ECG shows - Q waves seen in lead V2 - V5 suggestive of old anterior wall myocardial infarction X ray shows - Patchy opacities in right lower zone suggestive of Pulmonary oedema/ Bronchopneumonia
ECG Small voltage complexes. Qs in V1 to V5. OLD ANTERIOR WALL MYOCARDIAL INFARCTION X-ray chest KERLE B LINES.. Increased bronchovascular markings IMPRESSION POST MYOCARDIAL INFARCTION FAILURE Coronary artery disease Adv ECHO, reduction of beta blockers, add diuretics, ARBs, salt and fluid restriction,ADMISSION AND TREATMENT
ECG shows - Q waves seen in lead V2 - V5 suggestive of old anterior wall myocardial infarction X ray shows - Patchy opacities in right lower zone suggestive of Pulmonary oedema/ Bronchopneumonia
Poor progression of R wave Low voltage complexes in many leads b/l haziness in lung bases ?failure due to Anemia Blood Transfusion
Sir,ecg shows q waves in chest leads,low voltage complexes,cxr shows b/l hazziness d/t ?fluid overload .do 2 D echo to r/o pericarditis or cardiac tamponade.what about auscultation findings sir?
Old AWMI? Low Voltage ECG complexes Fluid Overload Anaemia of chronic disease? Iron Studies 2d ECHO TFT Urine RE
Ecg Low voltage Old AWMI Now to establish reason of failure is Anemia /Post MI
old Myocardial infarction looks like depresed EF below 30 due to that piture looks like angina diruretics recomended and blood trandusion will be helpful for early recovery
T wave inverse in lead v1-v3; probably myocardial ischemia, cxr seems to be within normal limits. Pt is anaemic.
Chest scan NAD.
I think the decision will depend on echo report I reduced EF heart failure is confirmed than adding of ORNI ( Valsartan-Scubutil) combination will be beneficial For Anaemia total dose of Orofer FCM IV in 100 ml saline should be beneficial It is better to hospitalise and monitor
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Dyspnea It is normal with all of us when we exert excessively.. But Dyspnea that is greater than expected with the degree of exertion... is a symptom of disease. Most cases of dyspnea result from asthma, heart failure and myocardial ischemia, chronic obstructive pulmonary disease, interstitial lung disease, pneumonia, or psychogenic disorders.. Below mentioned are the pathological causes of Dyspnea by Organ System…. CARDIO-VASCULAR… Pulmonary edema Acute valvular disease Myocardial infarction Cardiac tamponade Heart failure Angina Constrictive pericarditis RESPIRATORY… Acute exacerbations or persistent chronic asthma Acute exacerbation or persistent chronic obstructive lung disease Pulmonary embolism Pneumothorax Pneumonia ARDS Anaphylaxis COPD Asthma Interstitial lung diseases Pulmonary hypertension Malignancy (tumor related obstructive lesions and lymphangitic spread) Pleural effusions Sleep apnea Foreign body aspiration GASTROINTESTINAL/HEPATIC Acute liver failure and its consequences Abdominal distention of various causes Ascites Portopulmonary hypertension Hepatopulmonary syndrome RENAL CAUSE Acute or chronic renal failure and its consequences HEMATOLOGICAL… Hemorrhage Anemia NEUROMUSCULAR High cervical cord lesions Trauma to phrenic nerves Central apneas Myasthenia gravis Myopathies Amyotrophic lateral sclerosis ENT cause Vocal Cord Dysfunction Laryngeo-tracheal obstruction PSYCHOGENIC BREATHLESSNESS I hope this list of causes will be HELPFUL to diagnose the aetiology of DYSPNEA…Dr. K N Poddar19 Likes21 Answers
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Read carefully and tell me the probable dd 30 yrs female Leucorhoea +,oligomenorrhoea + Retrosternal chest pain with chest discomfort with doe type 2,with uneasiness with severe anorexia with pallor with severe generalised weakness with pitting pedal oedema ,puffiness of face since last two years .dropsy++ O/E bp 110/70 mmhg Pulse 80/minute regular Spo2 92% Ecg gross st-t changes tall r in v1, and avr Jvp raised and visible Cvs -pansystolic murmur +s1s2+ Rs aebe +,clear and equal Already adviced 2decho,cardiologist opinion to rule out - Rhd,mitral valve prolapse,dcmp,subendocardial infarction,ccf Adv:-abg,kft cbc rft thyroid profile,cpk total cpk mb tropnin hrct chestDr. Sagarprasad Dube1 Like28 Answers
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40/m smoker came to ED with chest pain,cough, breathlessness.kindly comment on ecgDr. Azam Mohd2 Likes14 Answers
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✍️✍️Late Effects Of Blood And Marrow Transplantation ___________________________________________ Abstract Hematopoietic cell transplantation is a curative treatment for a variety of hematologic diseases. Advances in transplantation technology have reduced early transplant-relatedmortality and expanded application of transplantation to older patients and to a wider variety of diseases. Management of late effects after transplantation is increasingly important for a growing number of long-term survivors that is estimated to be half a million worldwide. Many studies have shown that transplant survivors suffer from significant late effects that adversely affect morbidity, mortality, working status and quality of life. Late effects include diseases of the cardiovascular, pulmonary, and endocrine systems, dysfunction of the thyroid gland, gonads, liver and kidneys, infertility, iron overload, bone diseases, infection, solid cancer, and neuropsychological effects. The leading causes of late mortality include recurrent malignancy, lung diseases, infection, secondary cancers and chronic graft-versus-host disease. The aim of this review is to facilitate better care of adult transplant survivors by summarizing accumulated evidence, new insights, and practical information about individual late effects. Further research is needed to understand the biology of late effects allowing better prevention and treatment strategies to be developed. Introduction Hematopoietic cell transplantation (HCT) is a curative treatment for a variety of hematologic diseases.1 The safety of HCT has improved over the decades,2 indications for HCT have expanded to older patients,3 and almost all patients are able to find suitable allogeneic donors by the growing use of cord blood4 and haploidentical transplantation.5 These current conditions have contributed to a growing number of HCT survivors, estimated to be half a million worldwide.6 Patients who are disease-free at two or five years after HCT have a greater than 80% subsequent 10-year survival rate,7–10 but many studies show that HCT survivors suffer from significant late effects that adversely affect morbidity, mortality, working status and quality of life.7–13 A prospective observational study of 1022 survivors who underwent HCT between 1974 and 1998 showed that 66% of the survivors had at least one chronic condition and 18% had severe or life-threatening conditions.14 A retrospective study of 1087 contemporary survivors also showed that the cumulative incidence of any non-malignant late effect at five years after HCT was 45% among autologous and 79% among allogeneic recipients, and 2.5% of autologous and 26% of allogeneic recipients had three or more late effects.15 Life expectancy among 5-year survivors remained 30% lower compared with the general population, regardless of their current ages and years since HCT.9 The leading causes of excess deaths in 5-year survivors included secondary malignancies (27%) and recurrent disease (14%), followed by infections (12%), chronic graft-versus-host disease (GvHD) (11%), cardiovascular diseases (11%), and respiratory diseases (7%).9 The aim of this review is to facilitate better care of adult HCT survivors by summarizing accumulated evidence, new insights, and practical information about individual late effects (Figure 1). Recurrent disease and chronic GvHD are not discussed and readers are referred to other reviews.16–20 Figure 1. Download figure Open in new tab Download powerpoint Figure 1. Late effects of blood and marrow transplantation. Cardiovascular diseases Cardiovascular diseases (CVD) after HCT include cardiomyopathy, congestive heart failure, valvular dysfunction, arrhythmia, pericarditis, and coronary artery disease.21 Their cumulative incidences were 5%–10% at ten years after HCT,22–24 accounting for 2%–11% of mortality among long-term survivors.8,9,25 The incidence of CVD and its associated mortality were 1.4–3.5-fold higher compared with the general population.8,9,24,25 HCT survivors are more likely to have conventional risk factors such as dyslipidemia and diabetes than the general population.26 Early diagnosis and treatment of modifiable risk factors is important. We usually treat hypertension more than 140/90 mmHg on 2 separate visits or more than 130/80 mmHg for patients with diabetes or renal disease.27 The first step is lifestyle modification including weight reduction, dietary sodium reduction and regular physical activity, followed by initiating antihypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Anthracycline exposure and chest radiation are the major risk factors for CVD after HCT.21 Several studies showed that dexrazoxane, ACE inhibitors, ARBs and beta-blockers can prevent anthracycline-related cardiomyopathy in the non-HCT setting.28–32 Once cardiomyopathy is established, it is important to initiate appropriate treatment. ACE inhibitors and beta-blockers have been effective in improving left ventricular function.33 Pulmonary diseases Non-infectious late complications of the lung include bronchiolitis obliterans syndrome (BOS), cryptogenic organizing pneumonia (COP) and pulmonary hypertension. BOS represents chronic GvHD of the lung, and is characterized by the new onset of fixed airflow obstruction after allogeneic HCT.34 According to the strict 2005 National Institutes of Health (NIH) diagnostic criteria for chronic GvHD, incidence of BOS was 5.5% and its prevalence was 15% among patients with chronic GvHD.35 Symptoms of BOS include dyspnea on exertion, cough and wheezing, but early BOS may be asymptomatic until significant lung function is lost.36 One study showed rapid decline in %FEV1 during the six months before BOS diagnosis, with a lower %FEV1 at diagnosis associated with worse survival.37 In our practice, we perform pulmonary function tests every three months including %FEV1 and FEV1/FVC among patients with active chronic GvHD. When testing shows significant new airflow obstruction, we repeat testing every month until stability is confirmed.38 Plasma matrix metalloproteinase 3 levels39 and parametric response mapping from CT scans40 might be useful diagnostic tests for BOS but these have not yet entered clinical practice. Standard treatment of BOS is prednisone at 1 mg/kg per day, followed by a taper to reach a lower, alternate-day regimen.38 A multicenter prospective study showed that addition of FAM (inhaled fluticasone propionate at 440 μg twice a day, azithromycin at 250 mg taken 3 days per week, and montelukast at 10 mg nightly) to prednisone treatment stabilized pulmonary function in 70% of patients with newly diagnosed BOS and permitted systemic steroid exposure to be reduced.41 Cryptogenic organizing pneumonia is a disorder involving bronchioles, alveolar ducts, and alveoli, the lumen of which become filled with buds of granulation tissue consisting of fibroblasts.42 Clinical symptoms include dry cough, shortness of breath, and fever. Bronchoalveolar lavage is performed to exclude infection. Lung biopsy is required for definitive diagnosis, but an empiric diagnosis is often based on radiographic findings of diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Pulmonary function testing shows restrictive changes and low diffusing capacity of the lungs for carbon monoxide. The incidence of COP is 2%–10%,43,44 and it is strongly associated with acute and chronic GvHD.45 COP usually responds within 5–7 days to prednisone at 1 mg/kg per day, which is continued for one month followed by a slow taper over five months because COP can often recur. Small case series suggest potential benefits of macrolides for treatment of COP.46 Pulmonary hypertension is an uncommon but potentially fatal complication after HCT, with a reported prevalence of 2.4%.47 The most common symptoms are hypoxia, tachypnea, dyspnea, and acute respiratory failure,48 and if untreated, pulmonary hypertension can result in a progressive increase in pulmonary vascular resistance, right