glomerular filtration rate. However, rigorous blood pressure control resulted in a greater decline in the LVMI and a greater reduction in urinary albumin excretion, suggesting that there is indeed LVH that could be improved with intensive blood pressure control [11, 12].

There is evidence that factors other than hypertension contribute to LVH in ADPKD patients. Despite treatment with ACEI, the LVMI of ADPKD patients is higher than that of healthy controls [2]. One study found that there was no direct relationship between LVH and blood pressure [6]. Young normotensive ADPKD adults and children have been shown to have a higher LVMI compared to controls [13]. Consistent with these findings, LVMI is higher in normotensive ADPKD patients compared to controls with similar mean 24-h and daytime systolic, diastolic, and mean blood pressure [14]. The prevalence of LVH is 21.4% by echocardiography in a contemporary cohort of patients with ADPKD whose blood pressure is well controlled. In this study, there is an independent relationship between total kidney volume, one of the most significant markers of ADPKD severity and LVMI, suggesting a connection between the pathophysiology of ADPKD and increased LVM [15]. Thus, there are numerous studies that show that there is LVH in normotensive ADPKD patients. This review article aimed to summarize the pathophysiology of LVH, beyond hypertension, in ADPKD patients.

Pkd1 Gene Knockout and Cardiac Disease

Studies in myocytes in culture with knockout of Pkd1 or 2 genes and in mice with knockout of the Pkd1 or 2 gene have shown significant cardiac phenotypes, suggesting that factors other than hypertension can contribute to cardiac disease and LVH in ADPKD. These studies will be discussed next.

PC-1 is a cardiomyocyte mechano-sensor that governs L-type Ca2+ channel protein stability [16]. Localization of polycystin proteins to primary cilia and their role in calcium signaling may partially explain some cardiac pathologies in ADPKD. When there is a loss of PC-1 and/or PC-2, there is an increase in intracellular cyclic adenosine monophosphate signaling, a decrease in intracellular calcium signaling, and resultant cellular proliferation, increased apoptosis, and decreased cardiac contraction, factors that can influence cardiac structure and function.

The L-type calcium channel is localized in the primary cilia of epithelial cells. These channels of primary cilia are disrupted in Pkd cell lines, suggesting that polycystins are associated with the localization and functions of these channels. Abnormalities of L-type channels contribute to cardiac abnormalities. In cultured neonatal rat ventricular myocytes, mechanical stretch increases L-type calcium channel stability by a PC-1/AKT-dependent mechanism. There is a significant reduction in the density of the L-type calcium channels in cardiomyocyte-specific Pkd1 knockout mice. These mice had increased wall thickness and reduced fractional shortening compared to control mice [16].

To better understand the role of PC-1 in cardiac dysfunction, knockout of PKD1 in vitro and in vivo has been studied. In neonatal rat ventricular myocytes exposed to a hypertrophic stimulus, knockout of PC-1 blocked the hypertrophy [17]. To further study the role of Pkd1 in cardiac hypertrophy, mice with a cardiac-specific Pkd1 knockout were studied [17]. Cardiac-specific Pkd1 knockout mice have no phenotype at birth. At 8 weeks, there is a decrease in ventricular contractile function and decreased systolic and diastolic function driven by an increase in left ventricular (LV) end-systolic diameter [16, 17]. However, cardiac-specific Pkd1 knockout mice were protected against cardiac hypertrophy, increases in hypertrophic markers and interstitial fibrosis induced by transverse aortic constriction [16]. The mechanism of the protective effect of Pkd1 knockout on cardiac hypertrophy was investigated. It was found that PC-1 plays a role in regulating multiple Kv potassium channels, governing membrane repolarization and alterations in sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) activity that reduce cardiomyocyte contractility activity [17].

In contrast, another study found that PC-1 is required for insulin-like growth factor 1 (IGF-1)-induced cardiomyocyte hypertrophy [18]. In cardiomyocytes, Pkd1 knockdown completely blunted IGF-1-induced cardiomyocyte hypertrophy. Pkd1 silencing blunted the activation of the IGF-1 receptor, Akt, and ERK1/2 induced by IGF-1. These findings provide evidence that PC-1 regulates IGF-1-induced cardiomyocyte hypertrophy through a mechanism involving protein tyrosine phosphatase 1B.

