Heart failure is not only a global problem but also significantly limits the life prospects of these patients. The epidemiology and presentation of heart failure are intensively researched topics in cardiology. The risk factors leading to heart failure are well known; however, the real challenge is to provide effective treatments. A vicious cycle develops in heart failure of all etiologies, sooner or later compromising both cardiac and kidney functions simultaneously. This can explain the repeated hospital admissions due to decompensation and the significantly reduced quality of life. Moreover, diuretic-refractory heart failure represents a distinct challenge due to repeated hospital admissions and increased mortality. In our narrative review, we wanted to draw attention to nephrology treatment options for severe diuretic-resistant heart failure. The incremental value of peritoneal dialysis in severe heart failure and the feasibility of percutaneous peritoneal dialysis catheter insertion have been well known for many years. In contrast, the science and narrative of acute peritoneal dialysis in diuretic-resistant heart failure remains underrepresented. We believe that nephrologists are uniquely positioned to help these patients by providing acute peritoneal dialysis to reduce hospitalization dependency and increase their quality of life. Heart failure and cardiovascular diseases (CVDs) are the leading cause of death globally. The World Health Organization’s (WHO’s) declared goal is to reduce the number of premature deaths by 25% by 2025 through nine voluntary global targets . The epiIn treating heart failure, an effective fluid management program is crucial to reduce hospital readmissions and overall mortality. This is based on optimal diuretic use and other procedures. Therefore, cooperation with other professions, e.g., nephrologists, is often necessary to maintain euvolemia, but patient education is crucial and contributes to treatment success . AccordiConsidering the above, we aimed to explore possible nephrological treatments for severe diuretic-resistant heart failure in our narrative review. Diuretic resistance and cardiorenal syndrome are conditions where special nephrological therapies may be needed to influence the disease’s outcome or improve the patient’s quality of life.We searched the PubMed database and Google Scholar using the keywords “heart failure”, “diuretic resistance”, “diuretic-resistant heart failure”, “diuretic-resistant heart failure treatment”, “cardiorenal syndrome”, and “nephrologist” and their combinations. We followed the guidelines for literature search and manuscript preparation ,9. The iStudies addressing the objectives of the review and our hypotheses were extracted. Data collection for each study focused primarily on possible connections to our theory. Three authors independently screened each retrieved article for eligibility and extracted study data. Any discrepancies between the first and senior authors  were resolved by discussion and agreement.On the basis of the above, in our narrative review statement, we wanted to draw attention to the possibility of nephrological treatments for severe diuretic-resistant heart failure. The most studied connection was “heart failure” and “nephrologist”. The announcements corresponding to the search terms are listed in Not surprisingly, the epidemiology, molecular biology, symptomatology, and cardiology of heart failure have been intensively researched and published. In the same way, a very significant number of publications have been published on the topic of diuretic resistance. Unfortunately, however, only 15 publications have been published on intertwining diuretic resistance and nephrology. Furthermore, researchers have dealt with cardiorenal syndrome since 1946, but reports on its connection with nephrology have only been published since 2002. All these results draw attention to the fact that nephrological therapeutic options are not considered in treating certain cardiology diseases.Heart failure, including diuretic-resistant heart failure, can be responsible for the repeated hospitalization of such patients. Unfortunately, epidemiological data show that this number is regrettably increasing . In treaOther diuretics, such as thiazides, act on the distal ascending limb, while potassium-sparing diuretics work on the collecting ducts. Sodium reabsorption is lower in those sections of the nephron . The famNevertheless, this increase in RAAS activity can further inhibit tubuloglomerular feedback, thus reducing the glomerular filtration rate (GFR), i.e., a narrowing of kidney function . RAAS acAnother reason for diuretic resistance, in addition to the activation of the RAAS, is that structural changes in the nephrons also occur, also known as the “braking phenomenon”. Chronic use of loop diuretics results in hypertrophy and hyperplasia of the cells of the distal tubules. Hypertrophy of distal tubular cells reduces the response to diuretics due to compensatory increased sodium reabsorption .SGLT2 inhibitors are a promising new drug family in treating heart failure. The beneficial effects of SGLT2 inhibitors on heart failure were also confirmed by four large randomized controlled trials , in which a total of 15,684 patients participated. Studies have shown that using SGLT2i reduces the number of cardiovascular deaths and the hospitalization rate of patients with heart failure. The beneficial effect of SGLT2 inhibitors on heart failure was independent of left-ventricular ejection fraction (LVEF) status . In hearAnother interesting therapeutic option is that hypertonic solutions could help to break through the diuretic resistance in decompensated heart failure . The expAs discussed above, elevated serum renin levels raise intraglomerular pressure due to efferent arteriolar constriction. In severe, decompensated heart failure, due to significantly increased renal venous pressure and reduced renal blood flow, the compensation that preserves GFR fails, thus resulting in a further decrease in GFR . The proHowever, hemodynamic changes can lead to cardiorenal syndrome (CRS) and the activation of the sympathetic nervous system, through persistent RAAS activation. This also includes chronic inflammation and an imbalance in the ratio of reactive oxygen species/nitrogen monoxide production ,31. SpecRecognizing a broader clinical spectrum that may represent cardiorenal dysregulation, the Acute Dialysis Quality Initiative outlined a consensus approach in 2008 that phenotypes CRS into two main groups. Isolation was proposed to be defined on the basis of the primary disease process in the development of CRS; thus, we can differentiate between cardiorenal and renocardiac syndromes . The purPeritoneal dialysis (PD) treatment in severe diuretic-resistant heart failure can improve a patient’s quality of life and functional class stage of heart failure; however, cardiovascular mortality remains high . The firIn a retrospective study of nearly 11,000 patients, repeated hospitalizations of patients treated with hemodialysis (HD) and PD who required renal replacement therapy due to severe heart failure were compared. The study showed that the incidence of PD peritonitis and the resulting hospitalization rate were significantly higher in patients treated with PD. However, PD treatment still seemed more beneficial . DespitePD treatment in a group of patients suffering from severe diuretic-resistant heart failure has been known for several decades. However, it has not entered the everyday public consciousness, and no professional consensus has yet been formed. It has been shown to effectively reduce the need for hospital admissions and improve left-ventricular systolic function in several studies. In the case of associated kidney damage, the results were not favorable; in the CARESS HF study , kidney function did not improve significantly, although, from the point of view of the outcome, the aim was not necessarily to improve kidney function . The latThe mortality of patients with diuretic-resistant heart failure is very high; thus, extracorporeal treatment (HD) performed with a central venous catheter (CVK) represents an additional increased risk due to bloodstream infection and death . In the Atrial natriuretic peptide (ANP) and tumor necrosis factor-α (TNF-α) were removed during PD treatment in heart failure despite no improvement in renal function. In those patients with PD treatment, removed interleukin (IL)-1 and IL-6 also played a role in the functional phase and increased measurable ejection fraction . The effWe believe that the cardiotoxic molecules removed during PD treatment also contribute to improving cardiac status due to salt and fluid removal .Minimally invasive percutaneous PD catheter insertion has been a procedure described for decades. Of course, there are cases where surgical PD catheter (PDC) insertion is indispensable, e.g., in overweight, obese patients or individuals who have undergone major abdominal surgery, in whom there is a possibility of intra-abdominal adhesions . In the Recently, PD treatment with an emergency indication has been increasingly considered in treating severe septic conditions and acute kidney damage caused by the pandemic SARS-CoV-2 virus infection. Given the limited possibilities of extracorporeal treatment and those inflammatory markers—such as IL-6—being effectively removed with PD treatment, the cytokine storm caused by the COVID-19 infection can be mitigated ,68. It iWith the increasing acceptance of minimally invasive procedures, percutaneous PDC can be considered in patients with severe, critical circulatory failure under regional anesthesia. Most severely critically ill patients may already be sedated unconscious due to acute critical illness . PercutaOne major comorbidity to modulate risk is the presence of anemia, which emerges with both heart failure and kidney diseases. In heart failure, anemia also correlates with the functional stage of severe diuretic-resistant heart failure and the degree of clinical symptoms . It follThe presence of iron deficiency had a negative prognostic impact only in HFrEF but not in HFpEF. Persistent iron deficiency was strongly associated with mortality after a 6 month follow-up . Severalideal time point of intervention would be to address cardiorenal failure with PD, rather than awaiting the point of absolute necessity. As we have shown, few publications specifically dealt with the correlations between diuretic-resistant heart failure and the possibilities of nephrological treatments. However, the number of experiences and reports obtained by combining these procedures is negligible; few researchers have dealt with this possibility so far.As discussed above, a close relationship exists between heart and kidney functions. In this narrative review, our goal was to highlight that, in diuretic-resistant heart failure, PDC placement by a nephrologist or intervention specialist would enable acute PD and efficacious immediate control of fluid overload. It is critical to understand that this procedure is not curative for heart failure but intended to improve the patient’s quality of life and is vital for successful rehabilitation. Indeed, in the opinion of these writers, what is not well understood is when the We believe that, if conservative treatment options are exhausted in diuretic-resistant heart failure and extracorporeal ultrafiltration becomes necessary, in the absence of contraindications, PDC placement and acute PD treatment should be the preferential treatment to prevent repeated and long-term hospital admissions and to treat the development of fluid overload. The results of the publications published on this topic are encouraging, but prospective studies on many patients are necessary to verify our hypothesis. Furthermore, when planning prospective studies, we must also keep in mind the change in the quality of life since this represents a major outcome in this patient group.From the presented reports, we can confirm that, in the treatment of severe diuretic-resistant heart failure, acute nephrological procedures are underrepresented as acute PD treatment. Especially in cases with ascites, when this becomes necessary due to hypervolemia, it is recommended to consider acute PD treatment. The strength of our hypothesis and the narrative reviews is that both PD treatment in heart failure and PDC placement have been intensively researched and published for decades, and numerous publications have reported on the effectiveness of the procedures. The limitation of our hypothesis is that there are only a few publications about these involving patients.


Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and β-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection fraction (HFrEF). Novel drug classes, including angiotensin receptor blocker/neprilysin inhibitor (ARNI), sodium-glucose co-transporter-2 (SGLT2) inhibitor, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, soluble guanylyl cyclase (sGC) stimulator/activator, and cardiac myosin activator, have recently been introduced for HF intervention based on their proposed novel mechanisms. SGLT2 inhibitors have been shown to be effective not only for HFrEF but also for HF with preserved ejection fraction (HFpEF). In the myocardium, excess cyclic adenosine monophosphate (cAMP) stimulation has detrimental effects on HFrEF, whereas cyclic guanosine monophosphate (cGMP) signaling inhibits cAMP-mediated responses. Thus, molecules participating in cGMP signaling are promising targets of novel drugs for HF. In this review, we summarize molecular pathways of cGMP signaling and clinical trials of emerging drug classes targeting cGMP signaling in the treatment of HF. Heart failure (HF) is a condition where the heart’s ability to pump and deliver sufficient oxygen and nutrients to peripheral tissues is impaired. HF can be divided into two major categories based on the ejection fraction (EF) of the left ventricular (LV): HF with reduced EF  and HF with preserved EF , in which the EF is preserved but LV diastolic function is reduced. HFrEF and HFpEF patients account for 30–50% and 50%, respectively. Currently, most clinical drugs for HF are effective in treating HFrEF but not HFpEF .The current standard treatment for HFrEF includes many drug classes that are angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (if ACE inhibitors are not tolerated), β-blockers, and mineralocorticoid receptor blockers . However2+. cGMP, produced by guanylyl cyclase (GC), triggers responses by regulating the activities of downstream signaling molecules. cGMP signaling represents molecules participating in the pathway starting from the production of cGMP to the regulation of the molecule’s activity . sGC. sGC3]. 2+ form. In contrast, sGC activators act on oxidized sGC (Fe3+-sGC or Apo type sGC) and increase sGC activity . GL. GL43]. The SGLT family encompasses seven isoforms with different physiological functions . SGLT2 i+/H+ exchange transporter (NHE3), whose activity is increased in HF, has been implicated in cardiac tissue damage [Although the myocardium also expresses SGLT1 and sodium myoinositol cotransporter 1 (SMIT1), their activities are not affected by SGLT2 inhibitors . Thus, te damage . Improvee damage ,49.The selectivity of SGLT2 inhibitors for SGLT2 over SGLT1 varies from 290-fold for canagliflozin to 2900-fold for tofogliflozin . Current50 of about 0.4 μM. Furthermore, it also inhibited L-type Ca2+ channels and Na+ channels [HCN4 is mainly involved in slow depolarization during the action potential occurring in the SA node to control the HR . Ivabradchannels . Regardichannels . In the channels .If), which is triggered by the influx of cations through HCN4 channels [+ influx through HCN4 channels. As a result, the slope of phase IV depolarization becomes slower and the HR decreases. Because ivabradine acts on HCN4 channels only in the SA node, it reduces HR without affecting cardiac functions such as conduction, contractility, or repolarization of the heart [In patients with HFrEF, the risk of death or hospitalization increases when the resting HR exceeds 70 beats/min . Therefochannels . Ivabradhe heart ,54. In phe heart .+ channel (Nav1.5) is also inhibited by ivabradine [+ channels in the nervous system (Nav1.2) and skeletal muscles (Nav1.4) are also inhibited within a similar concentration range (low μM) [+ channels.Cardiac-specific HCN4-channel knockout mice showed slower conduction of excitation through the atrioventricular (AV) node , suggestabradine . Na+ cha(low μM) . Thus, i2+ influx or Ca2+ sensitivity to myocytes and therefore does not increase myocardial oxygen consumption [Inotropic agents have been reported to worsen life expectancy in patients with HFrEF. However, in patients with severe HF, inotropic agents may be necessary for maintaining the circulatory system and sustaining life . Thus, tsumption ,58.Since it does not act directly or indirectly via NO–cGMP signaling, the mechanism of action is briefly presented here. In cardiac muscle, actin binds to the Z-body and induces contractility by myosin sliding between actin fibers. A series of reactions occur between myosin and ATP during the contraction–relaxation cycle. ATP binds to myosin unoccupied by ADP. ATP is then hydrolyzed to ADP and inorganic phosphorus is liberated. ADP is then dissociated from the binding site. Myosin returns to the nucleotide-free state and binds strongly to actin from the inorganic phosphorus-released state to the ADP-dissociated state . OmecamtThe activity of NO-sGC-cGMP signaling is decreased in the hearts of HF patients, resulting in decreased activity of PKG, a target of cGMP. Since PKG has inhibitory effects on myocardial hypertrophy and vasodilation, decreased PKG activity is associated with the development or worsening of HF . RiociguIn patients with HF, NO production and NO-dependent responses are impaired, resulting in a failure of sGC stimulation. Decreased sGC activity leads to vasoconstriction and impaired cardiac function . BelisigIn patients with chronic HF, endothelial function is impaired by oxidative stress and inflammation. It has been shown that reduced endothelial function results in reduced NO production, which in turn results in defective sGC activity . cGMP isClinical trials using drugs targeting PKGI in patients with HF have shown varied efficacies across trials. In patients with HFrEF, PDE5 inhibitors, and the sGC activator vericiguat showed effective endpoints ,66,67. HDapagliflozin has been suggested to have a positive effect on cardiac function and metabolism by enhancing BNP bioactivity and reducing cardiac load. Empagliflozin improved NO signaling  and increased titin phosphorylation. Empagliflozin recovered diastolic function, inhibited tissue and molecular remodeling, and inhibited cardiomyocyte stiffness .+ and glucose excretion  SGLT2 inhibitors promote Naxcretion , therebyHF is often accompanied by titin-dependent cardiomyocyte stiffening. Phosphorylation of titin by PKGI increases myocyte stretching. The activation of GC-B–cGMP–PKGI signaling by CNP in cardiomyocytes was reported to play a protective role in preventing titin-based cardiomyocyte stiffening during the early phase of pressure overload . Empagli1, β2 and β3, all of which mainly couple to the Gs protein. However, β2AR and β3AR can couple to Gi protein and endothelial-type nitric oxide synthase (eNOS) (possibly via Gi), respectively, depending on cellular conditions [Adrenergic receptors are classified into three subfamilies, α1, α2, and β that couple to Gq, Gi, and Gs proteins, respectively. Each subfamily is further divided into three subtypes. βARs are classified into three subtypes, βnditions .2AR and β3AR is associated with cardiac protection. β1ARs regulate cardiac contractility and increase HR via Gs–PKA signaling. Excessive β1AR-mediated signaling adversely affects the heart. Persistent and prolonged β1AR stimulation triggers HF progression [1AR are antagonists such as carvedilol and bisoprolol [1AR stimulation. However, β2AR stimulation and other receptor-independent actions play a role in the cardioprotective effects of βAR antagonists.Activation of βgression . Sympathgression . Carvedigression . Carvedigression . Later, gression ,85. It isoprolol . The eff1ARs and β2ARs, β3ARs protect the heart against stress-induced hypertrophy and HF by activating eNOS  and neuronal-type nitric oxide synthase . eNOS and nNOS generate NO, which activates cGMP signaling [2+-calmodulin and phosphorylated by Ca2+-calmodulin-dependent kinase. eNOS is phosphorylated and activated by Akt, whose activity is stimulated by phosphatidylinositol--trisphosphate (PIP3), a product of phosphatidylinositol-3-phosphate kinase (PI3K). Since β3AR activates PI3K, β3AR stimulation enhances eNOS activity [3AR agonist used for the treatment of overactive bladder [Unlike βignaling . nNOS isactivity . Mirabeg bladder ; however bladder . Because3ARs, β2ARs couple with cGMP-producing systems (eNOS and nNOS) and increase cGMP. cGMP increases the phosphorylation of several intracellular proteins via PKG [+/K+-ATPase. It reduces intracellular Ca2+ concentrations by suppressing voltage-gated L-type Ca2+ channels. It also enhances the Ca2+-associated action of phospholamban. The effects of cGMP on PDEs have also been reported. The binding of cGMP to PDE2 stimulates the cAMP-degrading activity of PDE2; the cardioprotective effects of β2ARs and β3ARs may be mediated by these actions [2ARs and β3ARs activate eNOS and nNOS by coupling to Gi and enhancing NO–cGMP signaling. However, it has been reported that β1AR also increases cGMP production upon stimulation with the antagonist carvedilol [In addition to β via PKG ,91. PKG  actions ,91. β2ARrvedilol . Each βASeveral molecules have been reported to have positive effects on cardiac hypertrophy and/or remodeling in vitro or in vivo. In this Section, promising molecules for HF treatment are discussed and summarized, although their relationship to cGMP signaling is unclear.Fatty acids have been shown to exert cardiac effects by acting on GPCRs . GPR40  and docosahexaenoic acid (DHA) are omega-3 polyunsaturated fatty acids that play an important role in maintaining CV health . Even th1-adrenergic receptor and AT1R, expressed in cardiomyocytes prepared from neonatal rat hearts induced hypertrophic responses [1R of fibroblasts increased expression and extracellular release of TGF-β and connective tissue growth factor in the heart. These released factors directly acted on cardiomyocytes and induced a hypertrophic response [A recently developed powerful tool for analyzing specific G protein-mediated actions is the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) . Transgeesponses . In addiresponse . These rFatty acid receptors inhibit inflammation in many cells. Since inflammation plays an important role in cardiac remodeling, fatty acid receptors may inhibit remodeling by suppressing inflammatory mediators .The role of cannabinoid signaling in human health and disease has been comprehensively examined. Cannabinoid signaling consists of two main receptors, cannabinoid receptor type 1 (CB1) and type 2 (CB2), endogenous ligands, and metabolic enzymes . CB2 lig2+ permeability [The transient receptor potential (TRP) channel family is a non-selective cation channel with Caeability . TRPV cheability . Howevereability ,109.TRPV1 activity is regulated by cGMP signaling. TRPV1 is proposed as a component of the ANP, cGMP, and