ventricular failure and death. Since initial symptoms are non-specific, it is likely to be underdiagnosed after HCT. Although cardiac catheterization is the gold standard for diagnosis of pulmonary hypertension, high-resolution chest computed tomography and echocardiography are non-invasive and useful diagnostic modalities. The most common types are pulmonary arterial hypertension and pulmonary veno-occlusive disease, sometimes associated with transplant-associated microangiopathy and inherited or acquired hemolytic anemia.48 First-line therapies are supplemental oxygen and phosphodiesterase-5 inhibitors, followed by inhaled nitric oxide, diuretics, bipyridine inotropes and after-load reducing agents.48 Endocrine diseases Major late effects in the endocrine system include thyroid dysfunction, diabetes, dyslipidemia, and adrenal insufficiency. Hypothyroidism occurs in 30% of patients by 25 years after HCT.49 Risk factors include age under ten years, conditioning containing radiation, busulfan or cyclophosphamide, and hematologic malignancies.49,50 The international guidelines recommend checking serum thyroid-stimulating hormone and free thyroxine levels every year.21 For patients who received radiolabeled iodine antibody therapy, thyroid function should be checked earlier starting at three and six months after HCT, and other times as clinically indicated. Standard criteria are used to initiate replacement therapy for hypothyroidism. Some patients develop hyperthyroidism after HCT as a rare complication.51 Diabetes occurs in 8%–41% of patients after allogeneic HCT and in 3% of patients after autologous HCT.15,52,53 Its incidence after allogeneic HCT is 3.65 times higher compared with their siblings.54 Initial treatment is therapeutic lifestyle counseling, but many patients require hypoglycemic agents or insulin. Dyslipidemia occurs in 9%–61% of HCT survivors.53,55 Despite no established consensus for management of dyslipidemia after HCT, our practice is to initiate therapeutic lifestyle counseling followed by statin therapy when LDL cholesterol exceeds 130–190 mg/dL according to the estimated risk of CVD, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines56 and the recently suggested approach after allogeneic HCT.57 The 2013 ACC/AHA guidelines do not specify the targeted levels for LDL cholesterol, and addition of statin therapy is based on calculated risk for future cardiovascular events.58 Addition of omega-3-acid ethyl esters or fibrate is considered when fasting triglycerides exceed 200–499 mg/dL. Adrenal insufficiency occurs in 13% of patients after allogeneic HCT and 1% of patients after autologous HCT,15 and can be confirmed by a cortisol-stimulation test. Once adrenal insufficiency is diagnosed, physiological glucocorticoid replacement and a very slow terminal taper is needed. Patients should carry notification that they have adrenal insufficiency to alert emergency medical providers. For chronic GvHD therapy, the risk of adrenal insufficiency is lower with alternate-day administration of corticosteroids than with daily dosing,59 although patients with brittle diabetes need daily dosing to allow for optimal glucose control. Male gonadal dysfunction and infertility Hypogonadism is common after HCT. Impaired spermatogenesis, erectile dysfunction, low testosterone, and low libido occur in male patients. Erectile dysfunction and low libido have been associated with both physical and psychosocial factors.60,61 Testosterone replacement may be considered for patients with low testosterone levels and has improved sexual function, libido and bone mass, although monitoring prostate-specific antigen and testosterone levels is necessary.62,63 Azoospermia occurred in 70% of male patients, and spermatogenesis recovered in 90% of patients conditioned with cyclophosphamide alone, in 50% of patients conditioned with cyclophosphamide plus busulfan or thiotepa, and in 17% of patients conditioned with total body irradiation (TBI).64 Semen banking or cryopreservation of testicular tissue should be discussed before HCT with patients desiring fertility. Female gonadal dysfunction, infertility and pregnancy Ovarian insufficiency, vaginal changes and low libido occur in female patients. A historical study showed that ovarian failure occurred in more than 90% of female patients after HCT and recovered in 92% of patients conditioned with cyclophosphamide alone, but only in 24% of patients conditioned with cyclophosphamide and TBI.65 A pilot study showed that only 10% of patients had ovarian failure after reduced-intensity allogeneic HCT.66 The use of hormone replacement therapy for premature ovarian failure should be individualized based on the patient age, severity of menopausal symptoms, low bone density, risk of breast cancer, clotting predisposition and liver abnormalities.67 Since efficacy of gonadotropin-releasing hormone agonists in preserving fertility in cancer patients is controversial,68,69 cryopreservation of oocytes, ovarian tissue, or embryos should be discussed with patients desiring fertility.70 The largest study of pregnancy after HCT showed that 0.87% of patients or their partners had pregnancies after allogeneic HCT, and 0.36% of those after autologous HCT.71 We generally recommend that women wait 2–5 years after HCT before attempting conception since rates of relapse are generally highest in the first two years after HCT. Another concern is the theoretical risk of recurrent malignancy because of disturbance of the graft-versus-leukemia effect, and some cases of recurrent chronic myeloid leukemia after conception have been reported.71 Pregnancy outcomes are generally good with no increase in the risk of fetal malformations, although these pregnancies are considered high risk because of higher maternal risks of pregnancy complications.71 Iron overload Iron overload is rare after autologous HCT72 but common after allogeneic HCT.73,74 Previous prospective studies showed that 30%–60% of long-term survivors of allogeneic HCT had elevated serum ferritin levels and 25%–50% had elevated liver iron concentration on T2* magnetic resonance imaging (MRI).73,74 Since serum ferritin does not specifically reflect iron overload and can be elevated in hepatic and systemic inflammation, additional testing is required if the ferritin is elevated. We favor transferrin saturation, which is widely available and defined as the ratio of serum iron concentration divided by total iron-binding capacity.75 Normal transferrin saturation is less than 50% in males and less than 45% in females. Patients with iron overload usually have saturation more than 60%. HFE genotyping is considered in patients with a family history of hemochromatosis and in patients of Northern or Western European ethnicity. When saturation is not elevated, other etiologies for an elevated ferritin including inflammation, metabolic syndrome, and alcoholism should be ruled out. The most accurate test of tissue iron concentration is liver biopsy, but the procedure is invasive and may cause serious complications. Thus, T2* MRI and other modalities (FerriScan and superconducting quantum interference device) have been increasingly used.76 Importantly, liver tests are often normal among long-term survivors with iron overload, so hepatitis and GvHD should also be considered when results of liver tests are elevated.77 Iron overload may cause cardiomyopathy. Studies of thalassemia patients showed that cardiomyopathy typically took more than ten years to be clinically evident,78 and that many patients improved with intensive chelation therapy.79 Although a prospective study and a meta-analysis showed no statistical association of liver iron concentration with mortality after allogeneic HCT,80,81 our practice is to start phlebotomy of 5 mL/kg or 250–300 mL every 3–4 weeks as long as hematocrit is more than 35% until serum ferritin falls below 1000 ng/mL. Deferasirox, an oral chelating agent, is considered for patients with anemia precluding phlebotomy. Liver diseases Late liver diseases include chronic hepatitis B, chronic hepatitis C, liver cirrhosis, nodular regenerative hyperplasia and focal nodular hyperplasia.77 Hepatitis B-infected patients have an increased risk of fulminant liver failure. One study reported a 35% risk of HBV reactivation after HCT even among patients with isolated anti-HBc antibodies, mostly during steroid treatment for GvHD.82 Patients treated with anti-CD20 antibodies have an increased risk of HBV reactivation. Antiviral prophylaxis using entecavir or lamivudine will prevent almost all fulminant cases if initiated before the start of conditioning regimens in patients with positive blood HBV DNA levels.83 Patients with latent HBV (i.e. anti-HBc+/HBV DNA−) should be monitored monthly with HBV DNA levels after HCT and antiviral treatment should be initiated when viremia is detected.83 Hepatitis C virus infection in HCT survivors almost always results in chronic hepatitis.84,85 Typically, asymptomatic elevation of alanine aminotransferase occurs 2–4 months after HCT, coinciding with tapering of immunosuppressive medications. There may be little liver-related mortality in the first ten years after HCT,84 but liver cirrhosis occurs later with a cumulative incidence of 4%–24% at 20 years.85,86 A large retrospective study showed that hepatitis C-infected patients had an increased risk of 2-year non-relapse mortality due to hepatic problems and bacterial infection.87 Antiviral therapy for HCV has not been given early after HCT, but may improve both oncological and hepatic outcomes after HCT.88 Ribavirin and interferon-based therapy have been used for patients who have discontinued all immunosuppressive medications without active GvHD, but it can cause pancytopenia and GvHD. Recently, highly effective and well tolerated direct acting antiviral agents with more than 90% rates of sustained virological response have been developed, and interferon-free regimens are now the treatments of choice.89,90 Nodular regenerative hyperplasia is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules.77 This process is usually asymptomatic unless portal hypertension develops. Focal nodular hyperplasia occurs in 12% of HCT survivors, and possibly reflects sinusoidal injury caused by myeloablative conditioning regimens.91 Kidney diseases Chronic kidney disease (CKD) is defined as an elevated serum creatinine level, or a decreased glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for three months or longer.92 CKD occurs in approximately 20% of HCT recipients.93–95 There are three major etiologies of CKD after HCT: thrombotic microangiopathy (TMA), nephrotic syndrome and idiopathic CKD. Other etiologies include persistent acute kidney injury and BK virus nephropathy.96 Whenever possible, renal biopsy should be considered to accurately diagnose the etiology of CKD and to provide appropriate management.97 Thrombotic microangiopathy occurs in 2%–21% of patients after HCT, and is characterized by renal dysfunction, thrombocytopenia, neurological dysfunction, hemolytic anemia with schistocytes, elevated lactate dehydrogenase and decreased haptoglobin.98,99 Risk factors of TMA include TBI, calcineurin inhibitors, and acute and chronic GvHD.100–102 TMA-related kidney injury often improves with tapering or stopping calcineurin inhibitors, but full renal function is rarely restored.103 In some cases TMA did not improve until GvHD was treated.104 Efficacy of plasma exchange is limited.105 Nephrotic syndrome occurs in 6%–8% of patients after allogeneic HCT.106,107 Membranous nephropathy comprised 61% of cases, and minimal change disease comprised 22% of cases, with a median onset of 14 months and eight months after HCT, respectively.108 Mechanisms of membranous nephropathy are thought to be formation of immune complexes through allo- or auto-antibodies recognizing antigens expressed by the podocyte, while T cells are implicated with minimal change disease.109 Nephrotic syndrome after HCT is often associated with chronic GvHD and tapering of immunosuppressive medications. Initial treatment is prednisone 1 mg/kg/day in addition to calcineurin inhibitors. Complete response was observed in 90% of patients with minimal change in disease, but only in 27% of patients with membranous nephropathy.108 Refractory cases may be treated