Besides cardiomyocytes, fibroblast cells also have a critical regulatory role in regulating cardiac structure. Interestingly, recent studies have shown that PC-1 is a functionally important protein in the primary cilia of fibroblasts and the absence of PC-1 from cardiac fibroblasts results in increased hypertrophy [19]. In this study, it was found that the primary cilium and PC-1 are needed for transforming growth factor beta 1 (TGF-β1)-SMAD3 activation, production of extracellular matrix proteins, and cell contractility, which are important mechanisms in fibrosis.

The results showing that Pkd1 knockout improves cardiac hypertrophy beg the question why cardiac hypertrophy is seen in mouse models and humans that have Pkd1 mutations. The Pkd1RC/RC mouse is a hypomorphic model with a knock-in matching the likely disease variant Pkd1 p.R3277C (RC) [20]. In the Pkd1RC/RC mouse, there is still 40% PC-1 in the cells [20]. In the Pkd1RC/RC mouse, which mimics the human situation better than complete knockout of Pkd1 in the heart, there is still significant cardiac hypertrophy [21]. In the Pkd1RC/RC mouse, there is a dosage effect on the phenotype [20]. In ADPKD patients that have reduced PC-1, there is still cardiac hypertrophy, often at an early age before the onset of hypertension [2, 3, 13, 14]. There is likely a Pkd1 gene dosage effect on the development of cardiac hypertrophy where complete knockout of Pkd1 resulting in no PC-1 in cardiomyocytes may be protective, but partial knockout of Pkd1 where PC-1 is still present, may be associated with cardiac hypertrophy. The Pkd1 gene dosage effect on cardiac abnormalities is suggested by the following studies. Pkd1+/− noncystic mice have reduced but not absent PC-1 expression. In these mice, there is decreased myocardial deformation and systolic function as well as diastolic dysfunction in older mice associated with increased apoptosis and fibrosis. Pkd1 transgenic mice that overexpress the Pkd1 transgene in extrarenal and renal tissues by approximately 2- to 15-fold were developed [22]. The transgenic mice develop tubular and glomerular cysts, leading to renal insufficiency. A significant proportion of mice developed cardiac anomalies with severe LVH, marked aortic arch distention and/or valvular stenosis and calcification that affected cardiac function. Thus, studies show that the absence of PC-1 in myocytes protects against LVH, while a reduction in PC-1 or overexpression of PC-1 results in LVH

Pkd2 Gene Knockout and LVH

Cardiac functions are closely related to the calcium-dependent contractile apparatus of cardiomyocytes. For example, intracellular calcium flux from the sarcoplasmic reticulum, controlled by the ryanodine receptor two subtypes (RyR2), is directly related to the contractile cycle of ventricular cardiomyocytes. The Pkd2 protein product, PC-2, is a calcium channel that has an inhibitory effect on RyR2 activity. Pkd2−/− cardiomyocytes had a higher frequency of spontaneous Ca2+ oscillations, reduced Ca2+ release from the sarcoplasmic reticulum stores, and reduced Ca2+ content compared with Pkd2+/+ cardiomyocytes. PC-2 is an intracellular calcium channel expressed in cardiomyocytes. There is much evidence that Pkd2 gene knockout can cause cardiac hypertrophy independently of ADPKD, hypertension, and renal function impairment.

In Pkd2+/− mice, without kidney disease, decreased PC-2 levels shift the β-adrenergic pathway balance and change expression of calcium handling proteins, which results in altered cardiac contractility [23]. Nine-month old Pkd2+/− mice have thinner LV walls, consistent with dilated cardiomyopathy, and decreased LV ejection fraction [24]. In Pkd2 knockout mice, there is fetal death in mid-gestation with atrial and ventricular septal defects, pericardial effusions, and systemic edema that suggests the possibility of a cardiac-related death [25]. In Pkd2WS25/− mice, a Pkd2 knockout model that survives to adulthood, there is increased heart weight at an early age [21]. There is altered calcium-contraction in the heart in haploinsufficient Pkd2WS25+/− mice that do not have polycystic kidney disease (PKD) or hypertension [23].