PKG signaling complex . TRPV1 iAquaporins not only work as channels for water molecules but also allow ROS to pass through intracellularly . Aquapor1R, leading to a reduction in vasoconstriction and aldosterone production, providing CV benefits [LCZ696  is a first-in-class drug that belongs to a group of ARNIs, which is a combination of two drugs, valsartan, and sacubitril, in a fixed dose. LCZ696 targets the dual renin-angiotensin system and natriuretic peptide metabolism to treat hypertension and HF . Valsartbenefits . Sacubitbenefits . LCZ696 p = 0.005). This reduction in NT-proBNP levels was sustained from 12 to 36 weeks of treatment. Additionally, HFpEF patients receiving LCZ696 for 36 weeks also showed a decrease in left atrial size and an improvement in HF symptoms [The PARAMOUNT study  was a phsymptoms .p < 0.001). However, there was a higher occurrence of angioedema and hypotension in patients treated with LCZ696 compared with those receiving enalapril (14% versus 9.2%) [The efficacy of LCZ696 on a composite CV death or a first hospitalization with HF (primary endpoint) was also compared with enalapril, an ACE inhibitor, in a larger population of 8399 patients with HFrEF monitored in the PARADIGN-HF trial . In thisus 9.2%) .p = 0.06), especially the rates of HF hospitalizations and CV death. However, the LCZ696 group had a lower incidence of hyperkalemia and higher incidences of angioedema and hypotension compared with the valsartan group. These findings raise concerns regarding the potential side effects of LCZ696 in HFpEF patients [The impact of two drugs, sacubitril and valsartan, on the incidence of a composite outcome of total HF hospitalizations and deaths from CV causes was further investigated in the PARAGON-HF trial, a phase III, double-blind trial . A totalpatients .In the 2022 AHA/ACC/HFSA guideline for the management of HF , ARNI isIf channel, inhibiting the If current , which plays a crucial role in controlling HR. Specifically, ivabradine targets HCN4, the primary isoform found in the SA node of the heart, by entering the channel and blocking it from inside [If with ivabradine results in decreased SA node depolarization, leading to a lower HR and improved myocardial perfusion without altering myocardial contractility and electrophysiological properties, thus providing the pure HR lowering effect [A high HR can increase various CV risks and disrupt the balance of oxygen supply to the heart, leading to heart ischemic conditions and CV death . Ivabradm inside ,54. Inhig effect ,117,118.g effect . To datep = 0.94) [p = 0.016). The BEAUTIFUL echo sub-study aimed to examine the impact of ivabradine on the LV end-systolic volume index (LVESVI), which is a parameter used to assess the size and function of LV, and specifically focused on patients with stable CAD and LV systolic dysfunction [2), while the placebo group showed an increase (1.85 ± 10.54 mL/m2) (p = 0.018). Notably, this reduction was found to depend on the degree of HR reduction achieved in patients. Additionally, ivabradine had a greater ability to increase LVEF (2.00 ± 7.02%) compared with the placebo (0.01 ± 6.20%) (p = 0.009). These findings indicated the beneficial effects of ivabradine on LV remodeling in patients with CAD and LV systolic dysfunction [The BEAUTIFUL trial was a double-blind, placebo-controlled trial that sought to examine the HR-lowering effect of ivabradine on CV death and morbidity . The stu = 0.94) . Howeverfunction . A totalfunction .p < 0.0001) [A captivating study involving 6558 HF patients with moderate-to-severe symptoms and LV systolic dysfunction was undertaken in the SHIFT trial . The tri 0.0001) . However 0.0001) .p < 0.001), indicating a decrease in LV volume. Additionally, treatment with ivabradine demonstrated improvements in CV parameters. Specifically, it increased LVEF by 2.4% ± 7.7% (p < 0.001) and resulted in a decrease in LV end-diastolic volume index (LVEDVI) from a baseline value of 93.9 ± 32.8 mL/m2 to a lower value of 85.9 ± 30.9 mL/m2 (p = 0.002) at the 8-month mark. These suggested that ivabradine has the benefit of LV remodeling patients with HF and LV systolic dysfunction [The results of the SHIFT echocardiography sub-study proved the beneficial outcomes of ivabradine on the reversal of cardiac remodeling . This sufunction . FollowiCardiac contraction relies on the function and cross-bridging cycle of myosin and actin filaments in cardiomyocytes, and the impairment of cardiac contractility is a significant problem in systolic HF progression . Cardiacp = 0.0027), LVED diameter (p = 0.0128), NT-proBNP level (p = 0.0069), and HR (p = 0.007) compared with the placebo. These findings suggested that omecamtiv dosing guided by PK enhanced cardiac performance and promoted favorable ventricular remodeling in HFrEF patients [To date, several clinical studies have demonstrated the beneficial effects of omecamtiv in HFrEF patients . The phapatients .p = 0.03), with an association with a decrease in NT-proBNP levels. These insights highlight the beneficial effects of omecamtiv treatment on the overall well-being and quality of life of HF patients [The COSMIC-HF study provided additional data on the effect of omecamtiv on HF symptoms and health-related quality of life (HRQoL) in HFrEF patients . The effpatients .2) in HFrEF patients [2 between the group receiving omecamtiv (−0.24 mL/kg/min) and the placebo group (0.21 mL/kg/min) from baseline to a period of 20 weeks. Similarly, no other secondary endpoints were observed, suggesting that omecamtiv did not improve exercise capacity in HFrEF patients [Measuring exercise capacity is crucial in the management of HF as it allows for the assessment of the severity of the condition and HF progression. Improving exercise capacity is a key goal for HF patients who commonly experience exercise intolerance . In thispatients . The respatients .p = 0.03) demonstrated a significant decrease in the incidence of the primary outcome without increasing the risk of clinical adverse effects. However, the use of omecamtiv did not lead to improvements in secondary outcomes such as changes in the KCCQ score and various CV death [p = 0.004). This suggested that omecamtiv had stronger therapeutic benefits in HFrEF patients with lower baseline EF levels [GALACTIC-HF was a phase III, double-blind, placebo-controlled trial conducted to investigate the effectiveness and safety of omecamtiv in HFrEF patients . Within CV death . In 2021CV death  conducteF levels .p-interaction = 0.095). These findings highlight that the most prominent benefits of omecamtiv were observed in HFrEF patients with high levels of NT-proBNP [Recently, another study utilized the GALACTIC-HF trial to evaluate the efficacy of omecamtiv in HFrEF patients based on their baseline NT-proBNP levels, which were divided at the median  . OmecamtT-proBNP . However2+ sensitivity in muscle fibers and myofibrils taken from the left atrial (LA) and LV chambers. It also improved LV stroke volume and LA emptying fraction in dogs with HF [p < 0.01), myocardial strain (p < 0.01), and LA function index (p < 0.01), while decreased LA minimal volume index (p < 0.01), suggesting enhanced cardiac output and atrial function [In addition to omecamtiv, danicamtiv has been reported to have beneficial effects in pre-clinical as well as clinical studies involving HFrEF patients . In dogs with HF . A phasefunction .SGLT2 is the predominant transporter that is responsible for glucose reabsorption from the proximal renal tubule back into blood circulation. Blocking SGLT2 activity resulted in a reduction of glucose reabsorption and thus increased urinary glucose excretion. For this major reason, SGLT2 inhibitors  are approved for the treatment of type 2 diabetes mellitus (T2DM) . In addiThe recent canagliflozin CHIEF-HF clinical trial was conducted in HF patients regardless of EF or diabetes status  Table 9Table 9. In addition to reducing the risk of hospitalization with HF in patients with T2DM, dapagliflozin is indicated by the US FDA to reduce the risk of CV deaths and hospitalization in HFrEF patients with NYHA class II–IV. The expansion of the indication of dapagliflozin is based on clinical data from many trials conducted in HF patients . The DAPA-HF trial  was a do= 263) were randomized to receive a placebo or 10 mg/day of dapagliflozin for 12 weeks. Dual primary endpoints consisted of a composite of the proportion of patients who achieved improved health status and the average NT-proBNP levels at 6 and 12 weeks. In this trial, there were no significant differences in average adjusted NT-proBNP levels between dapagliflozin and placebo  [The DEFINE-HF trial was a double-blind, placebo-controlled trial conducted in HFrEF patients with LVEF ≤ 40% and NYHA class II–III to investigate the effects of dapagliflozin on symptoms, functional status, and biomarkers . Patientctively) . HoweverFurthermore, the DELIVER trial was conducted in HFpEF patients with or without T2DM to evaluate the efficacy and safety of dapagliflozin . In addi= 3730) were randomized to receive empagliflozin (10 mg OD) or placebo, and the primary outcome was a composite of CV death or hospitalization with worsening HF. Over 6 months of treatment, a primary outcome event occurred in 19.4% of the empagliflozin group and 24.7% of the placebo group  [Empagliflozin is one of the SGLT2 inhibitors indicated by the US FDA to reduce the risk of CV death in adults with T2DM and established CVDs as well as to reduce the risk of CV death and hospitalization with HF. The expansion of the indication for empagliflozin is based on clinical data from many trials in HF and diabetic patients, including CANVAS, DECLARE-TIMI58, EMPA-REG OUTCOME, EMPEROR-Reduced, and EMPEROR-Preserved studies. The EMPEROR-Reduced trial was conducted in HFrEF patients with LVEF ≤ 40%, NYHA class II–IV, and elevated NT-proBNP levels to investigate the efficacy and safety of empagliflozin as an adjunct to background therapy for HF  Table 9Table 9. < 0.001) . Subgrou< 0.001) .p < 0.001) [Empagliflozin was also investigated for its efficacy and safety in HFpEF patients with LVEF > 40%, NYHA class II–IV, and NT-proBNP levels > 300 pg/mL in the EMPEROR-Preserved study . The 598< 0.001) . For saf< 0.001) . This EMIn the 2022 AHA/ACC/HFSA guideline for the management of HF , SGLT2 isGC-mediated cGMP signaling plays a crucial role in regulating normal cardiovascular and cardiopulmonary functions . Activatp < 0.02) [The SOCRATES-REDUCED trial was a double-blind, placebo-controlled, phase II trial aimed at studying the effect of vericiguat on NT-proBNP levels in HFrEF patients . Differe < 0.02) .Similarly, the SOCRATES-PRESERVED trial compared the effects of vericiguat (fixed doses vs. titrated doses) and placebo on changes in NT-proBNP levels and left atrial volume (LAV) over 12 weeks in 447 HFpEF patients . The stup = 0.02) [Results of larger phase III clinical trials showing the efficacy of vericiguat in HFrEF patients were published in 2020 ,140. The = 0.02) . Further2), and at least two conditions associated with NO deficiency [2 (primary endpoint) from baseline. The results showed that treatment with praliciguat (0.04 mL/kg/min) had no significant effect on the primary endpoint compared with the placebo (−0.26 mL/kg/min) [In addition to vericiguat, clinical studies have also investigated the efficacy of other drugs belonging to the sGC stimulator group, such as praliciguat  and riocficiency . Patient/kg/min) . These fp < 0.0001), stroke volume index (p < 0.0018), systemic vascular resistance (SVR) (p = 0.0002), and pulmonary vascular resistance (PVR) (p = 0.03) but no effect on HR and BP [HF and pulmonary hypertension, a condition characterized by increased BP in the pulmonary arteries, often coexist and can mutually influence each other, impacting heart-related diseases. The LEPHT trial was a phase II trial that aimed to evaluate the hemodynamic effects of riociguat in patients with pulmonary hypertension caused by systolic LV dysfunction . This raR and BP .The 2022 AHA/ACC/HFSA guideline for the management of HF  indicate3AR. Stimulation of β3ARs leads to the relaxation of the detrusor smooth muscle of the urinary bladder during the storage phase, resulting in increasing bladder capacity [3ARs are expressed in the heart, and stimulation of β3ARs exhibits cardioprotective effects, including improved systolic functions.Mirabegron is an agonist of βcapacity . Due to p = 0.82) [p < 0.001) (baseline LVEF < 40% as measured using computed tomography). Based on the safety profile, mirabegron was generally well tolerated. Due to the small sample size of the BEAT-HF trial, additional studies on the effect of mirabegron in patients with HFrEF are needed.The BEAT-HF trial was the first clinical study of mirabegron in HFrEF patients with LVEF < 40% and NYHA class II–III . A total = 0.82) . Howeverp = 0.039) and PVR  [3AR-agonist mirabegron is one of the therapeutic targets for the treatment and prevention of HF. However, mirabegron needs to be investigated in phase II clinical studies conducted over a longer duration and with larger numbers of HF patients.The most recent trial of mirabegron efficacy and safety was the BEAT-HF-II trial, which was conducted in HFrEF patients with LVEF < 35% and NYHA class III–IV and measured the hemodynamic response to mirabegron . Patient = 0.02) . There w = 0.02) . In conccGMP signaling plays a crucial role in various pathophysiological processes, including HF and remodeling; thus, the identification of new molecules targeting cGMP signaling lead to the development of additional treatments for HF. The phosphoproteomic approach, a branch of proteomics that focuses on the identification and quantification of the phosphorylation process of proteins, in particular biological samples, is a valuable tool for searching for new targets in cGMP signaling . Since nThere is currently no specific drug approved for the treatment of HFpEF, although efforts are being made to identify and develop specific therapies. Although SGLT2 inhibitors are reportedly effective against both HFpEF and HFrEF, such clinical benefits on the heart may be indirect effects. In addition to the drug classes discussed in this review, several potential drug targets and therapeutic strategies are currently under investigation. Clinical trials of emerging drugs that regulate cGMP signaling are also ongoing. Some drugs are undergoing phase IV trials and may be offered to HF patients in the near future. Although it is not mentioned here, drugs targeting the remodeling  that occurs with the progression of HF may be developed based on the contribution of cGMP signaling to the remodeling process. However, it is important to note that while these advancements have shown promising results in clinical trials, the effectiveness of any treatment may vary depending on several factors, including the severity and type of HF, the presence of comorbidities, genetic factors, and individual response to medications.


Advanced heart failure is often accompanied by perturbations in cardiac chamber or valve geometries which result in worsening cardiac function and hemodynamics. Once limited to surgical procedures, recent developments in minimally invasive percutaneous techniques have demonstrated efficacy in patients with both reduced and preserved ejection fraction who are at an elevated surgical risk for perioperative events. This review highlights a subset of the interventions available in clinical practice or in development for the treatment of these valvular and structural alterations. Statistics from the American Heart Association in 2021 estimated that the prevalence of heart failure in the United States is approximately 6 million patients ≥20 years old, with the total percentage of heart failure patients projected to increase from 2.4% of the US population in 2012 to 3.0% in 2030 [Congestive heart failure is often accompanied by structural alterations in cardiac chamber dimensions or valvular geometry, and these perturbations have been the subject of numerous therapeutic interventions in various phases of clinical investigation. Treatment of patients with structural heart disease necessitates the implementation of heart failure guideline-directed medical therapies (GDMT) along with optimal intravascular volume optimization. The ACC/AHA/HFSA published an updated 2022 guideline summarizing recommendations for the optimization of HF GDMT, with recommendations based on ejection fraction . Despitep < 0.001) and severe FMR of 1.82  when compared to HF patients with no or mild MR [p = 0.01) and hospitalization for decompensated heart failure  compared to patients without FMR [Secondary or functional mitral regurgitation (FMR) is common in heart failure due to poor leaflet coaptation resulting from left ventricular dysfunction, annular dilatation, left atrial enlargement, or tethering of the mitral valve leaflets . Recent  mild MR . Retrosphout FMR . Surgicahout FMR . Recent Guideline for the Management of Patients with Valvular Heart Disease lists a class-IIa recommendation for transcatheter edge-to-edge repair in patients with severe primary MR with NYHA class III/IV symptoms and a prohibitive surgical risk [While the most robust data exist for functional mitral regurgitation, percutaneous mitral valve therapies may be considered in patients with primary mitral regurgitation with favorable anatomy or in patients with degenerated surgical prostheses. The 2020 ACC/AHA cal risk . The “Pecal risk .Guideline for the Management of Patients with Valvular Heart Disease and the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure list a class-IIa recommendation for transcatheter edge-to-edge mitral valve repair in patients with systolic dysfunction and severe symptomatic functional mitral regurgitation despite optimal guideline-directed medical therapy [The 2020 AHA/ACC  therapy ,4. Altho therapy ,31.p < 0.001) and all-cause mortality at 24 months  in patients undergoing MitraClip compared to optimal medical therapy alone [At the time of this publication, the MitraClip device  is the most prevalent transcatheter mitral valve repair technique used in the United States . This teThe PASCAL precision transcatheter valve repair system  was approved by the FDA in September 2022 as another edge-to-edge repair option for patients with significant mitral valve regurgitation. In the CLASP and CLASPIID trials, this device demonstrated a sustained reduction in mitral valve regurgitation at 2 years and similar rates of device implant complications when compared to the MitraClip ,34.There are several investigational devices seeking to reduce mitral regurgitation through annuloplasty-like effects. These include the Carillon mitral-contour system , Cardioband , Accucinch  and Mitralign . These devices are not approved for commercial use in the United States .The Carillon mitral-contour system  is a percutaneous mitral annuloplasty device that is placed in the coronary sinus to reduce mitral annular diameter by utilizing the close proximity of the posterior annulus and coronary sinus . Trials The Cardioband device  is a trans-septal mitral annuloplasty system consisting of a band which is anchored along the posterior annulus and contracted to reduce the septal–lateral dimension of the annulus, thereby reducing mitral regurgitation . A singlThe Mitralign system utilizes pledgeted sutures anterior and posterior to the mitral valve commissures to reduce annular dimensions via cinching the sutures . The MitSurgical literature has demonstrated a more durable response to mitral valve replacement compared to mitral valve repair in patients undergoing surgical intervention for ischemic mitral regurgitation ,39. UnfoThere are numerous additional TMVR systems currently under investigation for transseptal or transapical native mitral valve replacement ,40. The Guideline for the Management of Patients with Valvular Heart Disease lists a class-I recommendation for tricuspid valve surgery in patients with severe TR undergoing left-sided surgery and a class-IIa recommendation for surgery in patients with isolated severe TR and right-sided heart failure [Secondary or functional tricuspid regurgitation (TR) is the most common etiology for tricuspid valve disease in Western countries and is frequently associated with left-sided heart failure or pulmonary hypertension leading to RV dilation and dysfunction with resultant tricuspid annular dilation . The poo failure . Recent  failure . A detai failure . TranscaSeveral devices have been investigated for reducing the tricuspid annular diameter. These include suture annuloplasty devices such as the TriAlign and TriCinch systems, as well as direct ring annuloplasty devices such as the Cardioband and Millipede devices. The TriAlign system  is a replication of the modified Kay surgical bicuspidization procedure; an early feasibility study of the TriAlign system demonstrated improvement in the echocardiographic parameters of tricuspid annular area and EROA, as well as in patients’ functional status at 30 days . The Trip < 0.0001), 6-min walk distance , and KCCQ score  at 6 months [p < 0.0001) among patients who underwent the procedure [The Cardioband system  is a transcatheter tricuspid implant that is designed to reduce tricuspid regurgitation via a reduction in the annular dimension. The prospective TRI-REPAIR (Tricuspid Regurgitation Repair with Cardioband Transcatheter System) was a single-arm trial that investigated the use of the Cardioband system for treatment of severe tricuspid regurgitation in 30 patients  . There w6 months . One yearocedure .p < 0.0001) along with functional improvements in NYHA class , 6-min walk distance , and