with rituximab or mycophenolate mofetil.110 Idiopathic CKD comprises most cases of CKD. Risk factors include acute GvHD, chronic GvHD, acute kidney injury, long-term use of calcineurin inhibitors and previous autologous HCT,94,111 suggesting that GvHD, accompanying treatment and inflammatory conditions may have pathogenic roles in this entity. Associations of TBI with risk of CKD have been controversial.94,112 ACE inhibitors and ARBs have been used to treat CKD and hypertension associated with CKD.113 Bone diseases Late complications of bone include osteopenia, osteoporosis and avascular necrosis (AVN).114 Osteoporosis has been reported in as many as 50% of HCT recipients.115,116 The diagnoses of osteopenia and osteoporosis are made by measuring T-scores with dual-energy X-ray absorptiometry. A T-score between −1.0 and −2.5 indicates osteopenia, and a T-score less than −2.5 or presence of a fragility fracture indicates osteoporosis.117 Multiple risk factors are implicated including chemotherapy, radiation, corticosteroids, calcineurin inhibitors, vitamin D deficiency, and gonadal failure.116,118 Bone loss occurs within 6–12 months after HCT, and recovery of bone mineral density (BMD) begins from the lumber spine, followed by a slower recovery in the femoral neck. The use of corticosteroids is the strongest risk factor for osteoporosis. General preventative recommendations include adequate intake of calcium of 1200 mg per day or over and vitamin D of 1000 IU (25 μg) per day or over, regular weight-bearing exercise, and avoidance of smoking and excessive alcohol. Bisphosphonates are the primary treatment for bone loss.119 Patients who are taking 5 mg or more daily prednisone-equivalent steroids for three months or more should have screening BMD tests for osteoporosis, and bisphosphonate treatment may be indicated until corticosteroid treatment is discontinued or for up to five years.120 Second-line treatment includes calcitonin, raloxifene, denusomab, romosozumab, and blosozumab, though their reported use in HCT recipients is limited and adverse effects may be more prominent than with the bisphosphonates. Avascular necrosis occurs in 4%–19% of HCT survivors with a cumulative incidence of 3%–10% at five years after HCT.121,122 AVN causes severe bone pain and bone destruction, causing significant impairment in quality of life. AVN typically affects the femoral heads, but sometimes affects other joints such as the knee and shoulders.21 Risk factors for AVN include corticosteroids, calcineurin inhibitors, older age and TBI conditioning.114 When AVN is suspected, diagnostic MRI should be performed. Early involvement of an orthopedic specialist is important for management of AVN, including conservative treatment, joint-preserving surgery and joint replacement surgery.21,114 Infectious diseases All HCT survivors have some degree of immunodeficiency, particularly during the first year after HCT.123 If patients are able to stop immunosuppressive medications without GvHD or recurrent disease, many recover adequate immune function by one year after HCT. Patients with chronic GvHD, however, remain immunodeficient and have a high risk of infections. Common late infections are caused by Pneumocystis jirovecii, encapsulated bacteria, fungi, varicella-zoster virus (VZV), cytomegalovirus, and respiratory viruses. Patients may report more frequent episodes of upper respiratory infections and sinusitis. All patients should receive prophylaxis against Pneumocystis jirovecii for at least one year after HCT or until 3–6 months after all immunosuppressive medication is discontinued, whichever occurs later. The preferred drug is trimethoprim-sulfamethoxazole, but dapsone or atovaquone could be substituted for patients who are allergic to or intolerant of trimethoprim-sulfamethoxazole. In particular, patients with chronic GvHD are highly susceptible to encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis due to low levels of opsonizing antibodies, low CD4+ T-cell counts, poor reticuloendothelial function and suppressive effects of immunosuppressive medications on phagocytosis. Vaccination against these bacteria is recommended.124 Efficacy of vaccination in increasing antibody levels has been shown in several prospective studies.125,126 Chemoprophylaxis is always recommended due to the unpredictable protection provided by vaccination. The first-line drug is trimethoprim-sulfamethoxazole, but if it is not tolerated, penicillin or azithromycin is substituted until 3–6 months after discontinuation of all immunosuppressive medications. Invasive fungal infection occurs in 1% of patients after autologous HCT and in 6%–8% of patients after allogeneic HCT.127 GvHD and long-term use of corticosteroids have been a major risk factor associated with onset of invasive fungal infection.128 As recommended in the European guidelines, mold prophylaxis with posaconazole or voriconazole may be considered for patients with GvHD requiring high-dose corticosteroid treatment.129 Varicella-zoster virus-seropositive patients should receive prophylaxis with acyclovir or valacyclovir during the first year after HCT or until six months after discontinuation of immunosuppressive medications. A standard dose of acyclovir is 800 mg twice daily,130 but some studies showed that 200 mg once daily was effective in preventing VZV reactivation.131 Acyclovir should be started empirically if the patient presents with an acute abdomen or hepatitis typical of fulminant visceral VZV infection.132 CMV monitoring in blood is continued beyond 100 days after HCT until one year for patients at risk of late CMV disease, including CMV-seropositive patients receiving high-dose corticosteroids, those who have already experienced CMV reactivation, and cord blood transplantation.133 Pre-emptive therapy is usually considered for CMV levels of 250 IU/mL or more (equivalent to ≥1000 copies/mL) or a positive antigenemia test. Community-acquired respiratory virus infections are an important cause of morbidity and mortality after HCT. The most frequent viruses include rhinovirus, respiratory syncytial virus (RSV), parainfluenza viruses (PIV), human metapneumovirus, and influenza viruses as these frequently cause lower respiratory tract disease associated with 12%–100% mortality.134 An immunodeficiency scoring index can predict severity of RSV infection.135 Aerosolized ribavirin showed efficacy in treating lower tract RSV after HCT.136 Combination therapy with immunomodulators such as intravenous immunoglobulin or palivizumab has been seen to have variable success.137 Treatment for PIV infection has not been established. Efficacy of ribavirin has been limited for patients with lower respiratory tract infection of PIV.138 Novel drugs such as a recombinant sialidase fusion protein and a hemagglutinin-neuraminidase inhibitor are under investigation.138 Solid cancers There is an increased risk of solid cancers following both autologous and allogeneic HCT compared with the general population. The cumulative incidence is 1%–6% at ten years after HCT, and continues to rise over time without a plateau.139–142 The most common sites include oral cavity, skin, breast and thyroid, but rates are also elevated in esophagus, liver, nervous system, bone and connective tissues compared with the general population.143 Myeloablative TBI, young age at HCT, chronic GvHD and prolonged immunosuppressive medications beyond two years are well-documented risk factors for many types of cancers.143 All HCT recipients should be advised of the risk of second cancers and should be encouraged to undergo recommended screening tests based on their predisposition.143 The 5-year overall survival rates after diagnosis of solid cancers varied by cancer site, with 88%–100% for thyroid, testis and melanoma, approximately 50% for breast, mouth, soft tissue and female reproductive organs, and 20% or less for bone, lower gastrointestinal tract, and central nervous system.144 These rates were similar to those of de novo cancers, except that rates were lower for female reproductive organs, bone, colorectum, and central nervous system, although further studies are warranted to confirm this observation. There is emerging evidence that human papilloma virus (HPV) is involved in the pathogenesis of squamous cell cancer after HCT.145,146 The efficacy of HPV vaccination in preventing squamous cell cancer after HCT remains to be determined in prospective studies.147 Neuropsychological effects Neuropsychological effects after HCT are being increasingly recognized and include, among others, depression, post-traumatic stress disorder, and neurocognitive deficits. Depression occurs in 12%–30% of HCT survivors and is more frequent in female patients, younger patients and those with poor social support, history of recurrent disease, chronic pain, and chronic GvHD.148 Post-traumatic stress disorder occurs in 28% of patients at six months after HCT and may persist for 5%–13% of cases, although its risk factors are not yet clear.148–150 Neurocognitive deficits, so called “chemo brain”, have adverse functional impacts on HCT survivors who return to work and daily activities that require short-term memory, information-processing speed, multitasking and co-ordination.151 Neuropsychological tests can help identify neurocognitive deficits. Most evidence is derived from studies of breast cancer survivors, with estimated rates of deficits ranging from 16% to 50% up to ten years after treatment.152,153 Potential mechanisms for chemotherapy-induced neurocognitive changes include cytokine and immune dysregulation, damage to DNA and telomere length through cytotoxic agents, oxidative stress and hormonal changes.154 In cases of HCT survivors, there may be additional deficits derived from neurological complications including nervous system infection (HHV-6, fungi, etc.), immune-mediated damage, and toxicities of calcineurin inhibitors such as TMA and posterior reversible encephalopathy syndrome. A prospective observational study showed that neurocognitive function declined substantially at 80 days after HCT, returned to pre-transplantation levels at one year, and continued to improve between one and five years after HCT, except for motor dexterity and verbal learning and retention.155 Mostly mild, neurocognitive dysfunction according to the Global Deficit Score persisted at five years in 42% of long-term survivors.155 Rehabilitation programs have succeeded in improving neurocognitive functions,156 and methylphenidate and modafinil have demonstrated variable efficacies to improve neurocognitive function in non-HCT cancer patients.157,158 Efficacies of these interventions remaine to be determined among HCT survivors. Influence of newer practices on late effects An understanding of the influence of newer practices such as cord blood transplantation, non-TBI or reduced-intensity conditioning regimens and older patients on the incidence and severity of late effects awaits longer follow up. For example, TBI is associated with an increased risk of many late effects such as cardiovascular diseases, COP, hypothyroidism, diabetes, dyslipidemia, infertility, TMA-related kidney injury, bone density loss, avascular necrosis, and secondary solid cancer.49,54,100,102,114,118,143,159,160 The use of non-TBI conditioning regimens might reduce the burden of these late effects among HCT survivors. Some studies found that cumulative incidences of late effects did not differ much after reduced-intensity regimens compared with myeloablative regimens,15,161 and reduced-intensity conditioning was associated with a higher risk of recurrent malignancy among patients with myeloid malignancy.162 One study showed that the risk of AVN was elevated after cord blood transplantation, but graft source had a limited influence on other long-term health status and QOL.163 Consensus guidelines for late effects and prevention behaviors Incidence, mortality, morbidity and management of individual late effects are summarized in Tables 1 and 2. Recognizing the importance of managing late effects after HCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), the European Group for Blood and Marrow Transplantation (EBMT), and the American Society for Bone Marrow Transplantation (ASBMT) developed recommendations in 2006 for screening and prevention practices for HCT survivors.164 Consensus recommendations were up-dated in 2011 including other international transplant communities.21 The NIH convened working groups to formulate late effects initiatives in 2015.148,165–169 View inlineDownload powerpoint Table 1. Late effects after blood and marrow transplantation View inlineDownload powerpoint Table 2. Tests, preventive approaches and treatment of late effects. Despite higher levels of engagement with health care providers, HCT survivors had similar health and prevention behaviors as matched untransplanted controls, suggesting the need for further education of both HCT survivors and health practitioners.170 Major modifiable predictors of lower adherence to preventive care practices were concerns about medical costs and lack of knowledge.171 Conclusion While the number of HCT survivors is growing, there is no evidence that the burden of late effects is lessening. HCT survivors face myriad late effects that can limit their functioning, require prolonged or life-long medical treatment, reduce their quality of life and also shorten their survival. To the extent that the HCT procedure itself causes these late effects, the transplant community has a responsibility to appropriately monitor, treat and ultimately try to prevent late effects. Given the dispersion of survivors and the varied structure of health care, hematologists, oncologists, primary care physicians and medical subspecialists are all involved in providing this care. Further research is needed to understand the biology of late effects to help identify better prevention and treatment strategiesDr. V Srivastava3 Likes9 Answers