Pkd2 mutations also cause cardiac dysfunction in zebrafish and humans [26]. Pkd2 mutant zebrafish demonstrated low cardiac output and atrioventricular block with impaired intracellular calcium cycling and calcium alternans. In ADPKD patients, an idiopathic dilated cardiomyopathy is found in some patients. The association with idiopathic dilated cardiomyopathy is strongest in patients with Pkd2 mutations. This study suggests that PC-2 modulates intracellular calcium cycling and that abnormalities of PC-2 contribute to the development of heart failure.

In a recent study, it was found that arrhythmogenic hearts in Pkd2 mutant mice are characterized by cardiac fibrosis, systolic, and diastolic dysfunction [27]. In this study, there is macrophage1 (M1) and macrophage2 (M2) infiltration and increased TGF-β1 in Pkd2 mutant hearts. The increase in the extracellular matrix in Pkd2 mutant hearts leads to cardiac hypertrophy, interstitial, and conduction system fibrosis. LV expansion or compliance and LV filling were impaired in fibrotic Pkd2 knockout hearts, resulting in diastolic dysfunction.

In 864 patients from the HALT-PKD study, the presence of a Pkd1 or Pkd2 gene mutation correlated with LVH and cardiac hospitalizations [28]. Patients with the Pkd1 genotype versus the Pkd2 genotype had higher LVM. However, first cardiac hospitalizations were higher in patients with Pkd2 versus Pkd1 gene mutations. First cardiac hospitalization is 9.2% in patients with a Pkd1 genotype compared to 4.1% in patients with a Pkd1 genotype. After adjustment for age, sex, race, and study randomization, Pkd2 is associated with an increased hazard of cardiac hospitalization. This association remains after further adjustment for cardiac history, baseline systolic blood pressure, body mass index, smoking history, and baseline estimated glomerular filtration rate.

PC-2 levels were examined in a murine model of cardiomyopathy and were found to be increased in hearts exposed to chemical stress (isoproterenol) [29]. Increased PC-2 is accompanied by increases in cellular stress markers, 4-hydroxynonenal (HNE) and C/EBP-homologous protein (CHOP) in the isoproterenol-treated hearts. To test whether PC-2 was also transcriptionally upregulated in the hearts of mice exposed to physical stress, mRNA levels of Pkd2 in LV tissue samples were determined in mice exposed to transverse aortic constriction. There is an increase in Pkd2 mRNA in the hearts of mice exposed to transverse aortic constriction. Next, PC-2 levels were measured in LV tissue from nonfailing and failing human hearts obtained from patients with ischemic cardiomyopathy or nonischemic cardiomyopathy [29]. PC-2 is increased in the LV samples of ischemic cardiomyopathy or nonischemic cardiomyopathy compared to nonfailing hearts. Levels of the stress markers 4-HNE and CHOP are significantly increased in ischemic cardiomyopathy or nonischemic cardiomyopathy hearts. PC-2 levels are also increased in other cell injury models like acute kidney injury and brain stress, suggesting that PC-2 is increased in disease to protect against stress-induced cell death.

Abnormalities of Pkd2 in endothelial cells may contribute to cardiac disease. Pkd2 was knocked out in endothelial cells [30]. Flow-mediated Pkd2 channel activation resulted in calcium influx that activated calcium-activated potassium channels and endothelial nitric oxide synthase (eNOS) in endothelial cells. Endothelium-specific Pkd2 knockout in mice resulted in hypertension. The study concluded that Pkd2 channels are a major component of functional flow sensing in the vasculature.

In summary, there is overwhelming evidence in cardiomyocytes in vitro, zebrafish, mouse models, and humans that loss of PC-2 in the heart leads to a multitude of cardiac defects including LVH, independently of kidney disease and hypertension. Knockout of Pkd2 in the vasculature can result in hypertension that may further cause cardiac hypertrophy.