KCCQ score  when compared to baseline results [p = 0.02); however, there was no statistically significant difference in death or tricuspid valve surgery nor in the rate of heart failure hospitalizations. The KCCQ score changed by a mean of 12.3 ± 1.8 points in the TEER group compared to 0.6 ± 1.8 in the control group (p < 0.001). There was also a significant reduction in tricuspid regurgitation at 30 days post procedurally. These data support the efficacy and safety of TR reduction and indicate an improvement in heart-failure quality of life with reduction in TR.The TriClip device  is a transcatheter edge-to-edge approximation device which is deployed via a transfemoral delivery system for the percutaneous treatment of tricuspid regurgitation . The ini results . The TRI results . The prip < 0.001) with an improvement of right ventricular end-diastolic diameter  and NYHA functional class at follow-up (p < 0.001) [Although the TriClip device is the most thoroughly studied tricuspid edge-to-edge repair device, recent study results for the PASCAL repair system  in 235 high-risk patients demonstrated successful TR reduction to moderate or less in 78% of patients (< 0.001) .A number of tricuspid valve-replacement systems are currently under investigation as minimally-invasive options via either transvenous or transatrial approaches through mini-thoracotomy . InitialAdditional strategies for the mitigation of tricuspid regurgitation have been explored using percutaneous implantation of prosthetic valves into either the inferior vena cava or bicaval positioning to functionally reduce regurgitation into the systemic venous system. Currently employed valves include the balloon-expandable Sapien XT or Sapien 3 valves  following pre-stenting of the caval veins or the self-expanding TricValve system . Neither of these devices are currently approved for this indication; however, they have been performed under compassionate use or in clinical studies . The TriHeart failure with reduced ejection fraction results in progressive deleterious left ventricular remodeling leading to increased end-diastolic volumes, myocardial stress, functional mitral regurgitation, and worsening heart failure symptoms . Early si (p = 0.0056) at 3-year follow up [The Parachute device  is a conical nitinol frame covered with a fluoropolymer membrane that can be delivered into the left ventricular cavity via a percutaneous approach to partition off an akinetic or dyskinetic left ventricular apex . Initialollow up . Resultsollow up . This Paollow up .ClinicalTrials.gov identifier: NCT04331769) is a prospective, randomized, open-label study that is currently enrolling patients with an LVEF 20–40%, LVEDD ≥ 55 mm, and NYHA II–IV symptomatology to undergo optimal medical therapy compared to device + OMT.Another device currently under investigation for the reverse remodeling of altered left ventricular geometry is the AccuCinch  ventricular restoration system. This device is a nitinol anchor-based cinching cable that is percutaneously placed in the left ventricular cavity below the level of the mitral valve, functioning to reduce the size of the left ventricle . Early fp < 0.005) and a reduction in LVESVi  and LVEDVi  at one year, along with improvements in NYHA functional class, 6-min walk distance, and the Minnesota Living with Heart Failure Questionnaire scores [The Revivent TC system  is a left ventricular restoration device which functions to exclude scarred myocardium in the anteroseptal, anterolateral, or apical regions; this device is comprised of an internal anchor placed in the right ventricular septum via internal jugular venous access and external anchors placed in the LV epicardial wall via a left lateral thoracotomy approach . These ae scores .Dyspnea in heart failure patients is largely related to pulmonary venous congestion as a result of elevated left atrial pressures. Prior studies have reported an increased 10-year mortality among patients with suspected HFpEF and an elevated resting pulmonary capillary wedge pressure (PCWP) and for those with a low resting PCWP but increased exercise PCWP . A more p = 0.06) [The Interatrial Shunt Device  is a self-expanding nitinol cage that is placed percutaneously via the femoral vein to create an 8-mm-diameter communication between the atria . The ini = 0.06) . The lar = 0.06) . The V-w = 0.06) ,61.Structural perturbations represent both a cause and consequence of the deleterious hemodynamic effects of congestive heart failure. Valvular disease and adverse ventricular remodeling occur across the spectrum of left and right ventricular ejection fraction, and heart failure patients are frequently among the highest adverse surgical risk profiles. In this review, we highlight the advances in minimally invasive approaches to valvular heart disease, ventricular-geometry restoration, and intra-cardiac shunting for patients with heart failure with reduced and preserved ejection fractions.


Acute decompensated heart failure is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown if neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level Tragus stimulation on inflammation and oxidative stress in ADHF.19 patients with ejection fraction < 40% were randomized to neuromodulation- 4 hours twice daily (6 AM-10 AM and 6 PM-10 PM) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using dihydrodichlorofluorescein probe test (expressed as fluorescein units).Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum Interleukin-6 levels . Similarly, neuromodulation led to reduction of endothelial cell oxidative stress, in the neuromodulation group  compared to sham stimulation . No significant difference in heart rate, blood pressure or renal function were noted between the two groups.In this proof-of-concept pilot study, in acute systolic heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of cellular oxidative stress.NCT02898181 Pharmacological management with diuretics, correction of precipitating factors, and supportive measures including vasodilators or inotropes remain the mainstay for ADHF.2 Even with the most modernized treatment, ADHF carries poor outcome with recurrent hospitalizations and increased mortality.3 Considering the burden of ADHF and the limitations of currently available therapies, there is an unmet need for novel treatment strategies for ADHF.Acute decompensated heart failure (ADHF) is the most common cause of hospitalization in patients with heart failure.4 Although the enhanced sympathetic activity helps to maintain the end organ perfusion, in the long term it is associated with progressive and irreversible deterioration of cardiac function. Pro-inflammatory cytokines and oxidative stress contribute to disease progression by inducing contractile dysfunction, cell death, apoptosis, and fibrosis.6 β-adrenergic receptor mediated stimulation of intracellular cyclic adenosine monophosphate and subsequent downstream kinase activation is one principal cause of maladaptive contractile, metabolic, and structural remodeling of the ventricle in heart failure.7 Hemodynamic stress, neurohormonal activation, and hypoperfusion also contribute to deranged cardiac metabolism, abnormal cardiac redox state, and cardiac and systemic inflammation.A dysregulated autonomic nervous system, characterized by higher sympathetic and blunted parasympathetic response is the hallmark of heart failure.10 LLTS is found to ameliorate inflammation, remodeling in heart failure with preserved ejection fraction.12 However, the role of LLTS in ADHF has not been evaluated. The current study evaluated the effects of LLTS on biomarkers of inflammation and oxidative stress in patients with ADHF. Here, we harnessed the beneficial effects of the neuro-immune axis to potentially reduce inflammation and oxidative stress in ADHF.The tragus of the external ear is innervated by the auricular branch of the vagus nerve. Low-level tragus stimulation (LLTS) is an emerging noninvasive neuromodulation strategy that is found to be associated with beneficial remodeling of the cardiac autonomic nervous system and restoration of sympathovagal balance.This single-center, prospective, double-blind, randomized study was conducted at the University of Oklahoma Medical Center. Patients who were hospitalized with ADHF with left ventricular ejection fraction (LVEF) < 40% were recruited. Patients with any of the following criteria were excluded from the study: acute coronary syndrome, complex congenital heart disease, recurrent vasovagal syncope, history of unilateral or bilateral vagotomy, sick sinus syndrome, cardiac conduction abnormalities including 2nd, or 3rd -degree atrioventricular block, bifascicular block or prolonged 1st degree AV block (PR > 300ms), pregnancy, prisoners, or end-stage renal disease on dialysis. The study was approved by the local Institutional Review Board. After informed consent, included patients were randomly assigned  to either active LLTS or sham stimulation which was continued for the duration of their index hospital admission. The baseline clinical data including physical examination, routine laboratory investigation, electrocardiography, and echocardiography data were recorded. Patients were then instructed about the process of using the device and were asked to repeat the process themselves under direct supervision, to ensure the correct use of the device. This demonstration process was performed by a clinical coordinator who was not blinded to random allocation. All other investigators were blinded to the allocation arm. Blood samples were collected on the day of admission before the initiation of the treatment protocol and on the day of discharge. All procedures and protocols were approved by the Institutional Review Board at the University of Oklahoma. Informed consent was obtained from each participant.13 The PARASYM®  TENS Unit, was used for LLTS. The device was connected to a clip electrode that was attached to the external ear. In the active group, the ear clip electrode was attached to the tragus. In the sham stimulation group, the clip electrode was attached to the ear lobule where no vagal innervation is present. The unit was set at a pulse width of 200 μs, and a pulse frequency of 20 Hz. These parameters were chosen based on our previous published work in diastolic dysfunction and paroxysmal atrial fibrillation. The amplitude was titrated to the level of sensory threshold, typically in the range of 10–50 mA. The stimulation strength was gradually increased until the patient experienced mild discomfort and was then decreased by 1mA below the threshold of stimulation. LLTS was applied for 8 hours daily , and the device was used throughout the index hospital admission.Active LLTS was performed using electrodes attached to the tragus of the ear, which is innervated by the auricular branch of the vagus nerve.