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Myocardial reverse remodeling: how far can we rewind? ---------------------------------------------------------------------- Abstract Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions. heart failure (hf) is a systemic disease that subdivides into HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). For several years this distinction has not been recognized by most of the clinical or scientific community. Indeed, the first reports on HFpEF syndrome occurred nearly 30 yr ago (53). To differentiate from HFrEF, the condition was initially referred to as “diastolic heart failure” because systolic function, assessed by ejection fraction, was preserved. However, several studies began to emerge using newer cardiac measurements demonstrating that systolic function was not entirely normal in addition to atrial dysfunction, especially during exercise. Currently, in the clinical context, HFrEF associates to impaired pump function when left ventricle (LV) ejection fraction is ≤40% and HFpEF is related to diastolic dysfunction induced by myocardial increased stiffness or impaired relaxation when LV ejection fraction is preserved (≥50%) (273). HFpEF represents ∼50% of all HF cases (82) and nearly two-thirds of HFpEF patients die from cardiovascular causes (208, 280), showing a 6-mo mortality similar to patients with HFrEF (8). In clinical trials, the HFpEF population shows great diversity mostly due to the high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, atrial fibrillation (138), obesity, and chronic kidney disease (213). Besides diastolic dysfunction, HFpEF is also commonly associated with altered ventricular-arterial coupling (118), inflammation and endothelial dysfunction, chronotropic incompetence, as well as altered myocardial and peripheral skeletal muscle metabolism and perfusion (213). Until recently, there was a lot of controversy regarding the distinction between HFpEF and HFrEF with many clinicians considering that both represent a continuum within HF spectrum. However, recent studies have shown that these entities seem to have different pathophysiologic mechanisms, resulting from distinct molecular, cellular, tissue, and whole organ level maladaptations. These differences trigger distinct patterns of myocardial remodeling (119, 129, 213). Further supporting this theory is the fact that several clinical trials using standard therapeutics for HFrEF were not able to alter the prognosis or mortality of HFpEF patients despite improving HF symptoms (34, 40, 67). Indeed, in the last years, a major effort has been directed towards prevention (by targeting comorbidities) and early diagnosis of HFpEF; however, the lack of sufficient understanding on the mechanisms driving LV remodeling in HFpEF represents a major limitation. Nevertheless, considering that myocardial remodeling is clearly dissimilar between HFpEF and HFrEF, it is thus conceivable that these two entities also present distinct reverse remodeling (RR) processes. From an historical perspective, the term “ventricular remodeling” became popular in the mid-1980s, with the study of Pfeffer (189), who described it as a progressive LV dilatation and diminished function, after coronary occlusion in rats (166, 188). Over the years the term was used for virtually anything that was altered as a result of HF or a result of any other cardiac disease that spans maladaptation at molecular, cellular, tissue, and whole organ levels (38, 184). Nowadays, it is recognizable that these studies were only focusing on HFrEF. In turn, definition of “reverse remodeling” dates back to a study of cardiac myoplasty (115) in which the latissimus dorsi muscle was wrapped around a heart and paced synchronously with ventricular systole in an effort to enhance systolic function. One year after cardiac myoplasty, all patients showed a reduction in chamber volume and steeper end-systolic pressure-volume relation, allowing the ventricle to generate higher systolic pressure at a given LV volume and indicating that the heart had shrunk towards normal size. A key feature of this adaptation was that the geometric change persisted, even if therapy was turned off abruptly, and was thus intrinsic to the chamber. As with the term “remodeling,” “reverse remodeling” also became associated with any alteration in HF that could be chronically reversed by a given therapy, such pharmacological therapy, valve surgery (e.g., aortic stenosis) or assist devices (e.g., chronic HF). “Myocardial recovery” is another term widely used to describe the changes in HF after medical treatment (261). However, Mann and et al. (160) suggested that myocardial recovery is a different phenomenon, which is normally associated with no future failure events after HF treatment. Despite all efforts to understand RR in HF, it remains to clarified which of its components are necessary to accomplish myocardial recovery. Regarding HFrEF, research on its RR is broader with effective therapeutic strategies being employed for several decades based on a deeper knowledge of its pathophysiologic mechanisms (Fig. 1). These include inhibitors of the renin-angiotensin-aldosterone system (RAAS), β-blockers, and device therapies such as cardiac resynchronization therapy or left ventricular assist devices (LVAD), although not every method aiming for RR has shown long-lasting clinical efficacy (129). In general, cardiac RR in HFrEF, at the cellular level, is characterized by changes in cardiomyocyte size, function, excitation-contraction coupling, and bioenergetics and by “normalization” of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and other features (129). Studies on LVAD patients have contributed significantly to the current knowledge of RR in HFrEF, since it allows the collection of myocardial tissue in the same patient before and after RR, during implantation and removal of the LVAD, respectively. In this review, we will provide an integrated view of the continuum of changes taking place in myocardial RR, given focus to left ventricular hypertrophy (LVH) and fibrosis and diastolic dysfunction regression, important features of HFpEF pathophysiology. This review will briefly describe myocardial remodeling as the basis to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions. Moreover, there is currently a scarceness of studies focusing on HFpEF RR. Thus we will emphasize RR of human and experimental pressure overload studies as these conditions usually progresses to concentric LVH and diastolic dysfunction. Despite the reduced amount of information, whenever possible, we will emphasize RR in HFpEF patients whose pathophysiology has remained obscure due to the absence of a proper animal model and to the confounding effects of other prevalent comorbidities. Myocardial Remodeling The process of myocardial remodeling is influenced by hemodynamic load, neurohumoral activation, and other factors still under investigation (38). As the heart remodels, its geometry and ventricular mass changes in parallel with important cellular and molecular modifications, including cardiomyocyte size and shape changes, excitation-contraction coupling, cell-survival signaling and metabolic disturbances, and, in some animal models, reexpression of fetal gene program. In parallel, extracellular matrix (ECM) remodeling also occurs, triggering cardiac chamber deformation and alterations in the composition of fibrous and vascular elements in the myocardium (129). Despite that the first studies on remodeling were carried out in models of systolic dysfunction or HFrEF, currently a lot of effort has been gathered to understand the pathophysiology driving myocardial remodeling in HFpEF. Indeed, it is currently accepted that HFrEF and HFpEF remodeling processes are distinct (Fig. 1) (97). In this section we will briefly described some of the principal contributors for myocardial remodeling, focusing on LVH, ECM abnormalities, myocardial cell death, and metabolic disturbances and emphasizing the major differences between HFrEF and HFpEF. Detailed information on HFpEF and HFrEF myocardial remodeling is described in Refs 1, 31, and 27, respectively. LVH, as assessed by increased LV mass, has long been regarded as a compensatory response to preserve LV function under overload conditions. Contrary to the reversible physiological hypertrophy, induced by exercise training or pregnancy, chronic overload induced by conditions such as hypertension, coronary artery disease, or valvular heart disease leads to pathological hypertrophy. Reversal of myocardial hypertrophy in the pathologic condition is still a matter of debate, and the differences with the pathologic scenario remain controversial (184, 260). LVH can be classified into three groups: concentric hypertrophy (increased relative wall thickness and normal internal diameter), eccentric hypertrophy (increased relative wall thickness and increased internal diameter), and concentric remodeling (enlarged heart with normal relative wall thickness). While the first frequently develops in HFpEF patients, the second is more associated with an HFrEF phenotype and the latter with the RR process (75, 97). At the cellular level, the major differences between eccentric and concentric hypertrophy rely on the 1) shape of cardiomyocytes (long and thin vs. short and enlarged); 2) organization of sarcomeres (“in series” vs. “in parallel”) (128); and 3) mechanisms controlled by different proliferative signaling pathways (129). LVH itself is a major independent risk factor for cardiovascular morbidity and mortality (143). Specifically, in HFrEF, loss of cardiomyocytes (e.g., acutely with myocardial infarction or chronically with idiopathic cardiomyopathy) often results in left ventricular eccentric hypertrophy and cardiac failure. Contrarily, in HFpEF, concentric myocardial hypertrophy, as a result of multiple cardiovascular risk factors, imposes a bad prognosis since it is predictive of higher HF hospitalizations, cardiovascular death or sudden cardiac arrest (210), and reduced exercise capacity (168). In fact, an echocardiographic substudy of the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial including patients with HFpEF demonstrated a high prevalence of structural remodeling, with 59% having LVH in a pattern of concentric remodeling (281). However, eccentric hypertrophy can also occur in HFpEF patients, indicating a distinct subgroup of patients that may progress to HFrEF (117). In HFpEF clinical settings, as opposed to many experimental models, the transition to HFrEF is rarely observed (97) but, when it takes place, this transition is due to loss of contractile function within the remaining