Mammalian Target of Rapamycin Signaling and Autophagy

Mammalian target of rapamycin (mTOR), a serine/threonine kinase, has a central role in maintaining mammalian homeostasis. It regulates cell growth, cell survival, protein synthesis, autophagic processes, and transcription mechanisms. mTOR exists in two different chemical and functional complexes inside the cell: mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Activation of the mTORC1 pathway results in increased proliferation and decreased apoptosis while also suppressing autophagy. The mTORC1 pathway is activated in cyst-lined epithelial cells in both ADPKD patients and 3 different mouse models. Pkd1RC/RC [31, 32] and Pkd2WS25/− mice have increased mTORC1 (4E-BP1) and mTORC2 (p-Akt Ser473) signaling in the kidney [33].

There is increased mTORC1 and 2 signaling in the heart in rodent models of PKD. In the Han:SPRD rat model of PKD, there is increased phospho-S6 protein (a marker of mTORC1) in the heart that is inhibited by the mTOR inhibitor, rapamycin [34]. In addition, in this study, rapamycin also reduced heart weight. A recent study aimed at identifying cardiac mTORC1, and 2 signaling proteins in the Pkd1RC/RC mouse model demonstrates cardiac mTORC1 activation associated with suppressed autophagic flux in the heart [21]. There is a defect in the later stage of autophagy, the fusion of the autophagosome with the lysosome, known as autophagic flux, as evidenced by the lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin, in both 70-day-old and 150-days-old hearts. Treatment with the autophagy inducer, 2-deoxyglucose, did not affect the increased heart weight, while treatment with an autophagy inducer, Tat Beclin1 peptide, increased heart weight [21]. Recent studies have thrown light on how PC-1 and PC-2 control autophagy in the heart.

PC-1 regulates cardiomyocyte mitophagy [35]. Mitochondria have an essential role in the life cycle of cardiomyocytes. Changes in the number, shape, structure, and function of mitochondria are closely related to cardiovascular diseases. PC-1 downregulation in a murine model of ADPKD has been suggested to cause structural and functional changes in mitochondria in kidney tissue and contribute to cellular metabolic disturbances. In cardiomyocytes of heterozygous Pkd1 knockout mice, mitochondria are smaller and there is increased mitochondrial density and circularity on electron microscopy consistent with mitochondrial fission. Pkd1 knockout in cultured rat cardiomyocytes and human-induced pluri­potent stem cell-derived cardiomyocytes resulted in less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production) processes that activate the elimination of defective mitochondria by mitophagy [35].

There is experimental evidence showing the critical roles of intracellular calcium homeostasis and PC-2 in the modulation and control of autophagic activity in the context of time, space, and cell cycle [36]. PC-2 is critical in managing stress-induced autophagy. Although there is no significant change in cardiac function, stress-induced autophagy in cardiomyocyte-specific Pkd2 knockout mice results from defective PC-2-related impaired intracellular calcium trafficking [36].

PC-2 is a regulator of autophagy by control of intracellular Ca2+ homeostasis [36]. Activation of autophagic flux triggered by mTOR inhibition is decreased in cardiomyocytes depleted of PC-2. Also, cardiomyocyte-specific PC-2 knockout mice had impaired autophagic flux when subjected to nutrient deprivation. Stress-induced autophagy is blunted by intracellular Ca2+ chelation. PC-2 overexpression increased autophagic flux, while a Ca2+-channel deficient PC-2 mutant expression did not. Autophagy induced by PC-2 overexpression is attenuated by intracellular Ca2+ chelation. This study demonstrates a model of PC-2-dependent control of autophagy through intracellular Ca2+.

PC-2 promotes glucose starvation-induced autophagy and protects against apoptotic cell death in human cardiomyocytes. The mechanism involves Pkd2 interaction with RyR2 to alter Ca2+ release from the sarcoplasmic reticulum, resulting in modulation of AMP-activated protein kinase (AMPK) and mTOR. Knockdown of Pkd2 reduced autophagic flux and increased apoptosis under glucose starvation. Co-immunoprecipitation and in situ proximity ligation assays demonstrated an increased physical interaction of Pkd2 with RyR2 with glucose starvation. Also, Pkd2 knockout reduced the starvation-induced activation of AMPK and inactivation of mTOR. This study demonstrates that Pkd2 functions to promote autophagy under glucose starvation, thereby protecting cardiomyocytes from apoptotic cell death.