™, USA)Blood samples were centrifuged within 30 minutes of collection (4000g for 10 minutes), and serum/plasma was immediately stored in aliquots at −80°C. To determine systemic inflammation, serum levels of IL-6 were measured. As a proof of concept we also analyzed certain other markers in inflammation: CRP, TNFα, soluble intercellular adhesion molecule 1 (sICAM-1), and vascular cell adhesion molecule 1 (sVCAM-1) using commercially available enzyme linked immunosorbent assay kits , following published protocols.14 Sera collected before and after treatment was distributed in a 96-well plate in quadruplicates, samples, and from each patient were measured in the same plate. Production of reactive oxygen species (ROS) by cultured HCAECs was measured by flow cytometry after treatment with sera of ADHF patients. Intracellular production of ROS induced by serum factors was measured in detector HCAECs using 2,7 dihydrodichlorofluorescein (DCF) at 3 micromol concentration.15Primary human coronary endothelial cells (HCAECs) based bioassay was used to evaluate the oxidative stress-inducing capacity of patient sera. Detector HCAECs were cultured in an Endothelial Basal Medium supplemented with 10% fetal calf serum until the time of serum treatment, as described.The primary outcome of the study was the reduction in inflammatory activity and ROS (cytosolic peroxide content) during hospital admission. We did not perform power calculations in this first phase of feasibility trial. Categorical data were presented as percentages. For continuous variables, the distribution of data was assessed using the Shapiro-Wilk test and variance homogeneity with F-test. Normally distributed continuous data were presented as mean ± SD whereas median(IQR) values were used to present skewed data. The serum inflammatory and oxidative stress markers were compared between two groups (baseline LLTS vs baseline sham control or baseline vs predischarge) using the ANOVA test and within group changes were analyzed using Wilcoxon sum rank test at 5% significance.20 patients were enrolled in the study, but 19 patients completed the study, and data from these 19 patients were used for analysis. Of these 19 patients, 8 patients (42%) were randomized to the intervention group, and 11 (52%) patients were randomized to the sham stimulation (control) group. The demographics and baseline characteristics of both groups are presented in Supplemental Table 1. No adverse events were reported by patients and device was well tolerated by all subjects. One patient left the hospital against medical advice and hence follow up data was not available.p = 0.012) (p:0.182), CRP , sICAM-1  and sVCAM-1 levels were also favorably lowered by LLTS but when compared to sham control, but they did not reach statistical significance. (In = 0.012) . Other ificance. , Figs. 1p = 0.004) (p = 0.10) . Results were expressed in fluorescein units. LLTS was associated with a significant reduction in pre-discharge DCF fluorescence  . However = 0.10) . TherefoOur first-in-human, proof-of-concept, pilot study demonstrated the feasibility and safety of LLTS in ADHF and showed improvement in systemic inflammation, as evident in IL6. Similarly, changes were noted in oxidative stress with LLTS compared to sham. LLTS did not adversely affect heart rate, blood pressure, and renal function during hospitalization. This is the first study to demonstrate favorable effects of LLTS on inflammation and oxidative stress in ADHF.In our pilot, proof-of-concept study in acute heart failure, neuromodulation technique using LLTS was associated with a reduction in serum IL-6 but also favorably altered other cytokines . The reduction of systemic inflammation by LLTS in ADHF is a novel finding of our study. In addition, neuromodulation using LLTS led to favorable modulation of human coronary endothelial cell oxidative stress.18 The acute increase in cytokines may modulate the course of acute heart failure by negatively influencing ventricular systolic and diastolic function, systemic and pulmonary fluid homeostasis, and promoting prothrombotic and proapoptotic milieu. Serum cytokine levels are also reported to correlate with the degree of ventricular remodeling and adverse prognosis.17 IL-6 levels at admission are found to correlate with the severity of heart failure and mortality.21 IL-6, in acute myocarditis, also plays a crucial role in the transition from acute to chronic phase by promoting macrophage recruitment, and persistent elevation of IL-6 is known to predict the risk for recurrent hospitalization and non-recovery of ventricular function.22 The severity of myocardial damage and remodeling correlates with the degree of inflammation. In a canine model of ischemic heart failure, a greater reduction of inflammation with LLTS translated into more reverse remodeling and improvement of contractile function.23ADHF is considered a proinflammatory state and a significant increase in inflammatory cytokines  is reported in hospitalized patients with ADHF.24 A vagally mediated ‘inflammatory reflex’ is known to control the immune response and inflammation during pathogenic invasion as well as during tissue injury, the parasympathetic vagal system being the integral component of both afferent and efferent system in this communication.25 LLTS is thought to relay afferent information to the dorsal vagal complex and dorsal motor nucleus through the auricular branch of the vagus nerve.26 Modulation of the brainstem stem vagal centers is thought to modulate the interaction between the sympathetic and parasympathetic systems with a net increase in efferent vagal outflow to the heart and periphery, specifically the splenic tissue. This anti-inflammatory reflex is partly mediated via α7 nicotinic acetylcholine receptor receptors (α7nAchR) on splenic macrophages thereby modulating the peripheral generation of inflammatory cytokines.27 In summary, the vagomimetic and antiadrenergic action of LLTS, via the brain-cardiac-splenic axis, may explain the attenuation of inflammation in our study. LLTS-mediated reduction in systemic inflammation may suggest and uncover a novel, non-pharmacological intervention that may aid in treating a pathophysiological axis in ADHF.Mechanisms underlying vagal-mediated inflammatory modulation have been described previously. In experimental models of systolic heart failure, restoration of sympathovagal balance by chronic vagal stimulation is associated with inhibition of cytokine release and improvement of ventricular function.−), hydroxyl (OH−) and peroxide(H2O2). These  are principally generated in mitochondria and cytosol from electron leak through electron transport chain and oxidation of reduced nicotinamide adenine dinucleotide phosphate by its corresponding oxidase enzyme.28 Superoxide, an extremely unstable compound with half-life in nano seconds, is subsequently metabolized to H2O2 by superoxide dismutase. Due to rapid reduction by superoxide dismutase and very short half-life, superoxide is far more unstable compared to H2O2 and thereby rendering it as a less effective direct oxidative biomarker to measure. 28 Cytosolic peroxide is primarily dependent on diffusion of mitochondrial H2O2 into cytosol.30Coronary endothelium is an important source of ROS generation in HF and our study demonstrated an attenuation of endothelial oxidative stress with neuromodulation via LLTS. Reactive oxygen species are primarily comprised of superoxide  and redox active transition metals.32 In a previous study by Csiszar et.al., endothelial cells exposed to increased inflammatory stress (such as increased circulating cytokines-TNF- α) with subsequent increased oxidative stress and ROS generation, specifically peroxide, led to higher DCF values.33 Increased circulating cytokines perhaps exposed the HCAEC’s to an inflammatory milieu leading to increased ROS generation and subsequent increased DCF fluorescence. To our knowledge, this is the first study in ADHF to determine the extent of induced human coronary endothelial ROS quantification, using DCF based assays, specific for cytosolic peroxide content.Dihydrodichlorofluorescein diacetate is widely used to evaluate cellular oxidative stress. DCF passes through plasma membrane and this non fluorescent compound is ultimately oxidized to a fluorescent compound dichlorofluroscein (DCF), via a process that involves various ROS, but more specific to H6 Increased ROS may further induce contractile, electrical, and structural remodeling in HF.6 Serum ROS level correlates with prognosis and severity HF.34 Reduction of oxidative stress is reported to improve inflammation, provide cytoprotectant effects, and ameliorate post-infarction remodeling.35 Adrenergic stimulation promotes ROS production by inducing a reductive redox as well as by stimulation of nicotinamide oxidases by β2-adrenergic activity.37 Low-level vagal stimulation is reported to reduce ROS generation and improve antioxidant capacity in experimental models of myocardial infarction and heart failure.39 Both antiadrenergic and cholinomimetic action of LLTS might also contribute to the in vivo inhibition of ROS production by augmentation of muscarinic activation(M2 receptors), anti-beta2 activity, downstream improvement of metabolic balance, as well as reduction of nicotinamide oxidase activity.35An aberrant redox balance, characterized by enhanced pro-oxidant ROS generation and /or reduced activity of antioxidant mechanisms, plays a major role in the pathophysiology of heart failure.NCT02898181) of LLTS in acute heart failure (HFrEF and HFpEF) will further evaluate the effects on heart rate variability, inflammation, heart failure clinical biomarkers. In this ongoing study the duration of LLTS is now reduced to 2 hours/day.Our study carries several limitations, a small sample size being the first limitation. Second, the endpoints were focused on surrogate markers rather than clinical outcomes. However, this pilot study is hypothesis generating on the effects of LLTS on core pathogenic pathways in ADHF. Future prospective studies with large sample sizes are warranted to determine the effects of LLTS on clinical endpoints in ADHF. Third, although heart rate variability parameters are considered markers of cardiac autonomic activity, the effect of short-term LLTS on heart rate variability parameters has not been evaluated in our study. Our ongoing extended study (LLTS during hospital admission is safe in the acute decompensated heart failure patients with reduced ejection fraction and is associated with the mitigation of systemic inflammatory activity. Endothelial level oxidative stress activity, specifically cytosolic peroxide content, was also decreased with LLTS in ADHF, perhaps directly linked to attenuation in systemic inflammation. Further studies are underway to corroborate and extend these findings.