cardiomyocytes during LV remodeling, which is in line with distinct signaling pathways between HFpEF and HFrEF (97, 171). Although adaptive in the early stages, LVH eventually becomes maladaptive and contributes to the development of diastolic dysfunction (97). For instance, in chronic pressure overload associated with HFpEF, the development of LVH is simultaneous with remodeling of the ECM with progressive interstitial fibrosis and reduced ventricular compliance and diastolic dysfunction (80). Diastolic abnormalities, such as slow LV relaxation and elevated diastolic LV stiffness, are the most common finding in HFpEF patients at rest (1). The increased diastolic wall stiffness impairs cardiac relaxation and filling, decreases end-diastolic volume, and increases end-systolic pressure, resulting in a left and upward shift of the LV end-diastolic pressure-volume relation. Consequently to long-standing increased ventricular filling pressures, atrial enlargement, reflecting the degree of structural remodeling (113), occurs in 85% of HFpEF patients as demonstrated in I-PRESERVE trial (281). Indeed, moderate or severe diastolic dysfunction is a predictor of cardiovascular death or HF hospitalization in the HFpEF population (187). Nevertheless, the underlying pathomechanisms that may link LVH to diastolic dysfunction and HFpEF are not yet completely understood. In this regards, it was proposed that higher levels of cytosolic Ca2+ may contribute to slowed myofilament relaxation during diastole (153). In addition, hypophosphorylation of myofilaments leading to increased Ca2+ sensitivity may also contribute to impaired cardiomyocyte relaxation in HFpEF (91). In a mouse model, microvascular rarefaction preceding LVH suggested that microvascular dysfunction may also be a cause of diastolic dysfunction independently of LVH (186). LVH, as well as other risk factors associated with HFpEF such as age, diabetes, obesity, and hypertension, have been linked to coronary microvascular rarefaction in animal models and patients. Recently, Lee et al. (142) investigated vascular function in patients with HFpEF at the conduit and microvascular levels and identified a distinct pattern of vascular dysfunction that is specific to the microvasculature. Microvasculature impairment may be of particular importance in the context of coronary circulation (142). This was recently reinforced by Paulus and Tschope (185). These authors proposed that coronary microvascular dysfunction in HFpEF results in changes in ECM composition and cardiomyocytes function (185). This topic will be emphasized in Altered Signaling Pathways in HFpEF as Potential Targets for Reverse Remodeling. Modifications in ECM constitute the second most important myocardial adaptation that occurs during HFpEF and HFrEF remodeling. These include changes in overall and relative subtypes of collagen content, collagen cross linking, and connections between cells and the ECM via integrins (160). The presence of stress, leads to activation of fibroblasts triggering the disproportionate synthesis of collagen, fibronectin, and laminin. Specifically in HFpEF, several stimuli contribute to myocardial fibrosis (79) including cytokines [transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin family], angiotensin II, aldosterone, endothelin-1 (ET-1), and cathecolamines (30, 121, 205, 227). Collagen turnover is mainly regulated by matrix metalloproteinases (MMPs), as their expression and activation are significantly upregulated in pathological LVH (154). Nonetheless, the net deposition of fibrillar collagens prevails due to the production of tissue inhibitor of MMPs (TIMPs) associated with the increase in MMPs. The lower MMPs/TIMPs ratio favors excessive fibrosis and consequently compromises ventricular filling (36). Contrarily, LV biopsies from HFrEF patients displayed a decrease in fibrosis due to increased ECM degradation, which was related to upregulation of MMPs (MMP-9, -2, and -3) (221), providing evidence of the distinct pattern of ECM changes underlying HFpEF and HFrEF. Intrinsic cardiomyocyte changes also contribute to myocardial remodeling. For instance, the cytoskeletal protein titin is the main determinant of LV stiffness within physiological sarcomere lengths (SL; 1.8–2.2 μm), accounting for ∼80%, while the contribution of the ECM only becomes crucial at a SL higher than 2.2 μm (148). Alterations in cardiac titin isoform expression have been found in patients with HFpEF, wherein the N2BA:N2B expression ratio was decreased compared with HFrEF (243). Contrarily, in dilated explanted hearts or ischemic cardiomyopathy patients, the N2BA:N2B expression ratio is increased compared with normal hearts, resulting in reduced titin-based myocardial stiffness (177). Besides the long-term changes in the isoform ratio that accompany chronic cardiovascular disease, titin stiffness is also amenable to modulation by phosphorylation (24, 92, 99, 133, 134, 244) or by oxidative stress-induced formation of disulphide bridges within the titin molecule (87). We have gathered a substantial amount of data showing titin hypophosphorylation, both in failing human myocardium (22) and in an animal model of HFpEF (92). Studies carried out in an animal model of HFpEF described titin hypophosphorylation, which importantly contributed to the higher stiffness of cardiomyocytes and consequently to the diastolic dysfunction observed in these animals (92). Also, an animal model of HFrEF induced by volume overload presented decrease levels of titin phosphorylation. In this case, the hypophosphorylation of titin represented a compensatory mechanism to the lack of cardiac interstitial fibrosis and cardiomyocytes loss in disease animals (171). Cardiac cell loss, also observed in myocardial remodeling, typically results from exaggerated autophagy, apoptosis, or necrosis under conditions of injury-induced ventricular remodeling, such as in severe pressure overload-induced hypertrophy (85, 175), ischemic injury, or postmyocardial infarction (157) and in HFrEF patients (182). This feature is more closely associated with HFrEF rather than HFpEF remodeling (Fig. 1). In HFrEF, the excessive wall stress, triggered by cardiomyocyte loss shifts the balance in the ECM between collagen deposition and degradation, leading to the appearance of patchy areas of fibrosis. This phenomenon importantly contributes to HFrEF typical LV dilation and eccentric remodeling (185). In fact, a study using endomyocardial biopsy samples from HFrEF showed higher levels of patchy interstitial fibrosis compared with HFpEF patients biopsies (243, 245). Apoptotic cardiomyocyte death, oxidative stress (48), and metabolism abnormalities (110) were also related to the appearance of eccentric hypertrophy in an animal model of transverse aortic constriction (TAC), which initially triggers concentric hypertrophy. In humans, this progression is observed mostly in myocardial infarction patients (185). Abnormalities in cardiac energy metabolism occur in parallel with the development of LVH and myocardial remodeling (110). Under normal conditions, the oxidation of fatty acids is the major pathway, providing about 70% of the total energy demand, while glucose oxidation provides the rest (264). It is well known that depletion of myocardial energy reserve and mitochondrial dysfunction represents a major cause of dysfunction of the failing human heart (179). In fact, decreased fatty-acid oxidation and increased glucose utilization are observed in pathological hypertrophic and HFrEF (242). This shift enhances the glycolytic pathway, thus increasing anaerobic metabolism (242) and oxidative stress by increased reactive oxygen species (ROS) production. The latter mechanism is known to damage mitochondria inducing, for instance, mitochondrial permeability transition pore opening (60) and consequently cell death (132). Also, mitochondrial DNA damage leads to deficient functioning components of the cellular energetics machinery, thus directly contributing to increased oxidative stress underlying cardiac hypertrophy and HFrEF (44). In the healthy heart, buffering systems, such as the creatine kinase reaction, maintain adenosine triphosphate (ATP) levels (179). However, in pathological conditions, namely in HFpEF, a reduced energy reserve, as assessed by the phosphocreatine/adenosine triphosphate (PCr/ATP) ratio, is observed mostly due to PCr drop (>50%) (4). The principal consequence of low PCr and/or a reduced creatine kinase activity is the rise of cytosolic adenosine diphosphate (ADP) that was linked to severe LVH in a canine pressure overload model (110) and to increased LV end-diastolic pressure (234). Moreover, changes in relaxation were associated with mitochondrial functional disability in ATP production (66). This supports the idea that limited myocardial energy reserve via elevations of ADP is likely a cause of myocardial diastolic dysfunction. Indeed, Sequeira et al. (209) recently provided evidence that conditions that elevate myocardial ADP in the presence of diastolic Ca2+ contribute to diastolic dysfunction by increasing residual actomyosin interactions. The authors showed in rats that physiological ADP levels found in diseased hearts (100 μM) increase Ca2+ sensitivity and stiffness in membrane-permeabilized cardiomyocytes, limit diastolic sarcomere relengthening associated with high Ca2+-buffering of intact cardiomyocytes, and reduce ventricular compliance in isolated Langendorff-perfused hearts (209). The changes in myocardium metabolism and the structural and functional mitochondrial abnormalities reflects on energy production and oxygen consumption (224), which will eventually culminate in lower capacity to perform work. The clinical evidence of these disturbances is confirmed by the exercise intolerance observed in HFpEF patients, measured by a decrease in peak oxygen consumed during maximal effort exercise (V̇o2 peak) (241). Impaired V̇o2 is associated with decreased cardiac output, which was, in part, related to chronotropic incompetence (25), impaired systolic reserve (26), and abnormal ventricular-vascular coupling (118) in HFpEF patients. However, the role of these alterations in myocardial metabolism remains controversial, specifically, because it has not been possible to determine whether the metabolic alterations have been a primary or an epi-phenomenon (50). Myocardial “Reverse Remodeling” A variety of cardiac pathologies, including ischemic disease, hypertension, valvular diseases, and genetic forms of cardiomyopathies can lead to extensive myocardial remodeling and eventually to HF. Myocardial maladaptive remodeling is an important aspect of disease progression and its prevention or reversal is a desired strategy. Myocardial remodeling can be reversed completely upon treatment, while in other cases RR is incomplete and the underlying reasons remain to be clarified. In clinical practice, changes in ejection fraction, LV end-diastolic and end-systolic volumes, mass, and sphericity index are used as surrogate parameters for remodeling or RR. In some circumstances (if myocardium is available at different time points), remodeling may also be assessed on the cellular levels. In fact, the majority of the knowledge about cellular and molecular alterations during the RR process comes from studies with LVAD in which myocardial tissue is available before and after unloading of the heart. Besides LVAD, different drugs [ex., β-blockers and angiotensin II-converting enzyme inhibitors (ACEI)] and interventions (ventriculoplasty and resynchronization therapy) have been demonstrated to induce myocardial RR (on the basis of organ-level geometry) or improve clinical outcome, or both, primarily in HFrEF (129). However, in HFpEF less is known about myocardial RR, since its pathophysiology remains obscure, due to the absence of a proper animal model and to the confounding effects of coexisting comorbidities. In HFrEF, the severity of LV remodeling predicts the response to treatment and patient outcomes. Data from the Framingham study demonstrated that patients, without myocardial infarction but with cardiac dilation, had a 1.47-fold risk of developing HF compared with those without dilation (249). In myocardial infarction, patients with highest ventricular volumes and lowest baseline LV ejection fraction presented