In summary, there is activation of mTOR and suppressed autophagy in the heart in Pkd1RC/RC mice that have reduced PC-1 expression. Knockout of Pkd1 activates mitophagy while a decrease in PC-1 levels in the heart in Pkd1RC/RC mice results in suppressed autophagy. Knockout of Pkd2 suppresses autophagy. These studies beg the question of how Pkd1 or Pkd2 modulation of autophagy in the heart results in LVH. The role of autophagy in cardiac hypertrophy has been extensively studied and multiple lines of evidence reveal that there is suppressed autophagy from chronic pressure overload in the heart that contributes to defects in cardiac remodeling and heart failure [37]. It has been shown that constitutive autophagy in the heart is a homeostatic mechanism that maintains cardiomyocyte size and cardiac structure and function and that cardiac-specific loss of autophagy leads to cardiac hypertrophy, LV dilatation, and contractile dysfunction [37]. These studies suggest a link between Pkd1 and 2 mutations, suppressed autophagy and cardiac hypertrophy.

Polymorphism of the ACE Gene and LVH

Although RAAS activation is essential in developing hypertension and LVH, it has been found that RAAS is active even in normotensive ADPKD patients [38]. Polymorphisms in the ACE gene may play a role in developing LVH in ADPKD. In the presence of the homozygous D allele (DD genotype), an insertion (I)/deletion (D) polymorphism of the ACE gene is associated with higher serum ACE levels in humans [39]. The relationship between ACE DD polymorphism and increased LVMI is controversial. The association between LVH and ACE gene polymorphism in ADPKD is also contradictory. Similarly, in the ACE genotype analysis performed by Ecder et al. [40] on a large series of patients (409 Caucasians: 137 males, 272 females) with ADPKD, no significant effect of ACE polymorphism on the development of disease progression and the prevalence of LVH was detected. However, a more recent study of ADPKD with a relatively small patient series (55 patients with ADPKD; 24 males, 31 females) found that the DD genotype is associated with ESRD, LVH, and systolic-diastolic dysfunction compared to the II and ID genotypes [41].

Fibroblast Growth Factor-23

Fibroblast growth factor-23 (FGF-23) is significantly higher in ADPKD patients than in other chronic kidney disease (CKD) patients with similar stages [42]. The polycystic kidneys themselves can make FGF-23 in young rodent models of polycystic kidney disease, before the onset of renal failure [43]. It has been shown that polycystic livers make FGF-23, but FGF-23 levels are increased even in ADPKD patients without polycystic liver disease. Increased FGF-23 levels are associated with faster cyst growth and worse kidney end-points in ADPKD. FGF-23 contributes to the pathogenesis of LVH through stimulation of the calcineurin-nuclear factor of the activated T-cell pathway (NFAT) [44]. Injecting FGF-23 intravenously has been shown to induce LVH in klotho (a transmembrane protein that increases FGF-23 affinity for FGF-23 receptors)-deficient mice [45]. FGF-23 in the cardiac myocytes can also stimulate fibrosis-related pathways in fibroblasts and cause cardiac fibrosis in a paracrine fashion. Yildiz et al. [46] found higher FGF-23 levels in hypertensive and normotensive ADPKD patients with preserved renal function than healthy controls. They also found a lower arterial elasticity index in both groups of patients. However, there was no significant correlation between FGF-23 levels and arterial function parameters. FGF-23 is independently associated with increased LVMI and LVH in patients with CKD [47]. It is not known whether FGF-23 is associated with LVH in ADPKD patients. FGF-23 can cause LVH independent of hypertension in rodents and is independently associated with LVH in patients. It is not known whether increased FGF-23 is a marker or mediator of LVH in ADPKD patients.