Primary pulmonary artery hypertension (PAH) is a clinical diagnosis that requires the exclusion of other underlying causes of pulmonary hypertension (PH). Increased pulmonary artery (PA) pressure and subsequent right ventricular (RV) pressure overload often result in a flattening of the curved interventricular septum, leading to a D-shaped left ventricle (LV), as observed in echocardiographic short-axis views. A similar finding may be also observed on myocardial perfusion SPECT images, the so-called Movahed's sign. We present a clinical case of a female patient with PAH and progression of exertional dyspnea that underwent myocardial perfusion SPECT to investigate LV myocardial ischemia. The SPECT images revealed enhanced tracer uptake in the dilated right ventricle. Additionally, we observed a D-shaped LV or Movahed's sign, which may serve as a potential marker of RV pressure overload, along with a small stress-induced perfusion defect on the LV septal wall. Our findings highlight the importance of considering the presence of a D-shaped LV and signs of RV pressure overload, as they can alter the interpretation of LV perfusion deficits on SPECT images. This case report aims to emphasize the complex nature of right heart abnormalities in pathologies such as PAH and the consideration of the RV implications in myocardial SPECT images—which typically focus solely on the LV. Primary pulmonary artery hypertension (PAH) is characterized by abnormal echocardiographic findings of precapillary origin. Right ventricular (RV) overload is a common finding in patients with PAH and is primarily investigated using echocardiography, cardiac magnetic resonance imaging, and right heart catheterization . In geneWe report a case of a female patient with known PAH who underwent myocardial gated- SPECT to investigate a probable presence of CAD, due to the progression of exertional dyspnea.A 62-year-old female patient presented to the Outpatient Clinic of the Department of Cardiology at the Medical University of Vienna for her periodic 6-month routine visit to review her cardiovascular (CV) medication. Her past medical history included systemic hypertension, hypercholesterinemia, and a previously diagnosed precapillary PAH dating back to 2013. Since 2014, the patient has been receiving Treprostinil pump therapy with a concentration of 10 mg/ml starting with 140 ng/kg/min. Over the years, routine visits led to dose adjustments, eventually resulting in a dose up-titration of up to 268 ng/kg/min in 2019. Since 2021, a progression in pulmonary artery pressures as a non-responder to vasoreactivity testing could be observed, despite the absence of dyspnea in the patient's daily life.Recently, the patient presented to the Outpatient Clinic of the Department of Cardiology with exertional dyspnea (NYHA III) persisting for the previous 3 months. NT-proBNP value was 240 pg/ml. A transthoracic echocardiogram was performed and revealed mild LV hypertrophy with normal systolic LV function, a slight LV diastolic function reduction, and abnormal septal motion. D-shaped LV was demonstrated on echocardiographic short-axis views during systole .Furthermore, the patient showed mild dilation of the right atrium (RA) and the RV , along wConsidering the recent symptom progression and absence of recent angiographic information on coronary arteries, the patient was referred to the Division of Nuclear Medicine at the Medical University of Vienna to rule out LV myocardial ischemia associated with CAD.99mTc]Tc-Tetrofosmin, after pharmacological stress with Regadenoson® and at rest, conducted according to the 1-day protocol of our institution and using the D-SPECT®Cardio camera  in a sitting position. The baseline ECG findings, before the stress test began, were sinus rhythm, 89/min, P-mitrale, bifascicular block (left anterior hemiblock and right bundle branch block—QRS 148 ms), ST-segments not significantly pathological, terminal negative T-waves in aVL, V1–V4. During the stress test, as well as in the recovery phase, no specific ECG modifications and no specific symptoms were recorded. The patient's blood pressure was 95/60 mmHg at rest, 120/70 mmHg during hyperemia, and 110/65 mmHg during the recovery phase.The patient underwent myocardial perfusion ECG-gated SPECT with [99mTc]Tc-Tetrofosmin LV tracer uptake, interpreted as LV myocardial perfusion, was qualitatively and semi-quantitatively assessed using a 5-point scale on the 17-segments scheme, obtaining the summed rest (SRS), summed stress (SSS), and summed difference scores (SDS). The measurement of LV function as LV ejection fraction (LVEF), LV end-diastolic, and end-systolic  volumes was additionally performed by automated and validated methods using state-of-the-art imaging software QGS/QPS .Rest and stress SPECT studies were reconstructed using state-of-the-art imaging software protocols provided by Spectrum Dynamics Medical Processing Station 4.2.3 and analyzed on the Hermes Medical Solutions  platform. Then, the reconstructed images were realigned along the standard cardiac planes . The [Stress LV perfusion images showed a moderate perfusion defect in the mid-basal inferoseptal wall and a small perfusion defect in the basal segment of the inferolateral wall (SSS 5). At rest, we could observe a recovery of both perfusion defects as well as diffuse improvement of the LV perfusion (SRS 0), with an SDS of 5 . Gated aThe D-shaped LV observed on myocardial perfusion SPECT was consistent with the analogous sign observed on echocardiographic short-axis views during systole . The perPrimary PAH is a precapillary PH subgroup characterized by increased mean PA pressure (PAP) exceeding 25 mmHg . The exaOn the verge of a comprehensive assessment of underlying causes and unspecific symptoms related to PAH, gated myocardial SPECT may be a not-so-uncommon examination to study the LV. Nevertheless, the relatively smaller size and lower vascularization grade of the healthy RV wall in comparison to the LV myocardium renders it invisible on myocardial perfusion SPECT images. Consequently, routine imaging analysis and interpretation do not typically include the RV. In certain cases, an enhanced tracer uptake of the RV can be observed and may be an indicator of LV global perfusion deficits or RV hypertrophy, due to increased RV volumes and/or pressures , 12. Of The displacement and loss of curvature of the septum can be best assessed in short-axis parasternal views in echocardiography and analogous to the short-axis views in myocardial SPECT  Figure . When usThis case presents a unique scenario in routine myocardial SPECT imaging and warns us that the pathologies in the RV might impede the evaluation of the LV. The two ventricles are interconnected and the RV—although not frequently observed in SPECT perfusion images—influences morphology, motion, and perfusion of the LV in gated myocardial SPECT. The Movahed's sign or the D-shaped LV due to the flattening of the interventricular septum indicates the intricate and dynamic nature of the heart function.This case represents the first approach to the simultaneous evaluation of symptom origin within the context of cardiovascular risk factors, and PH under vasodilation therapy (Treprostinil) using routine cardiac perfusion imaging. Furthermore, it emphasizes the need for nuclear medicine physicians to consistently consider and integrate the Movahed's sign and other RV-related anomalies into the correct interpretation and reporting of images, recognizing the right heart changes in pathologies such as PAH and the diagnostic value of SPECT imaging.


Ruminococcus gnavus, Escherichia Shigella, Streptococcus sp, Veillonella sp, and Actinobacteria, and relative depletion of Eubacterium,Prevotella, Faecalibacterium, SMB53, and Megamonas. The composition varied according to age, heart failure stage, and decompensation level. The composition remained unaltered with ejection fraction. There was an increased expression of genes responsible for the metabolism of amino acids, carbohydrates, choline trimethylamine-lyase (TMA-lyase), lipopolysaccharide (LPS) biosynthesis, tryptophan, and lipid metabolism. The resultant changes affected the levels of metabolites, such as trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), and LPS, and inflammatory markers in the feces and plasma, which contributed to heart failure. These biomarkers of heart failure could serve as targets for the prevention and treatment of heart failure. Patients with heart failure harbor a unique constellation of gut microbiota that affect the pathogenesis of heart failure. Further studies are needed to understand the causal relationship between dysbiosis and heart failure.Heart failure (HF) contributes to the cardiovascular health burden worldwide. Patients with heart failure have been recently studied to possess unique changes in the gut microbiome that affect immune homeostasis and metabolism. In this systematic review of the literature, we aim to identify the impact of gut dysbiosis on heart failure. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to conduct our systematic review. We searched the literature on databases such as PubMed, PubMed Central (PMC), Medline, and ScienceDirect. Ten articles were included for review. There were significant differences in the gut microbiome composition in heart failure. Relative abundance of  Heart failure (HF) is a major public health burden worldwide. It has been estimated that about 6.5 million people suffer from chronic heart failure in the United States . It is aThe human body hosts a wide array of microbial species, known as the human microbiome, organized into distinct groups such as the oral, vaginal, gastrointestinal, and skin communities -6. They The gut microbiome has been widely studied recently because of its pertinent role in maintaining the immune system -16, and Despite a growing interest in this field, the exact relationship between the gut microbiome and heart failure still remains understudied. So far, only limited small-scale studies have been conducted to identify unique changes in the gut microbial composition and metabolic profiles in heart failure patients. Although studies have demonstrated that heart failure patients harbor a distinct set of microbes, whether these changes are a causative factor or a consequence of heart failure is unknown. It is crucial to identify a causal relationship between gut dysbiosis and heart failure and thereby discover specific fecal biomarkers that could serve as therapeutic targets to prevent and treat heart failure.This systematic review of the literature describes the association and role of dysbiosis in patients with chronic heart failure. Further studies are warranted to demonstrate a temporal relationship between dysbiosis and heart failure, if any exists.MethodsWe conducted this systematic review strictly adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines . Our stuLiterature Search StrategyWe thoroughly searched four databases - Pubmed, PubMed Central (PMC), Medline, and ScienceDirect - for articles that studied an association between intestinal microbial dysbiosis and chronic heart failure between January 1, 2022, and March 1, 2022. A systematic search strategy using medical subject headings (MeSH) terms and keywords was developed to extract all the relevant articles for analysis. The keywords included "chronic heart failure", "heart failure", "cardiac failure", "gut microbiome", "dysbiosis", "intestinal dysbiosis", and "intestinal microbiome". Using the Boolean method, we used keywords and the MeSH strategy to retrieve all the pertinent articles from the databases. The detailed search strategy for the databases has been stated Table Articles were limited to original observational studies. Additional inclusive criteria included papers from the last ten years, papers published in the English language, papers focusing on the population with age 19 years and above, and papers relevant to the question. We excluded papers discussing population with age 18 years and below, unpublished literature, and gray literature.Data ExtractionThe articles were screened by title, abstract, and full text for relevance by two authors independently. The data was extracted on an excel sheet. The information extracted from these articles included the year of publication, sample size, demographics of the patients (age), left ventricular ejection fraction (LVEF) % of the chronic heart failure (CHF) patients, inclusion criteria, results, and conclusion. In case of discrepancy between the reviewers, opinion