**4.2. Guidelines for short‐term management (acute pulmonary edema) of CMVI**

**Stage Ca (acute heart failure requiring hospitalization):** The goals of therapy are to relieve the severe pulmonary edema. For dogs with pulmonary edema from acute pulmonary edema, the therapy should be directed (1) to reduce the circulating blood volume by either/both aggressive and immediate diuretic therapy (e.g., furosemide IV or CRI) and/or phlebotomy (10 ml/kg), (2) to reduce the venous return to the cardiac chambers [e.g., topical 2% nitroglyc‐ erin cream, intravenous acepromazine, intravenous sodium nitroprusside (SNP) CRI], (3) to increase oxygen saturation (e.g., oxygen tent or nasal oxygen), and (4) to strengthen myocar‐ dial systolic function (e.g., intravenous dobutamine 5–15 μg/kg/min CRI).

**Stage Da (refractory heart failure requiring hospitalization):** Aggressive furosemide therapy [4 mg/kg IV followed by repeat injections every 4 h or 4 mg/kg IV followed by CRI (0.2–1 mg/ kg/hr for 8–12 h)] should be initiated as early as possible, till respiratory rate has fallen by 50%. Intravenous sodium nitroprusside (SNP) therapy along with furosemide would be ben‐ eficial to stabilize CHF dogs. To achieve this therapeutic goal, intravenous infusion of SNP should be administered at 2 μg/kg/min and then increased by increments of 1 μg/kg/min every 30 min (maximum dose should not be over 6 μg/kg/min) to reach desirable therapeutic effect, if mean and systolic blood pressure of dogs maintain above 75 and 90 mmHg, respec‐ tively. Intravenous inotropic support using dobutamine is often also required. Intravenous dobutamine infusion should be started at 5 μg/kg/min and then increased by 2.5 μg/kg/min every 4 h to reach therapeutic effect (a maximal dose of 15 μg/kg/min). The dose rate should be adjusted by mean heart rate (HR) of dogs. The infusion rate should be reduced, if the heart rate increases by 10% or rises over 180 bpm. It is also recommended to supply oxygen by tent, cage, mask, and neck collar or even mechanical ventilation. Clinicians should relieve dyspnea/discomfort via appropriate humidity, environmental temperature, and body posi‐ tioning during oxygen supplementation.

## **4.3. Guideline for asymptomatic dogs with CMVI**

Several studies have evaluated what cardiac medications can retard the progression of heart failure and can be more effective in asymptomatic HF dogs [18, 104], although most mono‐ therapy was not able to achieve these goals, to date. One recent study has evaluated the out‐ come of dogs with preclinical cardiomyopathy with atrial fibrillation after either pimobendan monotherapy or benazepril monotherapy, and has found that pimobendan monotherapy provided significantly better outcome (i.e., prolonged time to onset of HF or reduced inci‐ dence of sudden death [105]). Unfortunately, several studies failed to find beneficial effects on survival and onset of HF in asymptomatic dogs with various heart diseases after the long‐ term administration of ACEI including enalapril [99, 105]. One recent small pilot study in dogs with asymptomatic HF found modest evidence of beneficial effect on retarding the onset of clinical HF after pimobendan and enalapril dual therapy [106]. One other recent study in asymptomatic dogs with CMVI has also found echocardiographic evidences on improvement of cardiac performance (i.e., increased %LVEF and decreased ESVI) for the first few months after pimobendan monotherapy [107], although this effect did not last to the end of test period (6 months). One recent study on preclinical CMVI dogs after long‐term treatment of enalapril has found long‐term administration of enalapril could significantly delay onset of HF and the endpoint of HF‐all‐cause death [104], although the other study in asymptomatic Cavalier King Charles Spaniels with CMVI has failed to find this beneficial effect [99].

#### **4.4. New therapeutic agents in dogs with CMVI**

**Isosorbide dinitrate (ISDN)** is a moderate‐ to long‐acting organic nitrate, and its venodilatory effects may help reduce preload and hence pulmonary edema. In humans, ISDN is used for treating or preventing angina, treating esophageal spasm and achalasia [108, 109]. In addition, it is widely used for CHF outpatients as an adjunctive treatment in CHF [110, 111]. In dogs, it occasionally used to adjuvant agent for management of chronic heart failure or in combina‐ tion with an arteriolar dilator for patients unable to tolerate an ACEI [112]. However, there is limited experience in using this drug in veterinary medicine, and adverse effect is not well known. In humans, the most common adverse effects are headache and postural hypotension. Tachycardia, restlessness, or gastrointestinal effects are not uncommon. There have been rare cases of patients who are hypersensitive to organic nitrates. One recent study has evaluated the efficacy of ISDN for treating advanced stage CHF due to CMVI [113]. Twenty dogs with CMVI were enrolled in this study. All dogs were administered sustained‐release ISDN (1 mg/ kg, q12hr, PO) along with conventional cardiac medication. Changes in systolic blood pres‐ sure (SAP), heart rate (HR), and echocardiographic indices indicating the progression of CHF were evaluated at 7, 15, 30, and 60 days after the administration of ISDN. Significant improve‐ ments in echocardiographic indices were found at 7, 15, 30, and 60 days after the administra‐ tion of ISDN, although the Systolic arterial pressure (SAP) was slightly decreased and the HR was slightly increased. This study suggested that ISDN could effectively reduce the cardiac preload and thus improve cardiac performance in dogs with advanced heart failure [113].

**Angiotensin receptor blockers (ARBs)** inhibit type I angiotensin II (AT1) receptor distributed in blood vessels and heart, and thus exert similar pharmacological action of ACEI. Because the ARBs only block type I receptor, they can reduce risk of renal injury from full inhibition of ACE [114]. Therefore, it can use for treating dogs with CHF, when the ACEIs cause renal azotemia [115]. However, the application of these agents on veterinary medicine is limited due to lack of studies related to ARBs in dogs. The common ARBs in veterinary fields are candesartan, losartan, valsartan, and telmisartan.

**Pimobendan** is a benzimidazole‐pyridazinone drug which is used commonly for treating various heart diseases in dogs including CHF. It acts through calcium sensitization and inhi‐ bition of phosphodiesterase III [116, 117]. Pimobendan has vasorelaxation effect by inhibi‐ tion of phosphodiesterase III and positive inotropic effect through calcium sensitization in myocardial sarcomere [118, 119]. Pimobendan can improve myocardial contractility without increasing the risk of arrhythmia unlike digitalis, because this drug does not require oxygen consumption of myocardium [100, 120]. Pimobendan can effectively decrease afterload and peripheral vessel resistance by relaxing vascular smooth muscle through inhibiting a vaso‐ constriction factor like PDE III [121, 122]. Pimobendan can also delay inflammatory response of myocardium and can improve myocardial contraction by weakening revelation of inflam‐ mation precursor and nitric oxide synthesis [123, 124]. Pimobendan can increase sinus rate through rising of blood volume in normal dogs, although it rarely causes arrhythmia unlike digitalis [125, 126]. Therefore, those pharmacological effects are very useful for control clinical signs associated with CHF in dogs and have been well documented in veterinary literatures [127, 128].