higher mortality (266). HFrEF patients who present regression of ventricular dilation or increased ejection fraction after treatment have better quality of life. Hoshikawa et al. (101) observed that patients with no reversal of cardiac dilation, after therapy with ACEI, angiotensin II receptor antagonist (ARA) and β-blockers, died during the follow-up, which lasted an average of 5 yr. The extent of LV RR at 1 to 6 mo after starting the therapy is predictive of a long-term prognosis (101). An extensive description of RR in HFrEF is presented in Ref. 129. Less is known regarding the impact of RR on HFpEF mortality and morbidity partly and probably due to population heterogeneity, including variability in the underlying disease and other comorbidities and to unresolved pathophysiological mechanisms during the course of the disease. Nevertheless, exercise training was shown to improve exercise capacity and physical dimensions of quality of life in HFpEF by triggering atrial RR (decreased left atrial volume) and improved LV diastolic function (decreased E/E′ ratio) (58). Despite being a valvular disease, aortic stenosis frequently courses with diastolic dysfunction and presents with features similar to HFpEF. Thus, after aortic valve replacement (AVR), these patients provide a substantial amount of knowledge about the reversibility of LV diastolic dysfunction and the recovery of cardiac structure. AVR results in improvement of overall cardiac pump performance, diastolic function (76, 147, 173, 252), and subendocardial dysfunction earlier than regression of LVH (102, 147). Such a degree of preoperative subendocardial disturbances may represent early changes that if ignored are likely to substantiate and become irreversible. Thus the presence of such abnormalities in symptomatic patients, even with normal ejection fraction, may reinforce the need for AVR to maintain overall integral ventricular function and to avoid potential clinical complications (147). Apart from this study, several studies have shown that the improvement of ventricular performance, assessed namely by LV systolic strain, precedes changes in LVH (109). For instance, Villari et al. (251) showed that after AVR, diastolic perfusion increases due to the reduction of perivascular compression, which improves myocardial blood flow and restores the coronary vasodilatation reserve, decreasing the probability of myocardial ischemia and facilitating molecular mechanisms of RR. Importantly, current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF (97). In another study, including 45 patients with severe aortic stenosis, Poulsen et al. (193) reported 20 and 31% decreases in LV mass index, 19 and 22% decreases in LV-end-diastolic volume, 31 and 31% decreases in LV end-systolic volume, and 6.3 and 6.3% increases in LV ejection fraction, 3 and 12 mo following AVR, respectively. Interestingly, other studies demonstrated that RR occurs mostly within the first 6 mo following AVR since 90% of the changes in cardiac volumes and ejection fraction are complete within this time frame (16) in which 75% of patients display a significant reduction of LV mass. However, a multivariate analysis showed that LV mass remained 5 SDs above normal for more than 85% of the population without an evident explanation based on the age, sex, coronary artery disease, and pre-AVR characteristics such as gradient, valve type, and cross-clamp time (16). However, it is important to have in mind that in the clinical setting of HFpEF patients with compound comorbidities diastolic dysfunction may occur independently of LVH. This may explain why current approaches to reduce LVH have not been effective in improving symptoms and prognosis in HFpEF (97). Specifically in aortic stenosis, there are several possible explanations for incomplete LV mass regression after AVR: 1) AVR itself does not restore the transvalvular gradient to normal; 2) the afterload is surgically relieved only at the valve level; 3) the surgically induced relief of afterload may be counterbalanced by the resultant increase of another type of afterload, namely arterial hypertension (107); 4) coronary atherosclerosis seems to play a role in RR (16); and 5) there is established myocardial fibrosis. Regarding myocardial fibrosis, the ECM undergoes a complex process of remodeling wherein collagen deposition holds an important role. In fact, we have shown the importance of fibrosis in a low-risk cohort of patients with severe aortic stenosis. In these patients, higher levels of fibrosis had a negative prognostic impact and represented a predictor of events, independent of other well-established prognostic factors such as ejection fraction, age, baseline LV mass index, or New York Heart Association (NYHA) class (these data are part of a PhD thesis in Ref. 78). Milano et al. (170) in a retrospective analysis demonstrated that the 10-yr survival rate was lower in patients with severe fibrosis, calculated from myocardial biopsies obtained during AVR surgery, and there was no significant improvement in NYHA class (170). In both experimental and clinical observations of LV pressure overload, increased TIMPs levels have been identified, which in turn have been postulated to favor a reduction in ECM turnover, contributing to myocardial fibrosis and LV dysfunction (274). In fact, in aortic stenosis, there is an increased production of collagen and a shift towards inhibition of collagen degradation (63, 64, 98). When compared with controls, myocardial biopsies of aortic stenosis patients have a higher expression of collagens and an upregulation of TIMP-1 and -2 mRNA, favoring inhibition of collagen degradation, which significantly correlates with the degree of fibrosis (98). Therefore, not surprisingly, antifibrotic drugs targeting ECM changes represent an attractive strategy aiming for RR. In this context, animal models of reversible aortic banding have delivered important findings, namely complete regression of MMP and TIMP expression as well as an association between changes in LV mass index and MMP/TIMP ratio after debanding (78). In the same animal model but with a more prolonged period of aortic banding, the fibrotic content remained increased after debanding (19). Moreover, collagen isoform content suffers alterations during RR with a predominance of collagen isoform I early after debanding that shifts to isoform III a few days later (18). In a mouse model of pressure overload, TIMP-4 overexpression was shown to provide beneficial effects for survival and cardiac function and to mute the fibrotic response, since TIMP-4 overexpression may be beneficial in modulating adverse ECM remodeling in the context of pressure overload (274). The majority of “HFpEF” animal models consist of cardiac pressure-overload models that further develop LVH and diastolic dysfunction. For instance, TAC and systemic hypertension animal models develop LVH accompanied by diastolic dysfunction, ECM, and cardiomyocytes changes. While these observations support a role for LVH in mediating diastolic dysfunction and as a therapeutic target, many of these models later develop HFrEF, impeding translation of these results to the multifactorial setting of clinical HFpEF. For instance, TAC is a well-established surgical technique for inducing LV chronic pressure overload and consequently LVH. Moderate TAC imposed at an early age triggers concentric LVH with compensated chamber performance, markedly with prominent diastolic filling abnormalities. For instance, Yorkshire pigs subjected to surgical banding of the ascending aorta for 5 mo exhibited LVH with increased stiffness and normal systolic function, compared with control pigs (108). However, in severe TAC and long-standing aortic constriction, the myocardial remodeling will, eventually, lead to LV dilation, impairment of systolic function, and progression of the abnormal filling (150). A major limitation of using aortic-banded or hypertensive models is that the majority of patients with HFpEF continue to have HF symptoms even when the blood pressure is controlled. Conversely, less than 50% of HFpEF patients have LVH and often show no evidence of LV dilatation, thus making the value of the current preclinical model questionable (1). Nevertheless, in a variety of HFrEF models (e.g., rodents, rabbit, dogs), interference with LV hypertrophic signaling pathways reliably reduces LVH and improves diastolic function often independently of alterations in blood pressure. Besides improving function, the beneficial effects of exercise have been shown to be very promising on attenuating or reversing ECM changes during the course of RR (282). For instance, chronic low-intensity interval exercise training attenuated fibrosis and impaired cardiac mitochondrial function (60) and coronary vascular dysfunction (61) in a miniature swine animal model of aortic constriction. Moreover, reduced fibrosis, normal MMP-2 and TIMP-4 expression, and increased collagen III isoform mRNA levels were accompanied by an improvement in diastolic function following chronic training (162). In HFrEF, LVADs used as a “bridge to recovery” (129) have been shown to be capable of improving heart-rate reserve (125) systolic and diastolic function (95, 176), with no evidence of subsequent regression (54). The improvement of molecular mechanisms such as improvement of β-adrenergic density on ventricular cardiomyocytes (125), enhancement of developed tension and calcium cycling upon catecholamine stimulation (47), upregulation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) (9, 96), or recovery of T-tubule structure and function (105) underlies LAVDs benefits for contractile function. Also, in HFrEF, cardiac resynchronization, used to counter the delay in electrical conduction that leads to desynchronous contraction in HF (129), was implicated in the reduction of LV volumes after a period of several months and this adaptation persisted even if pacing was temporarily suspended (275). The RAAS seems to be a key factor in ECM remodeling process. Mechanical stretch induces local production of angiotensin II, which in turn stimulates the release of multiple growth factors and cytokines from cardiac fibroblasts that act in an autocrine and paracrine fashion, affecting the progression of hypertrophy, remodeling (206, 258), and RR (232). HFrEF patients treated either with ACEI or with a combination of ACEI and ARA show improvements in mortality rate and in disease progression partly due to capacity to reduce ventricular mass (55, 86, 127, 189). Besides RAAS, other pharmacological interventions, such as β-blockers, have been shown to impact myocardial hypertrophy. For example, compared with placebo treatment, carvedilol decreased LV mass while improving cardiac geometry in patients with HFrEF after 4 mo of treatment (156). Moreover, HFrEF patients treated with LVAD in combination with ACEI medication presented a decrease in myocardial collagen content and myocardial stiffness compared with patients with LVAD therapy alone (126), which can be potentially relevant for HFpEF. Disappointingly, despite its actions on hypertrophy and ECM, these studies failed to improve the clinical outcome of HFpEF patients. Thus more studies are necessary to better understand the role of this collagen shift in RR mechanisms, particularly in HFpEF. Altered Signaling Pathways in HFpEF as Potential Targets for Reverse Remodeling While myocardial remodeling and RR have been extensively studied for HFrEF, the current knowledge regarding detailed regulatory mechanisms of HFpEF pathophysiology is scarce. Consequently, despite several clinical trials attempting novel treatments for HFpEF, none have delivered convincing results. Thus it is mandatory to further explore and understand the most altered signaling pathways underlying it. This section will cover some of the most promising signaling pathways aiming to rewind myocardial remodeling in HFpEF patients including calcium handling and myofilamentary proteins alterations, ECM changes, activation of cyclic guanosine monophosphate (cGMP) signaling cascade, inflammation, and oxidative stress. Calcium-handling proteins. Cardiomyocyte contractile function is controlled by Ca2+-dependent myofilament activation and relaxation as well as by passive visco-elastic properties largely determined by the