was taken from the third author, and conflicts were resolved by mutual understanding considering the inclusion and exclusion criteria of the review.Quality Appraisal Of StudiesWe used the Joanna Briggs Institute (JBI) tool for the quality appraisal of the included articles. The score of each criterion was reported as "Yes", "No", or "Unclear". The articles that fulfilled >70% of the criteria were finally included for detailed review. The detailed quality check based on the criteria using the JBI tool is described in Table ResultsStudy SelectionInitially, our search included a total of 5697 articles from PubMed, PubMed Central (PMC), Medline, and ScienceDirect databases. After excluding duplicates and articles published more than 10 years ago and focusing on the pediatric population, we included 774 articles for further screening. Screening based on title, abstracts, and inclusion and exclusion criteria excluded 759 articles. We further excluded articles that were non-observational studies and did not meet the criteria during quality appraisal using the JBI tool. Ultimately, 10 articles were selected for review  classes I-IV, patients with left ventricular assist device (LVAD), and heart transplant (HT).Gut CompositionEight studies used the method of 16S rRNA gene amplification and sequencing to study compositional and functional changes in the microbiome. In contrast, one study used the 16S rDNA gene amplification and sequencing method. The remaining study identified the colonies using colony-forming units (CFU) after culturing on specific agar.Nine out of 10 articles compared the composition of the gut microbiome in patients with clinically diagnosed heart failure with controls. All these studies concluded a significant difference in both groups' beta diversity . One of 10 studies studied the effects of progressive stages of heart failure  on beta diversity.Functional and Metabolomic ChangesFour of the ten studies analyzed the functional alteration in the gut metagenome, and five of the ten articles analyzed the changes in the fecal and plasma metabolites in patients with heart failure. The pertinent characteristics of the studies have been discussed in Table DiscussionInteraction between gut microbiota with other organ systems in the body, including the cardiovascular system, has been a recent topic of interest, particularly due to their potential role in the pathogenesis and prognosis of heart failure. The effects of gut microbiota on the cardiovascular system are shown in Figure Our systematic review aimed to unravel gut microbial diversity, composition alterations, and associated functional and metabolomic changes in patients with chronic heart failure. Gut Microbial Richness and Diversity in Heart FailureA diverse gut microbiome consists of millions of microbial species, each contributing uniquely to maintaining homeostasis and coexisting in a healthy symbiotic relationship with the host gut. Alpha diversity is the total number of species . In contrast, beta diversity is the type and abundance of specific species  present at any time in the gut. In the following few paragraphs, we have described the alterations in gut microbial composition seen in CHF patients and their implications. The characteristics of the sample and the notable changes in the gut microbial composition have been described in Table Studies Involving Patients With Systolic and Diastolic Heart FailureEscherichia Shigella, Klebsiella, and Haemophilus as well a significant enrichment of Ruminococcus gnavus in CHF patients. Ruminococcus gnavus was particularly interesting since it was also elevated in a prior study [The interplay between the gastrointestinal and cardiovascular systems has been a recent topic of interest for many. Wang et al. found that the overall richness and diversity of bacteria in patients with clinically stable CHF was significantly lower than in controls . They idor study . It has or study . While tor study . In addior study .Eubacterium and Prevotella on network analysis [A recent study has described the most notable change in the gut microbiome in HF patients as the depletion of analysis . These gEubacterium rectale and Dorea longicatena. They further studied that the older patients had a lower proportion of Bacteroidetes and a larger proportion of Proteobacter than younger patients with heart failure. In addition, older patients also had elevated Lactobacillus and reduced Faecalibacterium prausnitzii and Clostridium clostridioforme in the feces. Depleting Eubacterium rectale and Faecalibacterium prausnitzii leads to depletion of butyrate production in the gut affecting the gut integrity and creating a pro-inflammatory state in older patients with HF. While they have elucidated the relationship of dysbiosis with age, the major limitation of their study remains the potential confounding effect of aging as a natural process, medications, diet, and comorbidities on the gut microbiome. The study could not establish a temporal relationship between aging in HF patients and gut dysbiosis. Therefore, long-term longitudinal studies are recommended to understand specific aging alterations to create unique treatment plans based on the patient's age [A small-sized study identified that patients with HF had no differences in alpha diversity; however, they had a decreased representation of nt's age .Blautia, Collinsella, unclassified Erysipelotrichaceae, and unclassified Ruminococcaceae genera. Furthermore, they proposed that the depletion of Collinsella was specific to HF due to its depletion even in patients with HF and comorbid diabetes mellitus or ischemic heart disease [A study also found a significant reduction in the total number of microbes in HF patients, apart from identifying a non-significant overgrowth of pathogenic bacteria in the gut. There was a significant reduction of  disease . BlautiaStudies Involving Patients With Only Systolic Heart FailureRuminococcus gnavus and decreased representation of Faecalibacterium prausnitzii, as identified in the feces [Faecalibacterium prausnitzii has been studied to possess an anti-inflammatory property due to its role in butyrate production [Cui et al. studied the samples' beta diversity (based on the Bray Curtis distances). They found that the microbiome composition was significantly different among HFrEF patients and independent of the usage of PPI or statins. However, there was no difference in the beta diversity between the ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) patients, concluding that the changes in the beta diversity are independent of the etiology of HFrEF. The essential characteristics were increased representation of the he feces . Faecalioduction . Since bActinobacteria and genus Bifidobacterium and a reduced abundance of genus Megamonas [Another study that evaluated the diversity in HFrEF patients identified that patients with systolic HF did not have a significant drop in the total number of species  comparable to the controls; however, they have notable alterations in the composition of the microbiome. They observed an increased relative abundance of phylum egamonas . They pregamonas . Howeveregamonas . There wA study conducted in patients with systolic heart failure identified that the patients with HFrEF have a significant overgrowth of pathogenic organisms such as Campylobacter, Shigella, Salmonella, Yersinia, and candida . SimilarYuzefpolskaya et al. conducted a large-scale study to identify the gut composition variation across varying stages of heart failure - NYHA Class I-IV, LVAD, and HT. They observed a decrease in the gut diversity across stages from NYHA class I to class IV. Moreover, the diversity remained low among patients with LVAD and HT. This diversity depletion was primarily due to a subset of taxa that possess anti-inflammatory features .Studies Involving Patients With Only Diastolic Heart FailureRuminococcus [While many studies had been conducted on HFrEF patients to evaluate gut dysbiosis, the study conducted by Beale et al. was unique since it included only patients with diastolic heart failure, aiming at identifying gut microbial dysbiosis in patients with HFpEF. They concluded that the patients with HFpEF had varying alpha as well as beta diversity compared to the controls. They observed that the major contributor to the variation in beta diversity was the significant depletion of SCFA-producing microbes, particularly nococcus . The intFurthermore, this study also observed that the changes in beta diversity in patients with HFpEF were independent of dietary factors . HoweverFunctional and Metabolomic Alterations in Heart FailureAlong with studying the gut microbiome composition in CHF patients, it is also pertinent to identify the implications of those changes on the functional expression of genes and metabolic pathways to understand the effect of dysbiosis in greater detail. Several studies have extrapolated their compositional findings to identify gene and metabolic expression changes, as summarized in Table Most recently, two studies have focused on the topic of interest. Wang et al. studied the serum concentrations of the markers of inflammation  in patients with stable chronic heart failure . EarlierA similar study conducted primarily in patients with systolic HF across varying stages concluded that the levels of inflammation such as IL-6, CRP, adiponectin, endothelin, and TNF-a, and oxidative stress, such as isoprostane increased along with the severity of heart failure. Eventually, they decreased in LVAD and HT patients . TherefoIn 2021, Hayashi et al. investigated the relationship between gut dysbiosis and changes in the metabolism of amino acids. At the metagenome level, they observed an increased abundance of genes responsible for degradation and decreased abundance of genes responsible for the biosynthesis of essential amino acids. As a result, the levels of essential amino acids, including branch-chain amino acids, alanine, and histidine, are in the blood of patients with heart failure. They also established a positive correlation between microbial essential amino acid biosynthesis genes and plasma branch-chain amino acid levels . AlthougThe role of TMAO on cardiovascular health has been widely studied recently. Upregulation of genes for choline trimethylamine-lyase (TMA-lyase) and Llpopolysaccheride (LPS) biosynthesis was observed in a cohort of patients with HFrEF . TMA-lyaEscherichia/ Shigella and levels of indoxyl sulfate and TMAO. Indoxyl sulfate is a microbial-dependent uremic toxin that is known to harm the cardiovascular system. Upregulation of the tryptophanase genes in the microbiota in the decompensated phase causes indoxyl sulfate production in the host. They also proposed an inverse correlation between the abundance of genus Bifidobacterium and the plasma indoxyl sulfate levels and that it has a cardioprotective effect in patients with HF [In patients with decompensated heart failure, an increased expression of TMA-lyase and tryptophanase genes was observed . TMAO wo with HF . LimitationsFirstly, most of the studies included were single-centered small-sized studies involving a small patient population. The gut microbiota is affected by many factors, including the patient's age, comorbid conditions, diet, medications, and exercise. Dietary and exercise history was not considered in most of the included studies. Moreover, there was a significant difference in the medication usage of the patients and the control subjects. None of these studies identified a temporal relationship between gut dysbiosis and heart failure. Therefore, large-scale, multi-center longitudinal studies must understand whether they have a causal relationship. There is a significant alteration in the richness and composition of the gut microbiome in patients with heart failure. The composition further varies according to the age, severity, and stage of heart failure. Gut dysbiosis further influences the metabolic homeostasis of the host. It creates an imbalance of important metabolites in plasma and feces, such as TMAO, indoxyl sulfate, amino acids, and inflammatory markers. These metabolic disturbances promote a pro-inflammatory state that further affects the severity and progression of heart failure. These are the fecal and plasma biomarkers of heart failure, and they could prove to be crucial targets for preventing the development and prognosis of heart failure. We propose further large-scale longitudinal studies to identify a temporal relationship between gut dysbiosis and heart failure, if any exists.