Cardiac Dysfunction and Galectin-3

Galectins are a family of β-galactoside-binding lectins. Changes in galectin-3 levels and subcellular localization are commonly seen in cancer. Galectin-3 plays important roles in cancer cell growth, transformation, apoptosis, angiogenesis, adhesion, invasion, and metastasis. In the kidney, galectin-3, plays a role in the terminal differentiation of collecting ducts Galectin-3 is expressed in the cyst epithelium in association with primary cilia. Galectin-3 regulates fibrosis by mediating the effects of TGF-β in the heart, liver, and kidney. Increased galectin-3 serum levels have been associated with CKD and a rapid decrease in glomerular filtration rate.

The role of galectin-3 in cardiac hypertrophy in PKD was investigated in 3 Pkd1 mouse models [48]. The cardiac phenotype was determined in Pkd1−/− mice with PKD and hypertension, Pkd1+/− mice that did not have PKD, and Pkd1−/− galectin-3−/− double knockout mice. On echocardiogram, there is decreased myocardial deformation and systolic function in Pkd1−/− and Pkd1+/− mice as well as diastolic dysfunction in older Pkd1−/− mice compared to controls. No evidence of increased LVM or dilated cardiomyopathy was found. There is reduced PC-1 expression, increased apoptosis, and mild fibrosis in Pkd1−/− and Pkd1+/− mice. Pkd1−/− galectin-3−/− double knockout mice have improved cardiac deformability and systolic parameters compared to single-mutants. The improvement of myocardial dysfunction in ADPKD by inhibiting galectin-3 expression suggests the potential use of galectin-3 as a biomarker of heart disease and a target for future therapies [48]. Potential mechanisms of how increased galectin-3 worsens cardiac disease include increased myocardial inflammation, increased collagen production, alterations in cardiac remodeling and worsening cardiac function. However, the role of galectin-3 in PKD models of cardiac hypertrophy remains to be determined.

Insulin Resistance

Multiple metabolic abnormalities related to ADPKD, including insulin resistance, have been reported [49, 50]. LVM measurements using M-mode and color Doppler echocardiography were performed in 106 ADPKD patients. LVH is detected in 18.9% of subjects. In multivariate regression analysis, they found a significant (p < 0.05) association between insulin resistance and LVMI in ADPKD patients, independent of age, weight, systolic blood pressure, and albuminuria [49]. The mechanism of increased LVMI in ADPKD patients with insulin resistance may be related to the early increase in proinflammatory cytokines and oxidative stress markers that were seen in normotensive ADPKD patients with normal kidney function.

Conclusion

There are numerous studies in ADPKD patients and animal models that suggest that there are factors other than hypertension that contribute to LVH (Fig. 1): (1) LVH is present in normotensive ADPKD patients; (2) PC-1 and PC-2 control Ca2+ channels in the heart; (3) knockout/knockdown/overexpression of Pkd1 or Pkd2 in the heart results in cardiac phenotypes independent of hypertension and kidney disease; (4) knockout of Pkd1 or Pkd2 affects autophagy and mitophagy in the heart; and (5) FGF-23, DD genotype of the ACE gene, insulin resistance, and galectin-3 may influence LVH in ADPKD. Understanding the pathophysiology of LVH in ADPKD may provide clues to therapies for LVH, in addition to treatment of hypertension with ACE inhibitors and ARBs.

Fig. 1.

Pathophysiology of LVH in ADPKD independent of hypertension. PC-1, polycystin-1; PC-2, polycystin-2; mTORC1, mammalian target of rapamycin complex 1; FGF-23, fibroblast growth factor-23; ACE, angiotensin-converting enzyme.

/WebMaterial/ShowPic/1447501Statement of Ethics

Not applicable.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the Department of Veteran’s Affairs Merit award to CLE under Grant BX003803-01A1; Zell Family Foundation.

Author Contributions

Charles L. Edelstein and Ozgur A. Oto concepted the review, analyzed relevant studies for inclusion, drafted, and revised the article. All the authors contributed equally to this study, revised the paper, and approved the final version of the manuscript.

Data Availability Statement

Not applicable.

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