myofilaments (e.g., titin). The relationship between “systolic” and “diastolic” function at the cellular level is expected to be highly interdependent. As in the whole organ, mechanical energy stored in the sarcomeric protein titin during contraction contributes to recoil during relaxation. On the other hand, resting cardiomyocyte tension in diastole is a determinant of contractile force during systole (97). Normally, contraction starts with depolarization of the cell membrane, which triggers the entry of small quantities of Ca2+ into the cardiomyocyte stimulating the nearby ryanodine receptors (RyR) (15). This results in a large increase in intracytoplasmic Ca2+, which acts on troponin C (TnC) to activate cross bridges between actin and myosin filaments in the sarcomeres, causing cardiac contraction (183). Cardiomyocyte relaxation starts as soon as membrane L-type Ca2+ channels close, the extrusion of Ca2+ from the cytosol by the Na+/Ca2+ exchanger starts, and sequestration of Ca2+ by SERCA to the sarcoplasmic reticulum (SR) begins. The action of SERCA is controlled by phospholamban. When it is dephosphorylated, phospholamban inhibits SERCA, and when it is phosphorylated, this inhibition is lost, SERCA is activated, the cytoplasmic Ca2+ decreases, and relaxation occurs (15). Several components in the Ca2+ cycling process could be disturbed and significantly impact diastolic and systolic function (Fig. 2). In HFrEF there is evidence supporting a decrease in intracellular Ca2+ transient and diminished SR Ca2+content, an outcome that constitutes the major origin of the altered contractility. This can be attributed to alterations in the expression/activity of different Ca2+ regulatory proteins, in particular a decrease in SERCA levels observed in experimental and human HFrEF (167). Modifications in RyR are also present in HFrEF. For instance, hyperphosphorylation of RyR by Ca2+/calmodulin-dependent protein kinase II (CaMK-II) or protein kinase A (PKA) might cause a diastolic leak of Ca2+, lowering the Ca2+ content of the SR, thereby reducing the quantity of Ca2+ released during the subsequent activation. This weakens systolic contraction and, by raising cytoplasmic Ca2+ during diastole, it also interferes with myocardial relaxation (27). New therapeutic strategies for HFrEF are underway to modify the actions of Ca2+, including enhancing the sensitivity of cardiac myosin to Ca2+ (159), repairing the leak in RyR channels, and increasing expression of SERCA (161). Contrarily to HFrEF, where cardiomyocyte contractile dysfunction is predominant, in HFpEF cardiomyocytes stiffness and relaxation dysfunction become more relevant and can be also associated with Ca2+ overload induced by higher sensitivity of myofilaments to Ca2+ or decreased rate of Ca2+ reuptake via SERCA and alterations in Na+/Ca2+ exchanger. Changes in the phosphorylation state of proteins that modify SERCA activity, such as phospholamban, CaMK-II, and calsequestrin, have been associated with increased levels of cytosolic diastolic Ca2+, inducing diastolic dysfunction associated with impaired active relaxation and/or increased passive stiffness of cardiomyocytes (279). Multiple approaches have been utilized to alter the function of phospholamban, SERCA, and the Na2+/Ca2+ exchanger with the goal of improving Ca2+ handling and thus diastolic function, including drugs that mimic, inactivate, or decrease phospholamban and adenoviral gene delivery of SERCA, to increase its activity (6). The use of the Na+/Ca2+ exchanger inhibitors was also explored in Wistar rats subjected to subtotal nephrectomy (acute treatment with SEA0400), showing a normalization of cytosolic Ca2+ transients, an improvement of trans-sarcolemmal Ca2+ export, and a decrease in SR Ca2+ leak in Na+/Ca2+ exchanger, in line with a role for reverse mode Na+/Ca2+ exchanger activity in HFpEF. This cellular changes were accompanied by in vivo enhancement of LV active relaxation as shown by a decreased isovolumetric relaxation constant (194). Ranolazine, a new anti-ischemic and anti-arrhythmic medication, inhibits the late influx Na+ current (typically increased in HF) leading to decreases in Na+ accumulation. Consequently, Ca2+ extrusion through the Na+/Ca2+ exchanger will increase and thereby diastolic tension decreases and relaxation improves (220). In fact, administration of ranolazine in DOCA-salt rats improved diastolic function through modulation of myofilament activity, including Ca2+ response and cross-bridge kinetics (155). Parvalbumin is a Ca2+ buffer protein expressed in the fast-twitch skeletal muscle and not normally expressed in the heart. In the former parvalbumin facilitates rapid relaxation by buffering Ca2+ away from myofilaments after contraction. The therapeutic potential of parvalbumin has been tested for increasing the relaxation rate of the heart under diastolic dysfunction conditions. In fact, gene transfer of parvalbumin to the heart triggered an in vivo improvement in different relaxation parameters in rats with slowed cardiac muscle relaxation (228) including aged rats (203). Changes in myofilament Ca2+ sensitivity, through changes in Ca2+ interaction with thin myofilaments (263), such as protein kinase C (PKC)-induced phosphorylation of troponin I (TnI) (104), can also change cardiomyocyte relaxation (104). CARDIAC MYOSIN-BINDING PROTEIN-C. Cardiac myosin-binding protein-C (cMyBP-C) is a component of the thick filament in cardiomyocytes that modulates the cross-bridge attachment/detachment cycling process (236). Experimental studies have suggested a potential role for cMyBP-C in diastolic function. For instance, the cMyBP-C null mouse model (116) and cMyBP-C homozygous and heterozygous knockin mouse exhibited diastolic dysfunction with elevated E/E' (120). Moreover, mutations in this protein were observed in patients with hypertrophic cardiomyopathy, among whom a significant percentage presented diastolic dysfunction, demonstrated by slowed cardiac relaxation (225). Apparently, the phosphorylation of cMyBP-C is able to modulate diastolic function (10, 41, 222, 237) (Fig. 3) by enhancing cardiac lusitropy whereas the absence of phosphorylation depresses lusitropy (226). cMyBP-C can be phosphorylated by different kinases known to be altered in HFpEF, including PKA (77), PKC (270), and CaMK-II (202). However, the development of therapies to increase or maintain cMyBP-C phosphorylation in HFpEF is still challenging, since in HF different signaling pathways can lead to alterations in cMyBP-C phosphorylation status. For instance, β-adrenergic receptor activation triggers PKA phosphorylation of cMyBP-C and can also activate G-protein receptor kinase-2 signaling (198), a pathway that can cause maladaptive remodeling (2). Additionally, in a hypertensive-animal model, diastolic dysfunction was accompanied by a decrease in S-glutathionylation of cMyBP-C, depression in myofilament cross-bridge kinetics (155), cardiac tetrahydrobiopterin (BH4) depletion, and nitric oxide (NO) synthase (NOS) dysfunction (216). Moreover, cMyBP-C glutathionylation correlated with the presence of diastolic dysfunction (112). Feeding hypertensive mice with BH4 increased cardiac stores of this molecule and improved diastolic dysfunction. The authors suggested that by depressing S-glutathionylation of cMyBP-C, BH4 ameliorates diastolic dysfunction by reversing a decrease in cross-bridge turnover kinetics. Importantly, preliminary studies from the same authors found that modified cMyBP-C can be measured in blood and is elevated in patients with diastolic dysfunction (112). TITIN. Titin, the largest human protein spanning the Z line to the M line of the sarcomere, has an important role in diastolic function. Titin, along with collagen, is the one of the major determinants of myocardial stiffness (144). As the SL increases, the contribution of titin decreases and collagen becomes mainly responsible for myocardial stiffness (>2.4 μm) (94). In adult cardiomyocytes, titin is expressed in two isoforms, the stiff N2B and the compliant N2BA. Stiffness of cardiomyocytes is defined by the ratio between these isoforms, for example, an increase in the N2B/N2BA ratio is associated with higher stiffness (268). Recently, Schwarzl et al. (207) observed myocyte hypertrophy, titin isoform shift, toward the stiffer titin isoform N2B, and reduced total titin phosphorylation in LV biopsies from a large animal model of hypertension and hyperlipidaemia. Posttranslational modifications are able to modify cardiomyocyte stiffness (20) as certain titin domains are substrates for different kinases (Fig. 3). While titin phosphorylation by PKA (134, 272), protein kinase G (PKG) (263), CaMK-II (93), and extracellular signal-regulated kinase 2 (ERK-2) (195) decrease cardiomyocytes passive tension (134, 272), PKC triggers an increase in passive tension (99). Specifically, in HFpEF, low myocardial PKG activity was associated with raised passive tension and with increased oxidative stress (244). For instance, a study using a robust animal model of HFpEF, the obese ZSF1 rats (hypertensive and diabetic), demonstrated that hypophosphorylation of titin contributed to the underlying myocardial diastolic dysfunction observed in these animals (92). Calcium is also responsible for cardiomyocyte stiffness alterations (20), namely, by its binding to the titin PEVK region, which increases stiffness (213), or by the activation of calcium-binding protein 1 (S100A1), a protein that directly regulates PEVK-actin interactions in the sarcomere (169). During systole (elevated Ca2+ levels), the complex Ca2+-S100A1 triggers the inhibition of PEVK-actin interaction, which would diminish PEVK-actin-dependent motility inhibition, facilitating myocardial contraction (169). At lower Ca2+ levels, this mechanism is reduced and titin-actin interactions lead to increased passive tension. It can be hypothesized that decreased levels of S100A1, observed in HF, can promote an increase in the titin-actin interaction, which contributes to the increased myocardial stiffness (56) observed in a great proportion of HFpEF patients. In fact, S100A1 overexpression improves cardiac function parameters (29, 201) and reverses LV remodeling in an animal model of myocardial infarction (192). However, it is still necessary to understand if S100A1 expression provides beneficial effects for HFpEF conditions. Furthermore, oxidative formation of disulphide bonds in titin's N2B region leads to increased cardiomyocyte stiffness (87) and S-glutathionylation of Ig domain cysteins is associated with a decrease in titin stiffness (3). Since higher passive tension of cardiomyocytes, as a consequence of titin changes, underlies the diastolic dysfunction of HFpEF, we think that targeting posttranslational modification on titin as herein described detain an enormous potential to reverse diastolic dysfunction in this condition. Extracellular matrix. The activation of myofibroblasts is the key of fibrotic tissue remodeling. As already mentioned, LVH is caused by an abnormal accumulation of collagen and other ECM components in the extracellular space. This reactive and progressive interstitial fibrosis contributes to myocardial stiffness and, ultimately, ventricular diastolic dysfunction, and it is believed to result from the persistent activation of cardiac myofibroblasts. Several studies have demonstrated that circulating hormones such as ET-1 and angiotensin II and fibrogenic cytokines/proteins such as TGF-β act in a network that contributes to myofibroblast differentiation and persistence (140). In fact, the majority of experimental antifibrotic strategies attempt to target activation, proliferation, and/or recruitment of fibroblasts (269). TGF-β is related to ECM gene expression and promotion of ECM deposition by simultaneously suppressing and inducing MMP and TIMP gene expression, respectively. Angiotensin II levels are increased in pressure overloaded hearts and are associated with remarkable profibrotic proprieties, in part, through stimulation of TGF-β (32, 205). Aldosterone also mediates vascular and cardiac remodeling and binds to the mineralocorticoid receptor stimulating cardiac fibroblasts and increasing collagen synthesis and deposition (259). Blocking the RAAS with ACEI and ARA was shown to effectively reduce fibrosis in different animal models (164, 235) and also in HFrEF patients (215). It is expected that these targets will also provide beneficial effects for HFpEF, since myocardial fibrosis is associated with the appearance of diastolic dysfunction in these patients. In an animal model of pressure overload, inhibition of TGF-β, with neutralizing antibodies, attenuated cardiac fibrosis and improved diastolic function without affecting cardiomyocyte hypertrophy (136). For instance, increased cardiac expression of monocyte chemoattractant protein (MCP-1) preceded TGF-β1 upregulation and was associated with cardiac fibrosis and diastolic dysfunction (136). The chronic treatment with an anti-MCP-1 antibody attenuated myocardial fibrosis and ameliorated diastolic dysfunction of hypertensive Wistar rats, without affecting blood pressure and systolic function (137), thus representing a potential new strategy to prevent inflammation and the consequent myocardial fibrosis and diastolic dysfunction. Advanced glycation end-products (AGEs), formed when glucose interacts nonenzymatically with proteins, can cause increased stiffness of the ECM directly by cross linking collagen or elastin and indirectly by stimulating the production of collagen and depleting NO thereby increasing oxidative stress (23). The beneficial effects of AGEs breakers in ventricular distensibility and arterial compliance improvement has been studied in recent years. In fact, elderly patients with HFpEF treated for 16 wk with an AGEs breaker showed LVH regression and diastolic function improvement (149). Activation of cGMP signaling cascade. cGMP-dependent protein kinase, PKG, is a serine/threonine kinase presenting three isoforms, PKG1α, PKG1β, and PKG2 (70). PKG1α is the primary cardiac isoform (229) and, in the cardiovascular system, it phosphorylates several key transcription factors and sarcomeric proteins involved in hypertrophy signaling, diastolic relaxation, myocardial stiffness, and vasorelaxation (62, 265). PKG is activated upstream by increased levels of cGMP. Interestingly, decreased PKG activity related to low concentration of cGMP was found in LV biopsies from HFpEF patients (244) and was associated with higher cardiomyocytes passive tension and greater myocardial oxidative stress (244). Excitingly, PKG administration decreased cardiomyocytes passive tension, which could be explained, as previously mentioned, by titin phosphorylation by PKG (244). This suggests that increases in cGMP and consequently activation of PKG could represent a potential therapeutic target for HFpEF. Elevation of myocyte cGMP levels in myocytes can be target by the natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)], NO, or sildenafil that pharmacologically inhibits phosphodiesterase type 5A (PDE5A), the enzyme that degrades cGMP (17, 213). In a TAC-mouse model, hypertrophy progression was paralleled by a compensatory increase in PKG1 activity (230). The role of PKG1α was studied in a knock in mouse model expressing constant levels of PKG1α activity but whose substrate interaction was disrupted (LZM mouse) (169). Compared with wild-type controls, the 8-mo-old adult LZM mouse developed HFpEF features, such as increased LV end-diastolic pressure and vascular relaxation abnormalities (200) but without LVH, which became significant only at the advanced age of 15 mo (20). When subjected to TAC, the LZM mouse developed impaired systolic and diastolic function as early as 2 days after aortic-constriction compared with TAC-wild type mouse. The onset of LVH was evident since the 7th day after TAC and progressively increased leading to premature death associated with congestive HF (21 days after TAC) (21). The same authors tested the hypothesis that the sildenafil antiremodeling effect was mediated by PKG1α and showed that it only triggered antihypertrophic effects in the wild-type and not in the LZM mouse subjected to TAC (21). Subsequent studies have demonstrated that phosphorylation of receptor potential canonical channel 6 (TRPC6) via PKG suppresses Ca2+ current into the cell. Low cytosolic Ca2+ prevents activation of calcineurin, which, in turn, decreases the desphosphorylation levels of nuclear factor of activated T-cells (NFAT), avoiding its nuclear translocation and the consequent expression of prohypertrophic genes (128, 172). Preclinical studies suggest that inhibition of PDE5A reverses cardiac structural and functional remodeling and enhances vascular, neuroendocrine, and renal function. However, despite showing preclinical promise, sildenafil was not successful in clinical trials for HFpEF (196). Recently, Lee et al. showed that phosphodiesterase type 9A (PDE9A) expression was increased in the myocardium of patients with various forms of HF, especially HFpEF (141). Using different approaches, the authors showed that PDE9A is localized in different compartments of the sarcomere in myocytes and that PDE5A and PDE9A target cGMP in the NO- and ANP-signaling pathways, respectively. Moreover, the genetic or selective pharmacological (PF-9613) inhibition of PDE9A protected the myocardium against neurohormones actions and sustained pressure-overload stress. According to Bray (28), this study showed that PDE9A, unlike PDE5A, specifically hydrolyzes NO-independent, ANP-coupled cGMP. Therefore, selective PDE9A inhibitors, such as PF-9613, could have greater effectiveness than PDE5A inhibitors for treating cases of HFpEF in which NO production is compromised (28). “Old” and “New” Promising Therapeutic Targets to Promote Reverse Remodeling in HFpEF Therapy in HF is aimed at amelioration of symptoms, improvement in function/quality of life, and/or prolongation of life. In general, HF therapies associated with positive long-term clinical outcome, such as reduced hospitalizations, mortality, or both, have been intimately associated with beneficial RR (126). One of the challenges and barriers in treating HF is the heterogeneity of the clinical syndrome. In patients with chronic HFrEF, both the survival and quality of life have improved with the use of β-blockers, RAAS inhibitors, and with devices, including pacemakers, which enhance cardiac synchronization, and implanted cardiac defibrillators (27). Many of these pharmacological approaches successful for HFrEF have been attempted for HFpEF. Such is the case of the RAAS and β-adrenergic signaling pathways, which seemed appealing due to their link to fibrosis, hypertension, and fluid balance. However, results from different clinical trials failed to provide consistent conclusions about the beneficial effects of HFrEF standard therapies such as β-blockers, ACEI, ARA, aldosterone antagonists, PDE5A inhibitors, statins, and calcium channels blockers on HFpEF. The most important pharmacological approaches already attempted for HFpEF in clinical trials are summarized in Fig. 4. Another drug with animal-tested benefits is ranolazine, which is a novel anti-ischemic and anti-arrhythmic medication used clinically to treat angina without lowering blood pressure or heart rate (37). The Ranolazine for the Treatment of Diastolic Heart Failure (RALI-DHF) study revealed that 30 min of ranolazine infusion improved hemodynamics, including LV end-diastolic pressure and pulmonary capillary wedge pressure. However, relaxation parameters, namely time constant (tau) and the rate of decline of LV pressure per minute, were unaltered. Also, the ratio E/E' did not change 22 h after infusion (158). As suggested by the authors their findings are consistent with an in vitro study that showed lack of an improvement by ranolazine in active relaxation of cardiomyocytes from the failing heart, although diastolic dysfunction over time was improved (220). Mechanistically, in HFpEF two types of relaxation exist, the passive (or late-phase) relaxation, which may well be related to diastolic dysfunction and hence improves with ranolazine due to improvement in slow Na+-dependent Ca2+ overload, and active (or early) relaxation, which is more related to SR reuptake of Ca2+ from beat to beat. In fact, SR Ca2+ content did not change significantly in the presence of ranolazine (220). Nevertheless, larger clinical trials are needed to better evaluate the potential role of ranolazine in HFpEF. In a placebo-controlled phase II study, Ivabradine, a selective inward funny (If) channel inhibitor, which reduces heart rate without a negative inotropic effect, significantly improved aerobic exercise capacity (V̇o2 peak), ventilatory efficiency (V̇e/V̇co2), myocardial relaxation (E'), and diastolic cardiac reserve in patients with HFpEF, independent of the maximal heart rate response to exercise (131). In a small pilot cross-over trial of 12 HFpEF patients, anakinra, an interleukin 1 (IL-1) blocker, led to a significant reduction in C reactive protein, a marker of systemic inflammation, and an improvement in aerobic exercise capacity (V̇o2 peak) and ventilatory efficiency (oxygen uptake efficiency slope) (247). As already mentioned, one of the mechanisms behind HFpEF is deregulation of the NO-cGMP protein kinase pathway. Two new drugs are currently under investigation to test whether this pathway can be significantly improved by either the angiotensin II receptor-neprilysin inhibitor LCZ696, which has been demonstrated to reduce NT-proBNP in a phase II trial in 300 patients with HFpEF (217), or by the sGC stimulator vericiguat, which is able to increase cGMP (190). Alagebrium chloride (ALT-711) has been tested as a AGEs cross-link breaker and may improve ventricular distensibility and arterial compliance. A prospective, open-label trial of alagebrium in elderly patients found that in clinically stable HFpEF the treatment with ALT-711 caused regression of LVH, improved Doppler indexes of diastolic function, and enhanced quality of life without altering blood pressure, arterial stiffness, or exercise tolerance (149). Prevention of the formation of new AGEs with exercise and breakdown of already formed AGEs with ALT-711 may represent a therapeutic strategy for age-related ventricular and vascular stiffness (223). Other treatments appear promising in preclinical studies but await translation (7, 130). The beneficial effects of lifestyle changes in HFpEF are also being explored. Currently, the most evidenced-based promising strategy to improve exercise intolerance in HFpEF patients appears to be exercise training, but the optimal approach is still unknown (241). Sixteen weeks of exercise training increased peakV̇o2, ventilatory anaerobic threshold, 6-min walk distance, and physical quality-of-life scores in patients with HFpEF (124). A recent trial showed an improvement in diastolic function, with reduction of the E/E' ratio, in HFpEF group patients subjected to aerobic interval training, compared with general health care groups (72). These studies suggest an important role for exercise in HFpEF patient's life, which must be considered in the treatment of this syndrome. Yet, it is still necessary to think about how to effectively and safely implement exercise training in an aged and frail population, such as HFpEF patients (241). Regarding this, exercise training may pair particularly well with other nonpharmacological interventions, including lifestyle interventions, such as nutrition, and disease management strategies. Indeed, clinical cardiac rehabilitation programs for coronary artery disease patients routinely include these in a multidimensional approach. In this light, research studies that strive to isolate the effects of exercise training alone likely underestimate the full range of potential benefits from a rehabilitation approach to HFpEF (123). Conclusion HFpEF is a major and growing public health problem. To date, no treatments have convincingly improved its clinical outcomes nor have positively altered RR. Moreover, the pathophysiological mechanisms underlying this syndrome remain to be clarified partly due to 1) the presence of highly confounding comorbidities that frequently coexist in HFpEF population; 2) limited myocardial biopsies from HFpEF patients; 3) the lack of proper animal models mimicking all the pathophysiological features of the human disease; and, lastly, 4) the long list of failed therapeutic strategies tested. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for preventing HFpEF or promoting its RR.Dr. V Srivastava1 Like7 Answers